Newcastle Disease Virus (PDQ®): Integrative, alternative, and complementary therapies - Health Professional Information [NCI]

Overview

This cancer information summary provides an overview of the use of Newcastle disease virus (NDV) as a treatment for people with cancer. The summary includes a brief history of NDV research, a review of laboratory and animal studies, the results of clinical trials, and possible side effects of NDV-based therapy. Several different strains of NDV will be discussed in the summary, including the Hungarian strain MTH (More Than Hope)-68. Information presented in some sections of the summary can also be found in tables located at the end of those sections.

This summary contains the following key information:

• NDV is usually thought to be an avian (i.e., bird) virus, but it also infects humans. Although NDV causes a potentially fatal, noncancerous disease (Newcastle disease) in birds, it causes only minor illness in humans.
• NDV appears to replicate (i.e., reproduce) substantially better in human cancer cells than it does in most normal human cells.
• Individual strains of NDV are classified as lytic or nonlytic. Viruses of both strain types can kill cancer cells, but lytic strains have the potential to do this more quickly because they damage the plasma membrane of infected cells. Nonlytic strains appear to kill by interfering with cell metabolism.
• Lytic strains of NDV have been studied in humans for their ability to kill cancer cells directly, but viruses of both strain types have been used to make vaccines in an attempt to stimulate the immune system to fight cancer.
• NDV-based anticancer therapy has been reported to be of benefit in more than a dozen clinical studies, but the results of these studies must be considered inconclusive because the study designs were weak and the study reports were generally incomplete.

Many of the medical and scientific terms used in the summary are hypertext linked (at first use in each section) to the NCI Dictionary of Cancer Terms, which is oriented toward nonexperts. When a linked term is clicked, a definition will appear in a separate window.

Reference citations in some PDQ cancer information summaries may include links to external websites that are operated by individuals or organizations for the purpose of marketing or advocating the use of specific treatments or products. These reference citations are included for informational purposes only. Their inclusion should not be viewed as an endorsement of the content of the websites, or of any treatment or product, by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board or the National Cancer Institute.

General Information

Information presented in this section about the use of Newcastle disease virus (NDV) in the treatment of human cancer is summarized in Table 1 below.

NDV is a paramyxovirus that causes Newcastle disease in a wide variety of birds (most notably, in chickens).[1,2,3] This often fatal disease is characterized by inflammation of respiratory tract and of either the brain or the gastrointestinal tract.[1,2,4,5] NDV can also infect humans, but, in humans, it is generally not very virulent, causing only mild flu-like symptoms or conjunctivitis and/or laryngitis.[1,6,7,8,9,10,11,12,13,14] The perception that NDV can replicate up to 10,000 times better in human cancer cells than in most normal human cells [2,6,7,8,9,10,12,13,15,16,17,18,19,20,21,22,23] has prompted much interest in this virus as a potential anticancer agent. This phenomenon is apparently caused by defects in intracellular antiviral defenses of some cancer cells.[24,25,26] NDV was historically considered a CAM approach, but in recent years it has been extensively studied by the conventional medical community. Also, genetically engineered NDV strains are being developed and studied for their anticancer activity.[27]

The genetic material of NDV is RNA rather than DNA.[1,3,13,18,23,28,29,30,31] As with other types of viruses, essentially all of NDV's replication cycle takes place inside infected cells, which are also known as host cells.[13,18,30,32] During a replication cycle, new virus proteins and copies of the NDV genetic material (i.e., genome) are made in the host cell's cytoplasm. NDV is also an enveloped virus, which means that progeny virus particles are released from infected cells by budding off from them.[18,30,33] In this process, single copies of the NDV genome become wrapped in an outer coat (i.e., an envelope) that is made from a small piece of the host cell's plasma membrane. Generally, the NDV outer coat contains only virus proteins that have been specifically inserted into the host cell's plasma membrane;[18,28,32,33] however, some host cell proteins may be included as well.[34,35] Two specific virus proteins, hemagglutinin-neuraminidase and the fusion protein, are the main NDV proteins found in the outer coat of isolated virus particles.[3,18,28,30]

There are many different strains of NDV, and they have been classified as either lytic or nonlytic for human cells. Lytic strains and nonlytic strains both appear to replicate much more efficiently in human cancer cells than they do in most normal human cells,[12,13,15,16,17,18,19,20,36] and viruses of both strain types have been investigated as potential anticancer agents. One major difference between lytic strains and nonlytic strains is that lytic strains are able to make infectious progeny virus particles in human cells, whereas nonlytic strains are not.[13,18,28,29,30,37] This difference is due to the ability of lytic strains to produce activated hemagglutinin-neuraminidase and fusion protein molecules in the outer coat of progeny viruses in human cells. The progeny virus particles made by nonlytic strains contain inactive versions of these molecules. Activated hemagglutinin-neuraminidase and fusion protein molecules are required for NDV to enter a cell to replicate. Initial binding of NDV to a host cell takes place through the interaction of hemagglutinin-neuraminidase molecules in the virus coat with sialic-acid -containing molecules (i.e., gangliosides) on the surface of the cell. It is important to note, however, that nonlytic strains of NDV can make infectious progeny viruses in some types of nonhuman cells (e.g., chicken embryo cells), thereby allowing these strains to be maintained.[13,18,28,29,36]

Another major difference between lytic strains and nonlytic strains is that, although they both have the potential to kill infected cells, the mechanisms by which they accomplish this result are different. The production of infectious progeny virus particles by lytic strains gives them the ability to kill host cells fairly quickly. The budding of progeny viruses that contain activated hemagglutinin-neuraminidase and fusion protein molecules in their outer coats causes the plasma membrane of NDV-infected cells to fuse with the plasma membrane of adjacent cells, leading to the production of large, inviable fused cells known as syncytia.[12,13,18,30] The more efficiently a lytic strain can replicate inside a host cell, the more quickly it can kill that cell. The preferential killing of cancer cells by a lytic virus is known as oncolysis; thus, lytic strains of NDV are also called oncolytic strains. Nonlytic strains of NDV kill infected cells more slowly, with death apparently the result of viral disruption of normal host cell metabolism.[36,38]

The specific mechanism by which nonlytic NDV strains cause cell death in cancer cells has not been completely elucidated, but in Vero cells (derived from kidney epithelium) it was determined that NDV caused cell death by decreasing DNA content, increasing the ratio of Bax to Bcl-2, increasing p53 level, and increasing caspase expression, resulting in apoptosis.[39,40,41]

As indicated previously, both lytic strains and nonlytic strains have been investigated for their anticancer potential. In fact, the major differences between the two strain types have been exploited to develop three different approaches to cancer therapy:

1. The infection of cancer patients with a lytic strain of NDV.
2. The use of oncolysates, i.e., preparations containing plasma membrane fragments from NDV-infected cancer calls, as anticancer vaccines.
3. The use of intact cancer cells infected with a nonlytic strain of NDV as whole cell vaccines.

One proposed advantage of the first approach is that virus replication may allow the spread of cytotoxic viruses to every cancer cell in the body;[8,34] however, the production of virus-neutralizing antibodies by the immune system might limit this possibility.[6,8,13,30,40] The rationale for the second and third approaches is that tumor-specific antigens (i.e., proteins or other molecules that are generally located in the plasma membrane of cancer cells and that are either unique to cancer cells or much more abundant in them) may be better recognized by the immune system if they are associated with virus antigens (i.e., virus proteins that have been inserted into the plasma membrane of host cells).[8,12,13,28,32,34,42,43,44,45,46,47,48] If this enhanced recognition takes place, then it may increase the chance that cancer cells, whether they are virus infected or not, will be recognized as foreign by the immune system and be destroyed.[8,12,28,47,48]

The principal developers of the third approach have stated that whole cell vaccines can stimulate the immune system better than oncolysates, and that cells infected with a nonlytic strain of NDV will remain intact in the body long enough to generate these more effective immune responses.[18,28,29,36,37,38,43,46,49,50,51] It should be noted that the cancer cells used in the third approach are treated with enough gamma radiation to prevent further cell division, but not enough to cause cell death, either before or after they are infected with the nonlytic virus.[49,50,52,53,54,55,56,57,58,13] This precaution ensures that patients are not given a vaccine that contains actively proliferating cancer cells.

Either a patient's own cancer cells (i.e., autologous cells) or cells from another patient with the same type of cancer (i.e., allogeneic cells) can be used to make oncolysates and whole cell vaccines. It is important to note that immune system responses similar to those obtained with oncolysates and whole cell vaccines may occur in patients infected with a lytic strain of NDV and that these responses would be expected to contribute to any observed anticancer effect.

To conduct human studies with viruses, vaccines, or other biological materials in the United States, researchers must file an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA). Biological materials and drugs have been held to similar safety and effectiveness standards since 1972. In an IND application, researchers must provide safety and toxicity data from laboratory and animal studies to justify the dose, the route, and the schedule of administration to be used in the proposed clinical studies. Among the safety issues to be addressed, researchers must demonstrate an absence of harmful contaminants. Most human studies of NDV as an anticancer agent have taken place outside the United States; therefore, they have not required an IND. At present, at least one group of U.S. investigators has filed an IND application to study NDV as an anticancer treatment.[59] It should be noted that the FDA has not approved the use of NDV to treat any medical condition.

The NDV strains that have been evaluated most widely for the treatment of cancer are 73-T, MTH-68, and Ulster.[1,6,11,22,42,45,49,50,51,52,53,54,55,56,57,58,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74] Strain 73-T is lytic, and Ulster is nonlytic. Strain MTH-68 has not been classified, but it is assumed to be lytic.[1,6,66,75,22,76,77] All three strains have shown little or no evidence of neurotropism (i.e., an ability to replicate efficiently in normal nerve cells or normal neural tissue).

