Joseph Horvath

Newcastle disease virus (NDV): brief history of its oncolytic strains

BACKGROUND While genetically engineered viruses are now being tested for the virus therapy of human cancers, some naturally occurring viruses display unmatched oncolytic activity. Newcastle disease virus (NDV) excels as an oncolytic agent. OBJECTIVES As its virulence versus attenuation can be explained on molecular biological bases, it may be possible to develop or select highly oncolytic strains of NDV without adverse toxicity. STUDY DESIGN Questions are posed as to the mechanisms of viral oncolysis, the appropriateness of tests to predict oncolytic activity of a given NDV strain and the best modes of administration for oncolytic effects. Answers are provided based on specific data or on considerations drawn from experience (the authors use NDV oncolysates to immunize against melanoma and kidney carcinoma) or from analogous clinical situations (therapeutic use of mumps or measles viruses). RESULTS AND CONCLUSIONS NDV oncolysates probably suit better for immunotherapy (providing also active tumor-specific immunization) than massive repeated inoculations of NDV strains, especially when the NDV strain used is not proven to be oncolytic by appropriate pre-clinical tests.

New Developments in the Virus Therapy of Cancer: A Historical Review

Since the 1920s, viruses had been used for oncolysis. Natural human viral infections can rarely induce remissions of leukemias or lymphomas. Inoculation of tumor-bearing patients with live viruses very seldom resulted in durable complete remissions. Genetically engineered or tumor-adapted virus strains may perform better. Virally modified tumor cell membrane vaccines can induce in the host rejection strength antitumor immunity. Modern technology and much more work is needed before the optimal procedures for viral oncolysis or active antitumor immunization with virally modified tumor cell vaccines are learned and can be implemented in the clinical practice. Laboratory monitoring of the hosts immunological reactions accompanying failure and success of tumor rejection is essential for the recognition and duplication of the successful and for the avoidance of the unsuccessful interventions.

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

Based on personal acquaintances and experience dating back to the early 1950s, the senior author reviews the history of viral therapy of cancer. He points out the difficulties encountered in the treatment of human cancers, as opposed by the highly successful viral therapy of experimentally maintained tumors in laboratory animals, especially that of ascites carcinomas in mice. A detailed account of viral therapy of human tumors with naturally oncolytic viruses follows, emphasizing the first clinical trials with viral oncolysates. The discrepancy between the high success rates, culminating in cures, in the treatment of tumors of laboratory animals, and the moderate results, such as stabilizations of disease, partial responses, very rare complete remissions, and frequent relapses with virally treated human tumors is recognized. The preclinical laboratory testing against established human tumor cell lines that were maintained in tissue cultures for decades, and against human tumors extricated from their natural habitat and grown in xenografts, may not yield valid results predictive of the viral therapy applied against human tumors growing in their natural environment, the human host. Since the recent discovery of the oncosuppressive efficacy of bacteriophages, the colon could be regarded as the battlefield, where incipient tumor cells and bacteriophages vie for dominance. The inner environment of the colon will be the teaching ground providing new knowledge on the value of the anti-tumor efficacy of phage-induced innate anti-tumor immune reactions. Genetically engineered oncolytic viruses are reviewed next. The molecular biology of viral oncolysis is explained in details. Elaborate efforts are presented to elucidate how gene product proteins of oncolytic viruses switch off the oncogenic cascades of cancer cells. The facts strongly support the conclusion that viral therapy of human cancers will remain in the front lines of modern cancer therapeutics. It may be a combination of naturally oncolytic viruses and wild-type viruses rendered oncolytic and harmless by genetic engineering, that will induce complete remissions of human tumors. It may be necessary to co-administer certain chemotherapeutic agents, advanced cancer vaccines, or even immune lymphocytes, and targeted therapeuticals, to ascertain, that remissions induced by the viral agents will remain complete and durable; will co-operate with anti-tumor host immune reactions, and eventually will result in cures of advanced metastatic human cancers.

HUMAN CANCER VACCINES

Immune T cells recognize peptide antigens presented to them within self-MHC molecules. Thus auto-tumor reactive lymphocyte populations can be generated. Antigenic expression can be modified and intensified and reactive lymphocyte populations can be expanded. Active immunization of the tumor-bearing human host can induce immune reactions of tumor rejection strength. Frequently, micrometastases can be eliminated and occasionally partial or complete remissions of gross metastases can be induced.