THERE is an obvious need for a marker that will differentiate one type of lymphocyte from another. The need has become urgent in view of recent evidence suggesting that there are at least two populations of lymphocytes, one thymus-derived and one bone marrow-derived, which participate in different ways in the immune response1. The theta (θ) isoantigen (θ is determined by a single locus with two alleles: θAKR found in AKR and RF mice and θC3H present in most other inbred strains of mice tested), described by Reif and Allen2,3, which is found chiefly in thymus lymphocytes and brain, and to a lesser extent in peripheral lymphocytes in mice, seemed a possible antigenic marker of thymus-derived lymphocytes. To establish that θ is such a marker, it is necessary to demonstrate that there is a discrete population of peripheral lymphocytes which carry the antigen and that these cells are thymus-dependent.

Theta isoantigen as a marker of thymus-derived lymphocytes in mice (Reprinted from Nature vol 224, pg 378-379, 1969)

The subject invention relates to viruses that are able to replicate and thereby kill neoplastic cells with a deficiency in the IFN-mediated antiviral response, and their use in treating neoplastic disease including cancer and large tumors. RNA and DNA viruses are useful in this regard. The invention also relates to methods for the selection, design, purification and use of such viruses for cancer therapy.

Treatment of neoplasms with viruses

Effective anti-metastatic therapy was achieved in a mouse tumor model by combining surgery with post-operative immunotherapy using virus-modified autologous tumor cells No therapeutic effect was observed when using for immunotherapy the nonmodified autologous tumor ESb, which is only weakly immunogenic and highly metastatic The viral modification was achieved by infecting the tumor with an avirulent strain of Newcastle disease virus (NDV), which led to expression of viral antigens and to an increase in the tumor cells' immunogenicity Parameters which were of decisive influence for success or failure of therapy were the time of operation of the primary tumor and the dose of virus which was admixed to a standard dose of irradiated tumor cells There was a low dose optimum of NDV at about 100 hemagglutinating units per 25 X 10(6) tumor cells The therapeutic effect observed was less pronounced if the virus was given separately from the tumor cells Post-operative immunotherapy with NDV-modified tumor cells had the following therapeutic effects: (1) disappearance of micrometastases from visceral organs as ascertained by a sensitive bioassay; (2) life prolongation in virtually all animals when compared to controls (operated only); (3) cures in about 50% of the treated animals The possible mechanism of this therapeutic effect and its potential for clinical application are discussed

Prevention of metastatic spread by postoperative immunotherapy with virally modified autologous tumor cells. I. Parameters for optimal therapeutic effects.

Spontaneously arising cytotoxicity to the P-815-Y mastocytoma in NZB mice.

Publisher Summary The membranes of tumor cells actively infected with the virus exhibit augmented immunogenicity Many animal tumor cells possess tumor-associated transplantation antigen (TATA) on their surface membrane; their immunogenicity is lost when the tumor cells are disrupted This chapter discusses the enhanced immunogenicity of tumor cell extracts Infection of tumor cells with a lytic virus that induces viral cell-surface antigens augment the TATA activity of the tumor cell homogenate or oncolysate The mechanism of virus augmentation operates through the host's immune system Positive results in immunoprophylaxis and immunotherapy with virus-augmented TATA in animal model systems lead to the initiation of several attempts at immunotherapy with virus-augmented TATA in human cancer patients In addition, virus-augmented crude membrane extracts of cultured human tumor cells elicit enhanced delayed hypersensitivity skin tests without any loss of skin test specificity The augmented immunogenicity of virus-infected tumor cell extracts is evaluated by animal model studies, immunotherapy of human cancer, and immunodiagnosis of human cancer with virus-augmented skin test antigens

Virus Augmentation of The Antigenicity of Tumor Cell

Cells of the transplantable ascites tumour sarcoma 37 (S37) have been infected in vitro with Newcastle disease virus (NDV). Infected cells, a virus-containing fraction of such cells, and X-irradiated S37 cells have been found to immunize mice against subsequent tumour challenge. Anti-lymphocyte serum and anti-theta serum interfered with this immune response. The level of humoral anti-tumour antibody did not correlate with immunity. Preimmunization with homologous virus (NDV) prior to inoculation with a virus-containing tumour cell fraction did not in this system enhance the immune response against tumour challenge. The implications of these findings are discussed. Caution is advocated in applying the results of experiments with such animal tumour virus models to the human clinical situation.

D. A. J. Tyrrell

Papers

Immune responses in mice to tumour challenge after immunization with newcastle disease virus‐infected or X‐irradiated tumour cells or cell fractions