In animal studies, NDV infection has been accomplished by intratumoral, intraperitoneal, intravenous, intramuscular, or subcutaneous injection.[9,10,12,23,28,36,36,43,78] NDV-infected, whole cell vaccines have been given to animals by intraperitoneal,[46]intradermal,[47] or subcutaneous injection,or by a combination of subcutaneous and intramuscular injection.[36,43,79]

In human studies, NDV oncolysates have been administered by subcutaneous [11,42,45,60,63,65,67,68,69,70] or intradermal [62,64] injection. NDV-infected, whole cell vaccines have been administered by intradermal injection only.[49,50,52,53,54,55,56,57,58,71,72,73] In cases where patients have been infected with a lytic strain of NDV, intratumoral,[20] intravenous,[1,59,66,80] or intramuscular [61] injection has been used, as have inhalation [1,6] and direct injection into the colon (i.e., via a colostomy opening).[1] In some instances, cytokine treatment has been combined with NDV therapy.[45,52,53,56,62,64,65,70]

References:

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50. Ockert D, Schirrmacher V, Beck N, et al.: Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res 2 (1): 21-8, 1996.
51. Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient's own immune system. Onkologie 16 (5): 290-6, 1993.
52. Ahlert T, Sauerbrei W, Bastert G, et al.: Tumor-cell number and viability as quality and efficacy parameters of autologous virus-modified cancer vaccines in patients with breast or ovarian cancer. J Clin Oncol 15 (4): 1354-66, 1997.
53. Ahlert T: Tumor cell vaccination and IL-2 therapy. Hybridoma 12 (5): 549-52, 1993.
54. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990.
55. Lehner B, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. Cancer Immunol Immunother 32 (3): 173-8, 1990.
56. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival-data of patients with advanced renal-cell carcinoma treated with autologous tumor vaccine and subcutaneous R-IL-2 and IFN-alpha(2b). Int J Oncol 6 (5): 947-54, 1995.
57. Schlag P, Manasterski M, Gerneth T, et al.: Active specific immunotherapy with Newcastle-disease-virus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunother 35 (5): 325-30, 1992.
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History

The first published report to establish a link between infection with a virus and the regression of cancer appeared in 1912.[1,2,3,4,5,6] This report described a woman whose cervical cancer improved following treatment to prevent rabies. The woman had been bitten by a dog, and she was subsequently injected with a vaccine made of attenuated (i.e., weakened) rabies virus. Over the next 60 years, many other viruses, including Newcastle disease virus (NDV), were shown to have anticancer potential.[1,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25] The first report of positive results using NDV as a treatment for human cancer was published in 1964.[9] By that time, attenuated strains of NDV had been used for almost 2 decades to prevent Newcastle disease in birds, and the inability of this virus to cause serious illness in humans had been established.

As indicated previously (refer to the General Information section of this summary for more information), cells infected with NDV can be killed directly by the virus or indirectly through an immune system response to the infection. The immune system uses a variety of approaches to kill virus-infected cells, including attack by cytotoxic cells (i.e., natural killer cells and/or cytotoxic T cells); attack by antivirus antibodies, which are made by B cells; and the release of cytokines.[2,6,15,18,22,25,26,27,28]

Cytokines can be directly cytotoxic to virus-infected cells (e.g., tumor necrosis factor [TNF] -alpha).[14,15,20] In addition, they can stimulate increases in the activity and/or numbers of specific types of immune system cells (e.g., interferon -alpha, interferon-gamma, and TNF-alpha).[2,29,30,31]

As also indicated previously (refer to the General Information section of this summary for more information), if the immune system is responding to virus-infected cancer cells (or fragments of cancer cells), then better recognition of tumor-specific antigens may occur, and an increased ability to kill uninfected cancer cells may be acquired.[15,18,19,23,26,30,32,33,34,35,36,37,38] The immune system would use the same approaches to kill uninfected cancer cells that it uses to kill virus-infected cells. For example, it has been shown that TNF-alpha is directly cytotoxic to some, but not all, cancer cells, whereas normal cells are not harmed by this cytokine.[39,40,41,42]

References:

1. Nelson NJ: Scientific interest in Newcastle disease virus is reviving. J Natl Cancer Inst 91 (20): 1708-10, 1999.
2. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993.
3. Nemunaitis J: Oncolytic viruses yesterday and today. J Oncol Manag 8 (5): 14-24, 1999.
4. Webb HE, Smith CE: Viruses in the treatment of cancer. Lancet 1 (7658): 1206-8, 1970.
5. Ahlert T, Schirrmacher V: Isolation of a human melanoma adapted Newcastle disease virus mutant with highly selective replication patterns. Cancer Res 50 (18): 5962-8, 1990.
6. Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 36 (4): 193-214, 1993.
7. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18 (7): 863-8, 1965.
8. Eaton MD, Heller JA, Scala AR: Enhancement of lymphoma cell immunogenicity by infection with nononcogenic virus. Cancer Res 33 (12): 3293-8, 1973.
9. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964.
10. Flanagan AD, Love R, Tesar W: Propagation of Newcastle disease virus in Ehrlich ascites cells in vitro and in vivo. Proc Soc Exp Biol Med 90 (1): 82-6, 1955.
11. Sinkovics JG, Howe CD: Superinfection of tumors with viruses. Experientia 25 (7): 733-4, 1969.
12. Eaton MD, Levinthal JD, Scala AR: Contribution of antiviral immunity to oncolysis by Newcastle disease virus in a murine lymphoma. J Natl Cancer Inst 39 (6): 1089-97, 1967.
13. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb.
14. Kenney S, Pagano JS: Viruses as oncolytic agents: a new age for "therapeutic" viruses? J Natl Cancer Inst 86 (16): 1185-6, 1994.
15. Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996.
16. Lorence RM, Reichard KW, Katubig BB, et al.: Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 86 (16): 1228-33, 1994.
17. Lorence RM, Katubig BB, Reichard KW, et al.: Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54 (23): 6017-21, 1994.
18. Reichard KW, Lorence RM, Cascino CJ, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52 (5): 448-53, 1992.
19. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.
20. Lorence RM, Rood PA, Kelley KW: Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-alpha and augmentation of its cytotoxicity. J Natl Cancer Inst 80 (16): 1305-12, 1988.
21. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999.
22. Sinkovics JG, Horvath JC: Newcastle disease virus (NDV): brief history of its oncolytic strains. J Clin Virol 16 (1): 1-15, 2000.
23. Shoham J, Hirsch R, Zakay-Rones Z, et al.: Augmentation of tumor cell immunogenicity by viruses--an approach to specific immunotherapy of cancer. Nat Immun Cell Growth Regul 9 (3): 165-72, 1990.
24. Csatary LK: Viruses in the treatment of cancer. Lancet 2 (7728): 825, 1971.
25. Bridgewater J, Collins M: Vaccine immunotherapy for cancer. Mol Cell Biol Hum Dis Ser 5: 140-56, 1995.
26. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986.
27. Cooper NR, Nemerow GR: The role of antibody and complement in the control of viral infections. J Invest Dermatol 83 (1 Suppl): 121s-127s, 1984.
28. Alberts B, Bray D, Lewis J, et al.: Molecular Biology of the Cell. 3rd ed. New York, NY: Garland Publishing, 1994.
29. Zorn U, Dallmann I, Grosse J, et al.: Induction of cytokines and cytotoxicity against tumor cells by Newcastle disease virus. Cancer Biother 9 (3): 225-35, 1994 Fall.
30. DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 5th ed. Philadelphia, Pa: Lippincott-Raven Publishers, 1997.
31. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990.
32. Haas C, Ertel C, Gerhards R, et al.: Introduction of adhesive and costimulatory immune functions into tumor cells by infection with Newcastle Disease Virus. Int J Oncol 13 (6): 1105-15, 1998.
33. Cassel WA, Murray DR: A ten-year follow-up on stage II malignant melanoma patients treated postsurgically with Newcastle disease virus oncolysate. Med Oncol Tumor Pharmacother 9 (4): 169-71, 1992.
34. Heicappell R, Schirrmacher V, von Hoegen P, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. I. Parameters for optimal therapeutic effects. Int J Cancer 37 (4): 569-77, 1986.
35. Zorn U, Duensing S, Langkopf F, et al.: Active specific immunotherapy of renal cell carcinoma: cellular and humoral immune responses. Cancer Biother Radiopharm 12 (3): 157-65, 1997.
36. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994.
37. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989.
38. Nesselhut T: Influence on antigen exposition of tumor cells by membrane active substances and viral infections. Hybridoma 12 (5): 553-7, 1993.
39. Helson L, Green S, Carswell E, et al.: Effect of tumour necrosis factor on cultured human melanoma cells. Nature 258 (5537): 731-2, 1975.
40. Haranaka K, Satomi N: Cytotoxic activity of tumor necrosis factor (TNF) on human cancer cells in vitro. Jpn J Exp Med 51 (3): 191-4, 1981.
41. Sugarman BJ, Aggarwal BB, Hass PE, et al.: Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science 230 (4728): 943-5, 1985.
42. Fransen L, Van der Heyden J, Ruysschaert R, et al.: Recombinant tumor necrosis factor: its effect and its synergism with interferon-gamma on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol 22 (4): 419-26, 1986.

Laboratory / Animal / Preclinical Studies

Effects of Newcastle Disease Virus on Human Cancer Cells

The ability of Newcastle disease virus (NDV) to replicate efficiently in human cancer cells has been demonstrated in both laboratory studies and animal studies.[1,2,3,4,5,6,7,8,9,10,11,12,13,14] Further, several of these studies suggest that lytic strains of NDV are also oncolytic, and one study has demonstrated that expression of the RAC1 gene is necessary for NDV replication.[15]

Lytic strain 73-T has been shown to replicate efficiently in human tumor cells [16] and kill the following types of human cancer cells in vitro: fibrosarcoma, osteosarcoma, neuroblastoma, bladder carcinoma, cervical carcinoma, melanoma, Wilms tumor, and myeloid leukemia.[3,6,8,9] It killed normal human lung fibroblasts in vitro at the same rate that it killed cancer cells.[8] However, this strain did not kill human B-cell lymphoma (i.e., Burkitt lymphoma) cells in vitro[8] and did not kill normal, proliferating human white blood cells or normal human skin fibroblasts in vitro.[3,6,8]

Lytic strain Roakin has been reported to kill human lymphoma B cells and T cells transformed in vitro from a Hodgkin lymphoma patient four to five times faster than it killed normal, resting human white blood cells.[4,5] This strain killed normal, proliferating human white blood cells in vitro, although at a lower rate than in cancer cells.[4]

Lytic strain Italien (or Italian) has been shown to kill human squamous cell lung carcinoma, melanoma, breast carcinoma, and larynx carcinoma, but not cervical carcinoma, cells in vitro.[12]

Overall, these results suggest that the lytic strains of NDV replicate well in some types of normal cells and replicate poorly in some types of cancer cells. These data and the absence of serious illness in individuals infected with NDV [1,2,3,10,13,17,18,19,20,21,22] are consistent with the view that NDV may replicate more efficiently in human cancer cells than it does in most types of normal human cells (i.e., "DBTRG.05MG human glioblastoma," "U-87MG human astrocytoma,"[23] "rat F98 glioblastoma cells,"[24] and "mouse Ehrlich ascites carcinoma").[25]

Nonlytic NDV strain Ulster has also been shown to replicate efficiently in human cancer cells in vitro, including cells of the following types of human tumors:

• Colorectal carcinoma.
• Gastric carcinoma.
• Pancreatic carcinoma.
• Bladder carcinoma.
• Breast carcinoma.
• Ovarian carcinoma.
• Renal cell carcinoma.
• Lung carcinoma.
• Larynx carcinoma.
• Cervical carcinoma.
• Glioblastoma.
• Melanoma.
• B-cell lymphoma.
• T-cell lymphoma.

This strain does not replicate efficiently in normal human white blood cells in vitro.[7] Other experiments have shown that NDV Ulster can kill infected cells [14,26] and that it can replicate in human cancer cells regardless of cell cycle.[7,21]

The ability of lytic strains of NDV to kill human cancer cells in vivo has also been examined. In xenograft studies, human cancer cells were injected either subcutaneously or intradermally into athymic, nude mice (i.e., mice that do not reject tumor cells from other animals because they have a defective immune system), and tumors were allowed to form. NDV was injected directly into the tumors, and tumor growth and animal survival were monitored. Injection produced complete tumor regression in 75% to 100% of mice bearing human fibrosarcoma, neuroblastoma, or cervical carcinoma tumors.[1,2,3,10] Intratumoral injection of 73-T was also associated with more than 80% tumor regression in 66% of mice bearing human synovial sarcoma tumors.[2] In addition, intratumoral injection inhibited 68% to 96% of tumor growth in mice bearing human epidermoid, colon, lung, breast, or prostate carcinoma tumors.[10]

Intratumoral injection of strain Italien was associated with complete tumor regression in 100% of mice bearing human melanoma tumors. The growth of metastatic tumors in these animals was not affected, suggesting that the virus was unable to disseminate widely throughout the body.[11,14,21]

In the above-mentioned neuroblastoma xenograft study, strain 73-T replicated over time in tumor tissue but replicated poorly when injected into the thigh muscle of athymic, nude mice.[1] This finding is consistent with the proposal that NDV replicates more efficiently in cancer cells than in most normal cells.

In another nude mouse study, strain V4UPM inhibited the growth of some cell lines of subcutaneously injected human glioblastoma multiforme cells.[23] All four mice with tumors from the U-87MG cell line experienced sustained complete responses after one injection. However, no complete responses were observed in mice with tumors from the DBTRG.05MG cell line despite a similar in vitro cytotoxicity compared with U-87MG.

In yet another nude mouse study, a single intraperitoneal injection of strain 73-T in mice bearing human neuroblastoma xenografts resulted in complete, durable tumor regressions in 9 of 12 (75%) of the treated mice.[10]

Athymic, nude mice make small numbers of T cells, and they produce interferons, natural killer cells, and macrophages.[11,27,28] It is possible that these residual components of the immune system, which may be activated by the presence of NDV, contributed to the antitumor effects observed in the xenograft studies.

NDV and Cancer Immunotherapy

Other laboratory and animal studies have shown that NDV and NDV-infected cancer cells can stimulate a variety of immune system responses that are essential to the successful immunotherapy of cancer.[6,8,11,21,26,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48] A few of these studies used human cells,[6,8,21,30,31,39,42,43,45,48] but most used animal cells and animal tumor models.[6,8,11,21,26,29,31,32,33,34,35,36,37,38,40,44,45,46,47]

Two of these in vitro studies demonstrated that infection of human immune cells with NDV causes the cells to produce and release cytokines interferon-alpha and tumor necrosis factor (TNF)-alpha.[6,8] In one of these studies,[6] infection of human cancer cells with NDV made the cells more sensitive to the cytotoxic effects of TNF-alpha.

Some in vitro studies have shown that NDV-infected human cancer cells are better at activating human cytotoxic T cells, helper T cells, and natural killer cells than uninfected cancer cells.[8,30,31,49] The NDV protein hemagglutinin-neuraminidase, which is present in the plasma membrane of virus-infected cells, appears to play a role in the enhancement of T cell activation. There is evidence that this protein makes infected cells more adhesive, thereby promoting the interaction between virus-infected cells and immune system cells.[21,31]

Laboratory studies have shown that the interaction between NDV-infected cancer cells and T cells can be improved if monoclonal antibodies that bind the hemagglutinin-neuraminidase protein on the cancer cells and either the CD3 protein or the CD28 protein on T cells (i.e., bispecific monoclonal antibodies) are also used.[21,30,39,45,48,50,51] It has been reported that this improved interaction leads to better T cell activation.[21,30,39,45,48] T cells exposed to NDV-infected human colon cancer cells and bispecific monoclonal antibodies showed not only an increased ability to kill the virus-infected cells but also an ability to inhibit the proliferation of uninfected colon cancer cells.[21,30,39] On the basis of these and other in vitro findings, it has been proposed that vaccines consisting of NDV-infected cancer cells and bispecific monoclonal antibodies be tested in humans.[21,30,39,45,48]

As noted above, animal cells and animal tumor models have also been used to explore the immunotherapy potential of NDV. ESb, a mouse model of metastatic T-cell lymphoma has been employed in most of this work;[11,21,26,29,32,36,37,38,40,41,44,45,46,47,48] however, additional experiments have utilized one or more of the following tumor models: mouse B16 melanoma,[34] mouse Lewis lung carcinoma,[33,36] mouse P815 mastocytoma,[36] mouse Ca 761-P93 mammary carcinoma,[36] and guinea pig L10 hepatocellular carcinoma.[35]

In one study,[36] it was shown that anticancer activity could be induced in mouse macrophages both in vitro and in vivo by infection with NDV strain Ulster. Similar activation of mouse macrophages in vitro was observed after infection with the NDV lytic strain Lasota. In this study, the activated macrophages showed cytotoxic activity toward ESb, P815 mastocytoma, and Ca 761-P93 mammary carcinoma cells in vitro. Other experiments demonstrated that much of the observed anticancer activity could be attributed to the production and release of TNF-alpha by the infected macrophages. In addition, the infected, activated macrophages showed anticancer activity in vivo when they were injected into mice bearing Ca 761-P93 mammary carcinoma or Lewis lung carcinoma tumors.[36] Human macrophages stimulated with NDV Ulster have also been shown to kill various types of human tumor cells.[52]

In another study,[11] intratumoral injection of NDV strain Ulster into growing ESb tumors in immunocompetent mice led to a cessation of tumor growth and an absence of metastases in 42% of treated animals. In the remaining mice, tumor growth and metastatic spread continued at the same rate as in control animals. Additional results from this study indicated that the anticancer effect in the responding animals was due primarily to the activation of T cells directed against a tumor-specific antigen on ESb cells rather than a virus antigen.

Other studies with NDV Ulster and the ESb tumor model support the idea that virus proteins inserted in the plasma membrane of NDV-infected cancer cells may help the immune system recognize tumor-specific antigens better, potentially leading to an increased ability to kill uninfected cancer cells and virus-infected cells.[11,21,26,29,32,37,38,40,44,46,47] At least four studies [26,29,38,40,46,47] have shown that T cells isolated from mice that have growing ESb tumors can be activated in vitro by co-culture with NDV-infected ESb cells and that the resulting activated T cells possess an enhanced ability to kill uninfected ESb cells in vitro. In addition, two in vivo studies [11,32] have shown that mice injected with NDV-infected, irradiated ESb cells are 30 to 250 times more resistant to later injection with proliferating ESb cells than mice that are initially injected with uninfected, irradiated ESb cells. Furthermore, at least two in vivo studies have demonstrated that vaccination of mice with NDV-infected, irradiated ESb cells after surgery to remove a growing ESb primary tumor can prevent the growth of metastatic tumors in approximately 50% of treated animals.[11,32,37,44,46,47] When the surviving mice were subsequently injected with proliferating ESb cells, they all remained free of cancer, indicating that the NDV/tumor cell vaccine had conferred anticancer immunity.[32,37] Similar results were obtained from in vivo studies that employed the mouse B16 melanoma model,[34] the mouse Lewis lung carcinoma model,[33] or the guinea pig L10 hepatocellular carcinoma model.[35]

One factor that may influence the effectiveness of NDV/tumor cell vaccines is overall tumor burden. Results obtained with the B16 mouse melanoma model suggest that these vaccines are less effective in individuals with advanced metastatic disease.[34]

References:

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2. Lorence RM, Katubig BB, Reichard KW, et al.: Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54 (23): 6017-21, 1994.
3. Reichard KW, Lorence RM, Cascino CJ, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52 (5): 448-53, 1992.
4. Bar-Eli N, Giloh H, Schlesinger M, et al.: Preferential cytotoxic effect of Newcastle disease virus on lymphoma cells. J Cancer Res Clin Oncol 122 (7): 409-15, 1996.
5. Tzadok-David Y, Metzkin-Eizenberg M, Zakay-Rones Z: The effect of a mesogenic and a lentogenic Newcastle disease virus strain on Burkitt lymphoma Daudi cells. J Cancer Res Clin Oncol 121 (3): 169-74, 1995.
6. Lorence RM, Rood PA, Kelley KW: Newcastle disease virus as an antineoplastic agent: induction of tumor necrosis factor-alpha and augmentation of its cytotoxicity. J Natl Cancer Inst 80 (16): 1305-12, 1988.
7. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999.
8. Zorn U, Dallmann I, Grosse J, et al.: Induction of cytokines and cytotoxicity against tumor cells by Newcastle disease virus. Cancer Biother 9 (3): 225-35, 1994 Fall.
9. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18 (7): 863-8, 1965.
10. Phuangsab A, Lorence RM, Reichard KW, et al.: Newcastle disease virus therapy of human tumor xenografts: antitumor effects of local or systemic administration. Cancer Lett 172 (1): 27-36, 2001.
11. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986.
12. Ahlert T, Schirrmacher V: Isolation of a human melanoma adapted Newcastle disease virus mutant with highly selective replication patterns. Cancer Res 50 (18): 5962-8, 1990.
13. Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996.
14. Schirrmacher V, Griesbach A, Ahlert T: Antitumor effects of Newcastle Disease Virus in vivo: local versus systemic effects. Int J Oncol 18 (5): 945-52, 2001.
15. Puhlmann J, Puehler F, Mumberg D, et al.: Rac1 is required for oncolytic NDV replication in human cancer cells and establishes a link between tumorigenesis and sensitivity to oncolytic virus. Oncogene 29 (15): 2205-16, 2010.
16. Russell SJ: RNA viruses as virotherapy agents. Cancer Gene Ther 9 (12): 961-6, 2002.
17. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb.
18. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993.
19. Kenney S, Pagano JS: Viruses as oncolytic agents: a new age for "therapeutic" viruses? J Natl Cancer Inst 86 (16): 1185-6, 1994.
20. Batliwalla FM, Bateman BA, Serrano D, et al.: A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. Mol Med 4 (12): 783-94, 1998.
21. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.
22. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996.
23. Zulkifli MM, Ibrahim R, Ali AM, et al.: Newcastle diseases virus strain V4UPM displayed oncolytic ability against experimental human malignant glioma. Neurol Res 31 (1): 3-10, 2009.
24. Schneider T, Gerhards R, Kirches E, et al.: Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme. J Neurooncol 53 (1): 39-46, 2001.
25. Sinkovics JG, Horvath JC: Newcastle disease virus (NDV): brief history of its oncolytic strains. J Clin Virol 16 (1): 1-15, 2000.
26. Schirrmacher V, Jurianz K, Roth C, et al.: Tumor stimulator cell modification by infection with Newcastle Disease Virus: analysis of effects and mechanism in MLTC-CML cultures. Int J Oncol 14 (2): 205-15, 1999.
27. Kadish AS, Doyle AT, Steinhauer EH, et al.: Natural cytotoxicity and interferon production in human cancer: deficient natural killer activity and normal interferon production in patients with advanced disease. J Immunol 127 (5): 1817-22, 1981.
28. Budzynski W, Radzikowski C: Cytotoxic cells in immunodeficient athymic mice. Immunopharmacol Immunotoxicol 16 (3): 319-46, 1994.
29. Schirrmacher V, Haas C, Bonifer R, et al.: Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection. Clin Cancer Res 3 (7): 1135-48, 1997.
30. Haas C, Herold-Mende C, Gerhards R, et al.: An effective strategy of human tumor vaccine modification by coupling bispecific costimulatory molecules. Cancer Gene Ther 6 (3): 254-62, 1999 May-Jun.
31. Haas C, Ertel C, Gerhards R, et al.: Introduction of adhesive and costimulatory immune functions into tumor cells by infection with Newcastle Disease Virus. Int J Oncol 13 (6): 1105-15, 1998.
32. Heicappell R, Schirrmacher V, von Hoegen P, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. I. Parameters for optimal therapeutic effects. Int J Cancer 37 (4): 569-77, 1986.
33. Shoham J, Hirsch R, Zakay-Rones Z, et al.: Augmentation of tumor cell immunogenicity by viruses--an approach to specific immunotherapy of cancer. Nat Immun Cell Growth Regul 9 (3): 165-72, 1990.
34. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994.
35. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989.
36. Schirrmacher V, Bai L, Umansky V, et al.: Newcastle disease virus activates macrophages for anti-tumor activity. Int J Oncol 16 (2): 363-73, 2000.
37. Schirrmacher V, Heicappell R: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity. Clin Exp Metastasis 5 (2): 147-56, 1987 Apr-Jun.
38. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990.
39. Haas C, Strauss G, Moldenhauer G, et al.: Bispecific antibodies increase T-cell stimulatory capacity in vitro of human autologous virus-modified tumor vaccine. Clin Cancer Res 4 (3): 721-30, 1998.
40. Von Hoegen P, Weber E, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. Augmentation of the tumor-specific T cell response in the absence of an anti-viral response. Eur J Immunol 18 (8): 1159-66, 1988.
41. Schirrmacher V, Schild HJ, Gückel B, et al.: Tumour-specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens. Immunol Cell Biol 71 ( Pt 4): 311-26, 1993.
42. Bai L, Koopmann J, Fiola C, et al.: Dendritic cells pulsed with viral oncolysates potently stimulate autologous T cells from cancer patients. Int J Oncol 21 (4): 685-94, 2002.
43. Washburn B, Schirrmacher V: Human tumor cell infection by Newcastle Disease Virus leads to upregulation of HLA and cell adhesion molecules and to induction of interferons, chemokines and finally apoptosis. Int J Oncol 21 (1): 85-93, 2002.
44. Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient's own immune system. Onkologie 16 (5): 290-6, 1993.
45. Haas C, Schirrmacher V: Immunogenicity increase of autologous tumor cell vaccines by virus infection and attachment of bispecific antibodies. Cancer Immunol Immunother 43 (3): 190-4, 1996.
46. Schirrmacher V, von Hoegen P, Heicappell R: Virus modified tumor cell vaccines for active specific immunotherapy of micrometastases: expansion and activation of tumor-specific T cells. Prog Clin Biol Res 288: 391-9, 1989.
47. Schirrmacher V, von Hoegen P, Heicappell R: Postoperative activation of tumor specific T cells by immunization with virus-modified tumor cells and effects on metastasis. Adv Exp Med Biol 233: 91-6, 1988.
48. Schirrmacher V, Haas C: Modification of cancer vaccines by virus infection and attachment of bispecific antibodies. In: Walden P, Trefzer U, Sterry W, et al., eds.: Gene Therapy of Cancer. New York, NY: Plenum Press, 1998, pp 251-7.
49. Termeer CC, Schirrmacher V, Bröcker EB, et al.: Newcastle disease virus infection induces B7-1/B7-2-independent T-cell costimulatory activity in human melanoma cells. Cancer Gene Ther 7 (2): 316-23, 2000.
50. Haas C, Lulei M, Fournier P, et al.: A tumor vaccine containing anti-CD3 and anti-CD28 bispecific antibodies triggers strong and durable antitumor activity in human lymphocytes. Int J Cancer 118 (3): 658-67, 2006.
51. Haas C, Lulei M, Fournier P, et al.: T-cell triggering by CD3- and CD28-binding molecules linked to a human virus-modified tumor cell vaccine. Vaccine 23 (19): 2439-53, 2005.
52. Washburn B, Weigand MA, Grosse-Wilde A, et al.: TNF-related apoptosis-inducing ligand mediates tumoricidal activity of human monocytes stimulated by Newcastle disease virus. J Immunol 170 (4): 1814-21, 2003.

Human / Clinical Studies

The anticancer potential of Newcastle disease virus (NDV) has been investigated in clinical studies in the United States, Canada, China, Germany, and Hungary. These studies have evaluated the use of oncolysates,[1,2,3,4,5,6,7,8,9,10,11,12,13,14]whole cell vaccines,[14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37] and infection of patients with a lytic strain of the virus.[14,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52] Findings from most of the studies, almost all of which were phase I or phase II clinical trials, have been reported in English-language biomedical journals. Overall, the results of these studies must be considered preliminary. Most studies enrolled only small numbers of patients, and historical control subjects, rather than actual control groups, which were often used for outcome comparisons. In addition, the evaluation of many studies is made difficult by poor descriptions of study design and the incomplete reporting of clinical data.

Immunotherapy With Oncolysates

The following information is summarized in Table 2 below.

The use of NDV oncolysates in patients with metastatic melanoma was evaluated in four clinical studies in the United States.[1,2,4,6,9,10,11,14] Three of these studies-a phase I clinical trial [9,10] and two phase II clinical trials [1,2,4,11]-were conducted by the same group of investigators. In all four studies, NDV strain 73-T was used to prepare oncolysate vaccines.

In the phase I study,[9,10] 13 patients who had advanced disease and who had not responded to conventional therapy (surgery alone or surgery plus chemotherapy and/or radiation therapy) were treated subcutaneously once a week or once every other week with injections of NDV oncolysates prepared from either their own tumor cells (i.e., autologous vaccines) or cultured melanoma cell lines (i.e., allogeneic vaccines). Several patients received additional conventional therapy while undergoing NDV treatment. Blood samples collected during the study showed increases in T cell numbers and the cytotoxic activity of lymphocytes in most patients (the latter was measured against melanoma cells in vitro).[9] One patient showed a complete response.[10] This patient, who was alive and apparently cancer-free at the end of the study period (a survival of more than 112 weeks), received six courses of chemotherapy while undergoing oncolysate treatment and had the least advanced disease of the patients studied. Minor responses in some skin and lymph node metastases were noted in several other patients, but no responses in visceral metastases were detected.

As indicated above, the researchers who conducted this phase I study also conducted two phase II studies. The phase II studies tested the ability of NDV oncolysates to delay the progression of melanoma from regional cancer to systemic disease.[1,2,4,11] The patients in these phase II studies had undergone surgery to remove the primary cancer and the radical lymph node dissection because of the presence of palpable disease in regional lymph nodes.

The first phase II study involved 32 patients, 5 of whom had been treated previously with other types of immunotherapy.[1,2,4,11] Melanoma was detected in 1 to 3 regional lymph nodes in 84% of the patients, in 4 to 5 regional lymph nodes in 9% of the patients, and in 6 to 8 regional lymph nodes in 6% of the patients. The second phase II study was initiated 4 years after the start of the first one, and it involved 51 additional patients.[1,2,11] Among these latter patients, 66% had melanoma detected in 1 to 3 regional lymph nodes, 16% had melanoma detected in 4 to 5 regional lymph nodes, and 18% had melanoma detected in 6 or more regional lymph nodes.[1,2,11]

In both studies, the patients were given subcutaneous injections of NDV oncolysates once a week for 4 weeks, beginning 4 to 8 weeks after surgery, followed by more subcutaneous injections given every 2 weeks until 1 year after surgery, and then continued subcutaneous injections given at intervals that increased gradually to every 3 months over the course of a 5-year period. From years 5 through 15 after surgery, some patients received additional oncolysate injections, which were given at intervals varying in length from 3 months to 6 months. Four of the patients in the first study were treated with both autologous and allogeneic vaccines, whereas the remaining patients in that study and all of the patients in the second study were treated with allogeneic vaccines only. Five years after surgery, 72% of the patients in the first study and 63% of the patients in the second study were reported to be alive and free of detectable melanoma.[11] The corresponding survival value for historical control subjects who had palpable regional disease was approximately 17% (a value derived from the scientific literature).[11] Ten years after surgery, 69% of the patients in the first study and 59% of the patients in the second study were reported to be alive and free of detectable melanoma,[2] compared with survival values of 5% to 15% for historical control subjects who had palpable regional disease or 33% for historical control subjects who had either palpable regional disease or microscopic evidence of regional lymph node metastasis.[1,2] Fifteen years after surgery, overall survival values of 59% and 53% were reported for patients in the first and second studies, respectively, with one survivor in the first study experiencing metastatic disease.[1] In general, survival in these two studies did not seem to be influenced by the number of regional lymph nodes that were positive for cancer at the time of radical lymph node dissection, and the patients who received both autologous and allogeneic vaccines did not appear to fare any better than the patients who received allogeneic vaccines only.[1]

The fourth U.S. study of NDV oncolysates in patients with melanoma was also a phase II trial.[6] This trial, which was conducted by a different group of researchers, involved 24 patients who likewise had disease that had spread to regional lymph nodes. The patients in this trial were treated in a manner similar to that of the patients in the other two phase II trials. In this trial, however, only 37% of the patients remained disease free 5 years after surgery; this disease-free survival percentage did not differ substantially from the 30% disease-free survival estimated for a group of historical control subjects who had been treated at the same institution with surgery alone or surgery and another type of adjuvant therapy.[6]

In contrast to the evidence of benefit found in the other phase II trials, the absence of benefit for NDV oncolysates in this fourth clinical trial remains to be explained. It has been reported that different methods of oncolysate preparation were used by the two groups of investigators who conducted these studies.[51] The positive results obtained by the first research group, however, must be viewed with caution. Until these results are confirmed independently in larger, randomized clinical trials, they should be considered preliminary.

Two additional phase II studies of NDV oncolysates have been conducted in Germany. One study involved 208 patients with locally advanced renal cell carcinoma (i.e., large tumors and no regional lymph node metastasis or tumors of any size and 1 or 2 regional lymph nodes positive for cancer).[8,12] The second study involved 22 patients with either metastatic breast cancer or metastatic ovarian cancer.[5,7]

In the advanced renal cell carcinoma study,[8,12] strain 73-T was used to prepare autologous oncolysates that were given to patients by subcutaneous injection once a week for 8 to 10 weeks beginning 1 to 3 months after radical surgery (i.e., nephrectomy and regional lymph node dissection). Two cytokines, low-dose recombinant interleukin-2 and recombinant interferon -alpha, were added to the oncolysate vaccines. Among the 208 patients who entered this study, 203 were followed for a period of time that ranged from 6 months to 64 months from the date of surgery, and these patients were considered evaluable for response. Approximately 91% of the evaluable patients remained free of detectable cancer during follow-up; 9% showed signs of progressive disease. The median time to relapse was more than 21 months. Fifty-six of the evaluable patients had 23 months to 64 months of follow-up from the time of surgery, and approximately 18% of these individuals showed signs of progressive disease during follow-up. All relapses in this subset of 56 patients occurred within 34 months of surgery.

The researchers who conducted this study concluded that the results demonstrated improved disease-free survival for the study subjects in comparison with survival data published in the scientific literature for similar patients who were treated with surgery alone.[8,12] Because this study was uncontrolled, however, it is not clear whether the improvement in disease-free survival was due to chance alone, to oncolysate therapy alone, to cytokine therapy alone, or to the combination of oncolysate therapy and cytokine therapy.

The same research group conducted a parallel investigation in which immune system responses to combination oncolysate and cytokine therapy were measured in 38 patients who had advanced renal cell carcinoma.[3] In this parallel study, responses to NDV antigens (i.e., the production of anti-NDV antibodies) and transient increases in blood levels of the cytokines interferon-alpha, interferon-gamma, and tumor necrosis factor (TNF)-alpha were found, but responses thought to be important to effective antitumor immunity (i.e., the production of antibodies against tumor-specific antigens, increases in natural killer (NK) cell activity, and increases in blood levels of helper T cells [i.e., CD4 antigen-positive cells] and cytotoxic T cells [i.e., CD8 antigen-positive cells]) were not.[3]

The phase II study of NDV oncolysates in patients with metastatic breast or metastatic ovarian cancer was described by its investigators as a study of autologous, whole cell vaccines.[5,7] The lytic strain Italien, however, was used in this study, so it is likely that immune system responses in the treated patients were stimulated by cellular fragments rather than by intact cancer cells.

In the study, 22 patients were vaccinated by intradermal injection at least 3 times during a 6- to 8-week period that began 2 weeks after surgery to remove malignant cells (either primary tumor cells or metastatic tumor cells). The patients also received intravenous injections of cyclophosphamide, high-dose recombinant interleukin-2, and autologous lymphocytes that had been simulated in vitro by treatment with interleukin-2. The cyclophosphamide was administered to block the activity of a class of T cells (i.e., suppressor T cells) that might weaken the desired immune responses. On average, the patients were followed for a period of 23 months from the time of surgery. Nine patients were reported to have either a complete response or a partial response after vaccine therapy. Five patients had stable disease, and eight had progressive disease. The average duration of response was 5 months, after which disease progression was again observed. Blood samples taken from the patients during therapy showed increases in the numbers of NK cells and increases in serum concentrations of the cytokines interferon-alpha and TNF-alpha, but these changes did not persist. No other immune system responses were detected. Because this was an uncontrolled study, it is unclear whether any of the observed clinical and/or immune system responses can be attributed to treatment with NDV oncolysates. Furthermore, because the lytic strain Italien was used in the study, the possibility that the observed tumor regressions were due, in part, to oncolysis cannot be ruled out.

Immunotherapy With Whole Cell Vaccines

The following information is summarized in Table 3 below.

Most clinical studies of NDV-infected, whole cell vaccines that have been reported in scientific literature were conducted in Germany.[15,16,17,18,19,20,21,22,23,24,25,26,27,31,32] However, the largest reported trial was performed in China.[14,33,34,35,36] Most of these studies involved patients with colorectal cancer,[15,16,19,20,22,33] breast cancer,[17,18,25] ovarian cancer,[17,18,23] renal cell cancer,[21,26] or malignant glioma.[31] The nonlytic strain NDV Ulster was used to prepare autologous tumor cell vaccines in all of the studies.

Data from a 2004 pilot clinical trial of an NDV-modified autologous tumor vaccine in 20 patients with stage III or IV head and neck squamous cell carcinomas suggest that the vaccine strategy can stimulate human antitumor immune responses in a manner similar to those found in animal models and may significantly prolong 5-year survival rates in this patient population. The study demonstrated the feasibility and safety of the vaccine regimen, and no major side effects were observed in any of the patients.[53]

The use of NDV-infected, whole cell vaccines in patients with either locally advanced or metastatic colorectal carcinoma was examined in one phase I clinical trial and two phase II clinical trials.[15,16,19,20,22] The phase I trial helped establish the optimum number of tumor cells and the optimum amount of virus to use in the average patient to produce the best possible immune response. Immune responses were monitored by means of a skin test that measured the extent of inflammation and hardening of the skin at vaccination sites (i.e., delayed-type hypersensitivity responses). The exact number of patients treated in this trial cannot be determined because nonidentical patient populations were described in the two published study reports.[19,20] One report lists 16 patients: 2 with stage II disease, 4 with stage III disease, and 10 with stage IV disease.[19] The second report lists 20 patients: 12 with stage II disease and 8 with stage III disease.[20] It is also not clear whether findings from individual patients were reported twice (i.e., in both trial reports). Patients with metastatic disease were allowed to enter this trial only if they had a solitary metastatic tumor.

In the trial, NDV-infected, autologous whole cell vaccines were administered to patients by intradermal injection beginning 4 weeks after surgery to remove the primary tumor or the metastatic tumor. Each patient received a total of 5 vaccinations, 4 given at 10-day intervals and a final booster given approximately 23 weeks after surgery. One of the study reports [19] states that 75% of the patients (12 of 16) showed increased immune system reactivity against uninfected, autologous tumor cells during the vaccination program. These responses were monitored by injecting uninfected, irradiated tumor cells into the skin and looking for delayed-type hypersensitivity responses. Histologic examination of several vaccination sites during the trial showed the presence of infiltrating immune system cells. These infiltrating cells were composed primarily of helper T cells; some cytotoxic T cells were also present, but B cells (i.e., antibody-producing cells) were either scarce or absent.[19]

The two phase II trials looked for evidence of therapeutic benefit in patients who had either metastatic colorectal carcinoma [15,22] or locally advanced colorectal carcinoma.[16] The trial that involved patients with metastatic disease recruited 23 individuals whose colorectal cancer had recurred in the liver following treatment of their primary tumor or whose colorectal cancer and liver metastases were diagnosed at the same time.[15,22] After surgery to remove the primary tumor and/or the metastases, all patients appeared to be free of residual cancer. NDV-infected, autologous tumor cells were then administered by intradermal injection every 2 weeks beginning 2 weeks after surgery. The total number of vaccinations given to the patients in this trial, however, is not clear. One of the two trial reports indicates that each patient received four vaccinations and a booster, which was given approximately 23 weeks after surgery.[15] The second trial report [22] indicates that each patient received five vaccinations and a booster. No additional treatment (chemotherapy or radiation therapy) was allowed during the trial.

During 18 months of follow-up, 14 of the 23 (61%) patients in this trial had relapses of their cancer, compared with relapses in 20 of 23 (87%) historical control subjects who were treated with surgery alone by the same surgeons at the same hospital. Although this difference in disease-free survival was statistically significant, there was no statistically significant difference in overall survival between the study subjects and the historical control subjects. The researchers also reported that, in general, the patients who had the strongest immune system responses against uninfected autologous tumor cells after vaccination had the longest disease-free survival times. It should be noted, however, that the reporting of patient responses against uninfected autologous tumor cells in this trial was inconsistent.[15,22] One trial report,[15] which described results after 12 months of follow-up, indicates that 11 of 23 patients showed increased immune system reactivity against uninfected autologous tumor cells during the vaccination program; whereas the second trial report,[22] which described results after 18 months of follow-up, indicates that only 9 of 23 patients showed increased reactivity against uninfected autologous tumor cells.

The phase II trial that involved patients with locally advanced colorectal carcinoma (i.e., large tumors and no regional lymph node metastasis or tumors of any size and regional lymph nodes that were positive for cancer) recruited 57 individuals.[16] Among these 57 patients, 48 were treated with NDV-infected, whole cell vaccines, and 9 were treated with vaccines composed of autologous tumor cells and the bacterium Bacillus Calmette Guerin (BCG), which also has been used as an immune system stimulator. Patients recruited for this trial were treated first with surgery and then were given a choice between participating in the trial or receiving chemotherapy. The individuals who chose to participate in the trial were injected intradermally with the appropriate autologous tumor cell vaccines every other week for a total of 6 weeks (i.e., 3 vaccinations per patient) beginning 6 to 8 weeks after surgery. The follow-up period ranged from 6 months to 43 months (median of 22 months), and disease-free survival and overall survival were estimated for the vaccinated patients and for 661 historical control subjects who were treated with surgery alone. Two years after surgery, overall survival for the patients who were treated with NDV-infected, autologous whole cell vaccines was 98%, compared with 67% overall survival for the patients who were treated with BCG tumor cell vaccines and 74% overall survival for the historical control subjects. The differences in survival between the NDV/tumor-cell-vaccinated group and the other two groups were statistically significant. Disease-free survival 2 years after surgery for the NDV/tumor-cell-treated patients was 72%. The researchers who conducted this trial also reported that overall survival for the NDV/tumor-cell-treated group was comparable to that of the group of patients (n = 15) who chose to be treated with chemotherapy rather than immunotherapy.[16]

Two additional phase II studies investigated the use of NDV-infected, autologous tumor cell vaccines in patients who had either ovarian cancer or renal cell cancer.[21,23] The ovarian cancer trial enrolled 82 patients, but only 39 were evaluable for response.[23] The published report of this trial, however, described clinical findings for just 24 evaluable patients who had stage III disease; results for the remaining evaluable patients (5 with stage I disease, 5 with stage II disease, and 5 with stage IV disease) were not presented. The patients in this trial were treated with surgery and six courses of chemotherapy in addition to three courses of intradermally administered immunotherapy, but details about the adjuvant treatments (e.g., what constituted a course of immunotherapy or what chemotherapy drugs were used in addition to cisplatin) were very limited. Among the 24 evaluable patients with reported clinical findings, 15 had a complete remission, 8 had a partial remission, and 1 had progressive disease. The median disease-free survival time for the patients who had a complete remission was 30 months. These results were described as very encouraging by the investigators who conducted the study, but the degree of benefit afforded by the immunotherapy in this uncontrolled study cannot be established. In common with other studies of NDV-infected tumor cell vaccines, histologic examination of individual vaccination sites revealed the presence of infiltrates consisting predominantly of helper T cells.[23]

The phase II trial of NDV-infected, autologous tumor cell vaccines in patients with renal cell cancer enrolled 40 individuals whose disease had spread from the kidney to at least 1 other organ.[21] The patients in this trial underwent surgery (i.e., radical nephrectomy) to remove the primary tumor and then were given intradermal injections of NDV-infected tumor cells at 3 weeks and 5 weeks after surgery. The patients were also given subcutaneous injections of low-dose recombinant interleukin-2 and recombinant interferon-alpha. Five patients had a complete response, and six had a partial response. After 4 years of follow-up, overall survival for these 11 responding patients was 100%. Among the remaining 29 patients, 12 had stable disease (median survival = 31 months) and 17 had progressive disease (median survival = 14 months). The researchers also reported a median survival time of 13 months for 36 historical control subjects who were treated with surgery and other types of adjuvant therapy (chemotherapy, radiation therapy, or hormonal therapy). The overall percentage of patients with either a complete response or a partial response in this uncontrolled study (i.e., 28%) is similar to that found in other studies in which comparable patients were treated with cytokine therapy but not vaccine therapy.[21] Therefore, it is not clear whether any of the apparent clinical benefit in this trial can be attributed to vaccination with NDV-infected tumor cells.

A fifth phase II clinical trial tested NDV-infected, autologous tumor cell vaccines in 43 patients who had various advanced cancers (16 ovarian, 22 breast, 1 cervical, 1 vaginal, 1 lung, and 1 chondrosarcoma) that had not responded to previous treatment.[18] The patients in this trial received intravenous injections of cyclophosphamide and epirubicin, subcutaneous injections of low-dose recombinant interleukin-2 and interferon-alpha, and intradermal injections of the tumor cell vaccines. The cyclophosphamide and epirubicin were administered to block the activity of suppressor T cells that might weaken the desired immune responses. The trial report provided no information about the treatments that had failed, the time intervals between the failure of the last treatment and the beginning of immunotherapy, or how many vaccinations each patient received. The researchers considered 31 of the 43 patients to be evaluable for response. Among the evaluable patients, one individual who had ovarian cancer had a complete response that lasted more than 2 months. The remaining evaluable patients had either partial responses (n = 11), stable disease (n = 10), or progressive disease (n = 9) following treatment. In view of the limited information given, no conclusions can be drawn from this uncontrolled study about the effectiveness of NDV-infected, autologous whole cell vaccines in this patient population.

One additional clinical study evaluated the effect of vaccine quality on the survival of patients who were treated with NDV-infected, autologous tumor cells.[17] In this retrospective study, survival was estimated separately for three groups of patients who had early breast cancer (n = 63), metastatic breast cancer (n = 27), or metastatic ovarian cancer (n = 31) and who had sufficient numbers of recovered tumor cells to allow at least two vaccinations. Most of the patients who had early breast cancer were treated after surgery with conventional adjuvant therapies (chemotherapy, radiation therapy, and/or hormonal therapy) in addition to vaccine therapy. The patients who had metastatic breast or ovarian cancer had failed to respond to conventional treatments before the start of vaccine therapy. In addition to receiving tumor cell vaccines, these latter patients were treated with oral indomethacin and cimetidine, intravenous cyclophosphamide and epirubicin, and subcutaneous low-dose recombinant interleukin-2 and interferon-alpha. The indomethacin, cimetidine, cyclophosphamide, and epirubicin were given in an attempt to prevent the suppression of desired immune system responses. The autologous vaccines were classified as either high quality or low quality on the basis of the following two parameters: the ratio of tumor cells to other types of cells and the percentage of live tumor cells. The median times from surgery to the start of immunotherapy were 13 days, 27 days, and 28 days for the patients who had early breast cancer, metastatic breast cancer, and metastatic ovarian cancer, respectively.

Overall survival 4 years after surgery was estimated to be 96% for the patients with early breast cancer who had received a high-quality vaccine (n = 32), compared with an overall survival of 68% for those who had received a low-quality vaccine (n = 31). For the patients with metastatic breast cancer, the median survival time was estimated to be 1.75 years from the start of immunotherapy for those who had received a high-quality vaccine (n = 13), compared with a median survival time of 0.75 years for those who had received a low-quality vaccine (n = 14) (median follow-up time = 1.4 years). For patients with metastatic ovarian cancer, the median survival time was estimated to be 1.16 years from the start of immunotherapy for those who had received a high-quality vaccine (n = 18), compared with a median survival time of 0.84 years for those who had received a low-quality vaccine (n = 13) (median follow-up time = 1.23 years). The only survival difference that was statistically significant was the one for the patients who had early breast cancer. The retrospective nature of this study and the small numbers of patients in each treatment group should be viewed as major weaknesses.

In two of the above-mentioned studies, the phase I colorectal cancer study [19,20] and the phase II ovarian cancer study,[23] histologic examination of several vaccination sites revealed the presence of infiltrating immune system cells. These infiltrating cells, however, consisted primarily of helper T cells (CD4 antigen-positive cells); cytotoxic T cells (CD8 antigen-positive cells) were present, but only as a minor component. In another study,[27] vaccination sites from five cancer patients (two with colon cancer, two with melanoma, and one with ovarian cancer) also contained infiltrates of predominantly helper T cells. In fact, CD8 antigen-positive T cells could not be detected in the lymphocytes cultured from vaccination sites of two of these five patients.[27,22] The presence of small numbers of cytotoxic T cells at vaccination sites may be an important factor to consider when evaluating the results of the whole cell vaccine trials because animal studies [54,55,56,57,16,19,58,59,60,61,62,63,64,65,66] and human studies [1] have suggested that this class of T cells is required for effective, long-term anticancer immunity. It should also be noted that, in another study,[67] increases in NK cell activity were measured in blood samples from two patients with colorectal cancer who exhibited delayed-type hypersensitivity responses at vaccination sites, but cytotoxic T cells directed against tumor-specific antigens could not be detected. Overall, these results indicate that NDV-infected, autologous, whole cell vaccines may be able to stimulate NK cell activity, which may have contributed the clinical outcomes described above, but also that these vaccines may be ineffective in promoting at least one additional immune system response (i.e., the production of tumor-specific antigen-targeted cytotoxic T cells) thought to be important to establishing long-term anticancer immunity. Whether the inclusion of bispecific monoclonal antibodies (refer to the Laboratory/Animal/Preclinical Studies section of this summary for more information) in the whole cell vaccines will make them more effective remains to be determined.

Infection of Patients With NDV (Including Strain MTH-68)

The following information is summarized in Table 4 below.

To date, most research into the treatment of human cancer by infection of patients with NDV has been conducted in Hungary.[38,39,41,42,14,49,50,51] The Hungarian research effort has been led by a single group of investigators who advocate the use of NDV strain MTH-68, which is presumed to be lytic. Findings from these investigations have been published in the form of an anecdotal report that briefly describes results for 3 patients who had metastatic disease;[41] a single case report about a child who had glioblastoma multiforme;[42] a report of a small case series that included 4 individuals with advanced cancer;[38] and a report of a placebo-controlled, phase II clinical trial that included 33 patients in the NDV treatment group and 26 patients in the placebo group.[39] The patients in the phase II trial had various advanced cancers.[39] According to the investigators, MTH-68 treatment was beneficial for the majority of these patients.

The five patients described in the case report and the small case series were reported to have had either a complete remission or a partial remission following NDV therapy.[38,42] Two of the patients in the case series had advanced colorectal cancer, another had melanoma, and the fourth had advanced Hodgkin disease.[38] These five patients were treated with NDV daily for periods of time that ranged from 1 month to 7 years. Inhalation and intravenous injection were the main routes of virus administration. One of the patients with colorectal cancer, however, was treated by means of intracolonic injection (i.e., via a colostomy opening) for 4 weeks. It is important to note that all five patients were treated with conventional therapy before the start of NDV therapy and that four of the five received conventional therapy either concurrently with NDV therapy or after it. Given the small number of patients, the absence of control subjects, and the overlapping treatments, it is difficult to draw conclusions about the effectiveness of NDV therapy from these small studies. Nonetheless, taken as a whole the results of the available NDV studies suggest potential clinical value warranting further study with controlled clinical trials.

In the phase II trial,[39] NDV was administered by inhalation only 2 times a week for a period of 6 months. The 33 patients in the NDV treatment group had the following types of cancer: colorectal (n = 13), stomach (n = 6), kidney (n = 3), pancreatic (n = 3), lung (n = 1), breast (n = 1), ovarian (n = 1), melanoma (n = 1), bile duct (n = 1), gallbladder (n = 1), sarcoma (n = 1), and ependymoma (n = 1). The distribution of cancers among the 26 patients in the placebo group was as follows: colorectal (n = 5), stomach (n = 3), kidney (n = 6), lung (n = 1), breast (n = 1), melanoma (n = 7), bile duct (n = 1), sarcoma (n = 1), and bladder (n = 1). Twenty-four (73%) of the patients in the NDV treatment group had distant metastases when they were recruited into the trial, compared with 22 (85%) of the patients in the placebo group. Thirty-one (94%) of the patients in the NDV treatment group received some form of conventional therapy (surgery, chemotherapy, or radiation therapy) before the start of virus therapy; 9 (29%) of these patients were treated with more than one type of conventional therapy. All (100%) of the patients in the placebo group received conventional therapy before the start of virus therapy; 15 (58%) of these individuals were treated with more than one type of conventional therapy. The average age of the patients in the NDV treatment group was 62.6 years, compared with an average age of 55.4 years for the patients in the placebo group. The two groups, however, were well-balanced with respect to gender distribution (61% males and 39% females in each treatment group) and average performance status (1.39 for each group, based on the following scale: 0 = free from complaints, 1 = capable of easy work, 2 = less than 50% bed rest required, 3 = more than 50% bed rest required, 4 = 100% bedridden). Two complete responses and six partial responses were reported for patients in the NDV treatment group, whereas no responses were observed in the placebo group. In the NDV treatment group, ten patients were reported to have stable disease, compared with just two patients in the placebo group. In addition, more patients in the NDV treatment group than in the placebo group reported subjective improvements in their quality of life. Twenty-two (67%) of the patients in the NDV treatment group survived at least 1 year, compared with 4 (15%) of the patients in the placebo group. The 2-year survival proportions were 21% and 0% for patients in the NDV treatment group and the placebo group, respectively.

This phase II trial had a number of weaknesses that could have influenced its outcome. The most important weakness is the fact that the patients were not randomly assigned to the two treatment groups. This lack of randomization raises the possibility of selection bias. In this regard, it is noteworthy that a larger percentage of patients in the NDV treatment group than in the placebo group received conventional therapy within the 3 months preceding the initiation of NDV therapy (82% vs. 58%).[39] In fact, the average time between the completion of conventional therapy and the start of NDV therapy among the patients who had a either a complete response or a partial response was 1.8 months.[39] Therefore, the contribution of NDV therapy to the observed clinical outcomes is difficult to determine.

In a phase I trial that was conducted in the United States, another lytic NDV strain, PV701, was tested in patients with various advanced cancers.[44] In this trial, 79 patients whose tumors had not responded to conventional therapy were given intravenous injections of virus. Four different treatment regimens were evaluated as follows:

1. A single dose of NDV given once every 28 days (17 patients).
2. A single dose of NDV given 3 times during a 1-week period, repeated every 28 days (13 patients).
3. Three injections of NDV given during a 1-week period, with the first injection containing a lower dose of virus than the remaining 2, repeated every 28 days (37 patients).
4. Six injections of NDV given during a 2-week period, with the first injection containing a lower dose of virus than the remaining 5, repeated every 21 days (12 patients).

The researchers found that the use of lower initial doses of virus allowed the administration of higher subsequent doses. A complete response was reported for one patient, and partial tumor regression was observed in eight patients. Thirteen patients had stable disease for periods of time that lasted from 4 months to more than 30 months. Five patients died during the trial: four due to progressive disease and one due, possibly, to a treatment-related complication (refer to the Adverse Effects section of this summary for more information). Several patients experienced significant adverse side effects from NDV treatment, including fever, fatigue, dehydration, low blood pressure, shortness of breath, and hypoxia. Some patients who experienced these adverse effects required hospitalization. The researchers who conducted this trial have indicated that additional clinical studies are under way.

A major concern about the effectiveness of treating cancer patients by repeated administration of a lytic strain of NDV is the possibility that the immune system will produce virus-neutralizing antibodies. Virus-neutralizing antibodies would prevent NDV from reaching and infecting malignant cells, thereby blocking oncolysis. Impairment of NDV infection would also limit the ability of cytotoxic T cells that target virus antigens to kill virus-infected cancer cells. In addition, limiting the infection of cancer cells would lessen the likelihood that the immune system would become trained to better recognize tumor-specific antigens. The Hungarian investigators have shown that anti-NDV antibodies are produced in MTH-68-treated patients,[38] but they apparently have not determined whether these antibodies are virus-neutralizing. However, the recent observation that immune system tolerance to viruses can be induced by repeated oral administration of virus proteins suggests that the concern about virus-neutralizing antibodies may not be entirely warranted.[68,69] It is conceivable that frequent inhalation (or injection) of NDV may lead to immune system tolerance of this virus. This possibility should be explored in future studies.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials for integrative, alternative, and complementary therapies clinical trials on oncolytic Newcastle disease virus that are actively enrolling patients.

General information about clinical trials is also available from the NCI website.

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19. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990.
20. Lehner B, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. Cancer Immunol Immunother 32 (3): 173-8, 1990.
21. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival-data of patients with advanced renal-cell carcinoma treated with autologous tumor vaccine and subcutaneous R-IL-2 and IFN-alpha(2b). Int J Oncol 6 (5): 947-54, 1995.
22. Schlag P, Manasterski M, Gerneth T, et al.: Active specific immunotherapy with Newcastle-disease-virus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunother 35 (5): 325-30, 1992.
23. Möbus V, Horn S, Stöck M, et al.: Tumor cell vaccination for gynecological tumors. Hybridoma 12 (5): 543-7, 1993.
24. Proebstle TM, Staib G, Kaufmann R, et al.: Autologous active specific immunization (ASI) therapy for metastatic melanoma [abstract from Fifth World Conference on Cancers of the Skin]. [Abstract] Melanoma Res 3: A-133, 35, 1993.
25. Schirrmacher V: [Anti-tumor vaccination] Zentralbl Chir 125 (Suppl 1): 33-6, 2000.
26. Pomer S, Thiele R, Staehler G, et al.: [Tumor vaccination in renal cell carcinoma with and without interleukin-2 (IL-2) as adjuvant. A clinical contribution to the development of effective active specific immunization] Urologe A 34 (3): 215-20, 1995.
27. Stoeck M, Marland-Noske C, Manasterski M, et al.: In vitro expansion and analysis of T lymphocyte microcultures obtained from the vaccination sites of cancer patients undergoing active specific immunization with autologous Newcastle-disease-virus-modified tumour cells. Cancer Immunol Immunother 37 (4): 240-4, 1993.
28. Herold-Mende C, Karcher J, Dyckhoff G, et al.: Antitumor immunization of head and neck squamous cell carcinoma patients with a virus-modified autologous tumor cell vaccine. Adv Otorhinolaryngol 62: 173-83, 2005.
29. Schulze T, Kemmner W, Weitz J, et al.: Efficiency of adjuvant active specific immunization with Newcastle disease virus modified tumor cells in colorectal cancer patients following resection of liver metastases: results of a prospective randomized trial. Cancer Immunol Immunother 58 (1): 61-9, 2009.
30. Schneider T, Gerhards R, Kirches E, et al.: Preliminary results of active specific immunization with modified tumor cell vaccine in glioblastoma multiforme. J Neurooncol 53 (1): 39-46, 2001.
31. Steiner HH, Bonsanto MM, Beckhove P, et al.: Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. J Clin Oncol 22 (21): 4272-81, 2004.
32. Voit C, Kron M, Schwürzer-Voit M, et al.: Intradermal injection of Newcastle disease virus-modified autologous melanoma cell lysate and interleukin-2 for adjuvant treatment of melanoma patients with resectable stage III disease. J Dtsch Dermatol Ges 1 (2): 120-5, 2003.
33. Liang W, Wang H, Sun TM, et al.: Application of autologous tumor cell vaccine and NDV vaccine in treatment of tumors of digestive tract. World J Gastroenterol 9 (3): 495-8, 2003.
34. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.
35. Schirrmacher V: Active specific immunotherapy: a new modality of cancer treatment involving the patient's own immune system. Onkologie 16 (5): 290-6, 1993.
36. Schirrmacher V, Schlag P, Liebrich W, et al.: Specific immunotherapy of colorectal carcinoma with Newcastle-disease virus-modified autologous tumor cells prepared from resected liver metastasis. Ann N Y Acad Sci 690: 364-6, 1993.
37. Schirrmacher V: Clinical trials of antitumor vaccination with an autologous tumor cell vaccine modified by virus infection: improvement of patient survival based on improved antitumor immune memory. Cancer Immunol Immunother 54 (6): 587-98, 2005.
38. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb.
39. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993.
40. Cassel WA, Garrett RE: Newcastle disease virus as an antineoplastic agent. Cancer 18 (7): 863-8, 1965.
41. Csatary LK: Viruses in the treatment of cancer. Lancet 2 (7728): 825, 1971.
42. Csatary LK, Bakács T: Use of Newcastle disease virus vaccine (MTH-68/H) in a patient with high-grade glioblastoma. JAMA 281 (17): 1588-9, 1999.
43. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964.
44. Pecora AL, Rizvi N, Cohen GI, et al.: Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20 (9): 2251-66, 2002.
45. Laurie SA, Bell JC, Atkins HL, et al.: A phase 1 clinical study of intravenous administration of PV701, an oncolytic virus, using two-step desensitization. Clin Cancer Res 12 (8): 2555-62, 2006.
46. Freeman AI, Zakay-Rones Z, Gomori JM, et al.: Phase I/II trial of intravenous NDV-HUJ oncolytic virus in recurrent glioblastoma multiforme. Mol Ther 13 (1): 221-8, 2006.
47. Csatary LK, Gosztonyi G, Szeberenyi J, et al.: MTH-68/H oncolytic viral treatment in human high-grade gliomas. J Neurooncol 67 (1-2): 83-93, 2004 Mar-Apr.
48. Wagner S, Csatary CM, Gosztonyi G, et al.: Combined treatment of pediatric high-grade glioma with the oncolytic viral strain MTH-68/H and oral valproic acid. APMIS 114 (10): 731-43, 2006.
49. Nelson NJ: Scientific interest in Newcastle disease virus is reviving. J Natl Cancer Inst 91 (20): 1708-10, 1999.
50. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996.
51. Sinkovics J, Horvath J: New developments in the virus therapy of cancer: a historical review. Intervirology 36 (4): 193-214, 1993.
52. Lorence RM, Roberts MS, O'Neil JD, et al.: Phase 1 clinical experience using intravenous administration of PV701, an oncolytic Newcastle disease virus. Curr Cancer Drug Targets 7 (2): 157-67, 2007.
53. Karcher J, Dyckhoff G, Beckhove P, et al.: Antitumor vaccination in patients with head and neck squamous cell carcinomas with autologous virus-modified tumor cells. Cancer Res 64 (21): 8057-61, 2004.
54. Plaksin D, Porgador A, Vadai E, et al.: Effective anti-metastatic melanoma vaccination with tumor cells transfected with MHC genes and/or infected with Newcastle disease virus (NDV). Int J Cancer 59 (6): 796-801, 1994.
55. Von Hoegen P, Weber E, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. Augmentation of the tumor-specific T cell response in the absence of an anti-viral response. Eur J Immunol 18 (8): 1159-66, 1988.
56. Schirrmacher V, Schild HJ, Gückel B, et al.: Tumour-specific CTL response requiring interactions of four different cell types and recognition of MHC class I and class II restricted tumour antigens. Immunol Cell Biol 71 ( Pt 4): 311-26, 1993.
57. Bosslet K, Schirrmacher V, Shantz G: Tumor metastases and cell-mediated immunity in a model system in DBA/2 mice. VI. Similar specificity patterns of protective anti-tumor immunity in vivo and of cytolytic T cells in vitro. Int J Cancer 24 (3): 303-13, 1979.
58. Schirrmacher V, Haas C, Bonifer R, et al.: Human tumor cell modification by virus infection: an efficient and safe way to produce cancer vaccine with pleiotropic immune stimulatory properties when using Newcastle disease virus. Gene Ther 6 (1): 63-73, 1999.
59. Schirrmacher V, Ahlert T, Heicappell R, et al.: Successful application of non-oncogenic viruses for antimetastatic cancer immunotherapy. Cancer Rev 5: 19-49, 1986.
60. Schirrmacher V, Haas C, Bonifer R, et al.: Virus potentiation of tumor vaccine T-cell stimulatory capacity requires cell surface binding but not infection. Clin Cancer Res 3 (7): 1135-48, 1997.
61. Bier H, Armonat G, Bier J, et al.: Postoperative active-specific immunotherapy of lymph node micrometastasis in a guinea pig tumor model. ORL J Otorhinolaryngol Relat Spec 51 (4): 197-205, 1989.
62. Schirrmacher V, Heicappell R: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. II. Establishment of specific systemic anti-tumor immunity. Clin Exp Metastasis 5 (2): 147-56, 1987 Apr-Jun.
63. von Hoegen P, Zawatzky R, Schirrmacher V: Modification of tumor cells by a low dose of Newcastle disease virus. III. Potentiation of tumor-specific cytolytic T cell activity via induction of interferon-alpha/beta. Cell Immunol 126 (1): 80-90, 1990.
64. Schirrmacher V, von Hoegen P, Heicappell R: Virus modified tumor cell vaccines for active specific immunotherapy of micrometastases: expansion and activation of tumor-specific T cells. Prog Clin Biol Res 288: 391-9, 1989.
65. Schirrmacher V, von Hoegen P, Heicappell R: Postoperative activation of tumor specific T cells by immunization with virus-modified tumor cells and effects on metastasis. Adv Exp Med Biol 233: 91-6, 1988.
66. von Hoegen P, Heicappell R, Griesbach A, et al.: Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. III. Postoperative activation of tumor-specific CTLP from mice with metastases requires stimulation with the specific antigen plus additional signals. Invasion Metastasis 9 (2): 117-33, 1989.
67. Patel BT, Lutz MB, Schlag P, et al.: An analysis of autologous T-cell anti-tumour responses in colon-carcinoma patients following active specific immunization (ASI). Int J Cancer 51 (6): 878-85, 1992.
68. Ilan Y, Sauter B, Chowdhury NR, et al.: Oral tolerization to adenoviral proteins permits repeated adenovirus-mediated gene therapy in rats with pre-existing immunity to adenoviruses. Hepatology 27 (5): 1368-76, 1998.
69. Ilan Y, Chowdhury JR: Induction of tolerance to hepatitis B virus: can we 'eat the disease' and live with the virus? Med Hypotheses 52 (6): 505-9, 1999.

Adverse Effects

The side effects associated with exposure to Newcastle disease virus (NDV) have generally been described as mild to moderate in severity. As noted previously (refer to the General Information section of this summary for more information), NDV has been reported to cause mild flu-like symptoms, conjunctivitis, and laryngitis in humans. [1,2,3,4,5,6,7,8,9,10]

The most commonly reported side effect after treatment of cancer patients with the virus alone is fever, which usually subsides within 24 hours.[2,11,12] In one study of infectious virus, localized adverse effects, such as inflammation and edema, were observed in the vicinity of some tumors.[12] These adverse effects may have contributed to the death of one patient.[12] Other adverse effects reported in this study included fatigue, low blood pressure, shortness of breath, and hypoxia. Some of these adverse effects were serious enough to require hospitalization.

Mild headache, mild fever on the day of vaccination, and itching, swelling, and erythema at injection sites are the most commonly reported side effects following injection of NDV-infected whole cell vaccines.[13,14,15,16,17]

The only adverse effect associated with administration of NDV oncolysate vaccines is inflammation at injection sites.[18,19,20]

Most of the flu-like symptoms, fever, and edema observed in studies in which cytokines were combined with NDV oncolysates or whole cell vaccines have been attributed to treatment with interleukin-2.[18,19,20,21,22]

References:

1. Csatary LK, Moss RW, Beuth J, et al.: Beneficial treatment of patients with advanced cancer using a Newcastle disease virus vaccine (MTH-68/H). Anticancer Res 19 (1B): 635-8, 1999 Jan-Feb.
2. Csatary LK, Eckhardt S, Bukosza I, et al.: Attenuated veterinary virus vaccine for the treatment of cancer. Cancer Detect Prev 17 (6): 619-27, 1993.
3. Kenney S, Pagano JS: Viruses as oncolytic agents: a new age for "therapeutic" viruses? J Natl Cancer Inst 86 (16): 1185-6, 1994.
4. Kirn DH, McCormick F: Replicating viruses as selective cancer therapeutics. Mol Med Today 2 (12): 519-27, 1996.
5. Lorence RM, Reichard KW, Katubig BB, et al.: Complete regression of human neuroblastoma xenografts in athymic mice after local Newcastle disease virus therapy. J Natl Cancer Inst 86 (16): 1228-33, 1994.
6. Lorence RM, Katubig BB, Reichard KW, et al.: Complete regression of human fibrosarcoma xenografts after local Newcastle disease virus therapy. Cancer Res 54 (23): 6017-21, 1994.
7. Batliwalla FM, Bateman BA, Serrano D, et al.: A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire. Mol Med 4 (12): 783-94, 1998.
8. Reichard KW, Lorence RM, Cascino CJ, et al.: Newcastle disease virus selectively kills human tumor cells. J Surg Res 52 (5): 448-53, 1992.
9. Schirrmacher V, Ahlert T, Pröbstle T, et al.: Immunization with virus-modified tumor cells. Semin Oncol 25 (6): 677-96, 1998.
10. Moss RW: Alternative pharmacological and biological treatments for cancer: ten promising approaches. J Naturopathic Med 6 (1): 23-32, 1996.
11. Wheelock EF, Dingle JH: Observations on the repeated administration of viruses to a patient with acute leukemia. A preliminary report. N Engl J Med 271(13): 645-51, 1964.
12. Pecora AL, Rizvi N, Cohen GI, et al.: Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers. J Clin Oncol 20 (9): 2251-66, 2002.
13. Liebrich W, Schlag P, Manasterski M, et al.: In vitro and clinical characterisation of a Newcastle disease virus-modified autologous tumour cell vaccine for treatment of colorectal cancer patients. Eur J Cancer 27 (6): 703-10, 1991.
14. Ockert D, Schirrmacher V, Beck N, et al.: Newcastle disease virus-infected intact autologous tumor cell vaccine for adjuvant active specific immunotherapy of resected colorectal carcinoma. Clin Cancer Res 2 (1): 21-8, 1996.
15. Bohle W, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in colorectal cancer patients with virus-modified autologous tumor-cell vaccine. First clinical results with tumor-cell vaccines modified with live but avirulent Newcastle disease virus. Cancer 66 (7): 1517-23, 1990.
16. Lehner B, Schlag P, Liebrich W, et al.: Postoperative active specific immunization in curatively resected colorectal cancer patients with a virus-modified autologous tumor cell vaccine. Cancer Immunol Immunother 32 (3): 173-8, 1990.
17. Schlag P, Manasterski M, Gerneth T, et al.: Active specific immunotherapy with Newcastle-disease-virus-modified autologous tumor cells following resection of liver metastases in colorectal cancer. First evaluation of clinical response of a phase II-trial. Cancer Immunol Immunother 35 (5): 325-30, 1992.
18. Mallmann P, Eis-Hubinger AM, Krebs D: Lymphokine-activated tumor-infiltrating lymphocytes and autologous tumor vaccine in breast and ovarian cancer. Onkologie 15 (6): 490-6, 1992.
19. Anton P, Kirchner H, Jonas U, et al.: Cytokines and tumor vaccination. Cancer Biother Radiopharm 11 (5): 315-8, 1996.
20. Kirchner HH, Anton P, Atzpodien J: Adjuvant treatment of locally advanced renal cancer with autologous virus-modified tumor vaccines. World J Urol 13 (3): 171-3, 1995.
21. Pomer S, Schirrmacher V, Thiele R, et al.: Tumor response and 4 year survival-data of patients with advanced renal-cell carcinoma treated with autologous tumor vaccine and subcutaneous R-IL-2 and IFN-alpha(2b). Int J Oncol 6 (5): 947-54, 1995.
22. Mallmann P: Autologous tumor-cell vaccination and lymphokine-activated tumor-infiltrating lymphocytes (LAK-TIL). Hybridoma 12 (5): 559-66, 1993.

Summary of the Evidence for Newcastle Disease Virus

In view of the evidence accumulated to date, no conclusions can be drawn about the effectiveness of using Newcastle disease virus in the treatment of cancer. Most reported clinical studies have involved few patients, and historical control subjects rather than actual control groups have often been used for outcome comparisons. Poor descriptions of study design and incomplete reporting of clinical data have hindered evaluation of many of the reported findings. However, while most studies are small and lack adequate controls, the number of studies suggesting a potential clinical value warrants further attention.

Separate levels of evidence scores are assigned to qualifying human studies on the basis of statistical strength of the study design and scientific strength of the treatment outcomes (i.e., endpoints) measured. The resulting two scores are then combined to produce an overall score. For additional information about levels of evidence analysis, refer to Levels of Evidence for Human Studies of Integrative, Alternative, and Complementary Therapies.

Changes to This Summary (11 / 02 / 2016)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the use of Newcastle disease virus in the treatment of people with cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Integrative, Alternative, and Complementary Therapies Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Newcastle Disease Virus are:

• Keith I. Block, MD (Block Center for Integrative Cancer Treatment & University of Illinois College of Medicine)
• Jeffrey D. White, MD (National Cancer Institute)

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Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Integrative, Alternative, and Complementary Therapies Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ® Integrative, Alternative, and Complementary Therapies Editorial Board. PDQ Newcastle Disease Virus. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/cam/hp/ndv-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389195]

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Last Revised: 2016-11-02