William A. Cassel

A phase II study on the postsurgical management of stage II malignant melanoma with a Newcastle disease virus oncolysate

A Newcastle disease virus lysate of malignant melanoma cells was examined for its possible value in delaying the progression of malignant melanoma with palpable regional node disease (Stage II) to disseminated melanoma (Stage III). This Phase II study was carried out in a group of 32 patients following therapeutic lymphadenectomy. The patients were not prospectively randomized. In each patient, the viral oncolysate was administered subcutaneously at regular intervals over 3 years. The cumulated progressions to disseminated disease at 1, 2 and 3 years were 6%, 8% and 12% of the study group, respectively. These experienced losses were considerably lower than in the control group and in similar control groups described by other investigators. The results suggest that an oncolysate prepared with Newcastle disease virus is a helpful adjunct to surgery in the management of Stage II malignant melanoma.

A ten-year follow-up on stage II Malignant Melanoma patients treated postsurgically with newcastle disease virus oncolysate

Newcastle disease virus oncolysate was examined as an adjunctive immunotherapeutic agent in the postsurgical management of 83 cases of Stage II malignant melanoma. At this time, all the patients have been under observation for at least 10 years, and over 60% are alive and free of recurrent disease. Older studies in the United States report postsurgical survival figures for Stage II cases of 5-15%. More contemporary studies indicate a 33% survival at 10 years. The unusual disease-free survival periods in the present study, including exceptional survivals in 21 patients with head and neck disease and six cases with cerebral metastases, suggest a unique role for the administration of Newcastle disease virus oncolysate in the management of Stage II malignant melanoma patients.

VIRAL ONCOLYSATE IN THE MANAGEMENT OF MALIGNANT MELANOMA I. Preparation of the Oncolysate and Measurement of Immunologic Responses

Primary explants of human malignant melanoma were utilized in the preparation of oncolysates by Newcastle disease virus. The concentrated lysate, administered parenterally, was employed in an effort to augment antitumor immunologic responses in patients with metastatic melanoma. Observed cellular changes suggested a benefit, but humoral antibody measurements were not impressive. Cancer 40:672–679, 1977.

Malignant melanoma. Inflammatory mononuclear cell infiltrates in cerebral metastases during concurrent therapy with viral oncolysate.

Five patients with advanced malignant melanomatreated with viral oncolysatehad solitary central nervous system metastases that were removed surgically. Histologic examination revealed striking and significant mononuclear inflammatory cell infiltratesconsisting of a mean of 60% plasma cells and a lesser proportion of lymphocytes at the edges of the lesionswithin their supporting fibrovascular trabeculaeand among the tumor cells. Comparable inflammatory changes were not found in solitary metastatic malignant melanomas removed surgically from the brains of 19 patients not treated with viral oncolysate. Similarlymultiple metastatic malignant melanomas obtained postmortem from the brains of 12 patients not treated with viral oncolysate showed minimal inflammatory responses. Ultrastructural examination of material from a single treated patient revealed morphologic abnormalities of the blood–brain barrierchanges that were perhaps conducive to infiltration of the neoplasm by inflammatory cells. The authors suggest that administration of viral oncolysate enhances the inflammatory cell response to metastatic malignant melanoma in the brain.

Relationship between viral neurotropism and oncolysis. I. Study of vaccinia virus

Several strains of vaccinia virus were examined in a study of the relationship of viral oncolysis to viral neurotropism. Various animal hosts were challenged intracerebrally with the L strain of vaccinia virus but the virus multiplied only in the brain of one-day-old mice. After 238 passages in mouse brain the virus finally acquired the ability to multiply in the Ehrlich ascites tumor of the mouse and to cause oncolysis. The NEL and LEV vaccinia virus strains initially showed a moderate degree of neurotropism but did not become oncolytic until they were fully adapted to nervous tissue. These results support the concept of a distinct correlation between viral neurotropism and oncolysis and suggest an undetermined similarity between neoplastic and nervous tissues. The findings are significant in considering the application of viruses to human cancers.

Light and Electron Microscopic Studies of the Pathogenesis of Vaccinia Virus Infection in Mouse Brain

Abstract Vaccinia virus replication in weanling mouse brains was examined by light and electron microscopy 2 to 5 days after inoculation, i.e., during the period of maximal viral infectivity. Replication sites were detected in meningeal cells, adventitial cells of meningeal arterioles, and small nonneuronal cells of the brain. No evidence was found for replication in neurons, although these cells were altered indirectly. The virus can be described most accurately as being leptomeningoencephalitic.

A comparison of vaccinia virus multiplication and hemagglutinin loss in hyperdiploid and hypotetraploid Ehrlich ascites tumors.

Abstract Hyperdiploid (2X) and hypotetraploid (4X) lines of the Ehrlich ascites tumor both developed an inhibitor of vaccinia virus hemagglutinin. During tumor growth, the inhibitor emerged at higher levels in the 4X tumor than in the 2X tumor. Serial passage of vaccinia virus in these tumors is associated with an eventual loss of hemagglutinin, but this requires twice the number of passages in the 4X tumor as in the 2X. This would not have been anticipated in view of the higher inhibitor content of the 4X tumor. To investigate the observed result, virus multiplication studies were carried out in the two tumors, and it was established that vaccinia virus multiplies to a lesser degree in the 4X tumor than in the 2X. This would appear to be at least part of the explanation for the slower selection of a hemagglutinin-negative virus in the 4X tumor.

A further study of hemagglutinin loss by vaccinia virus.

Summary The present study strengthens the evidence for the role of a hemagglutinin inhibitor in the loss of hemagglutinin by vaccinia virus, and answers a criticism of a previous study. It has also been demonstrated that on serial passage in the Ehrlich ascites tumor loss of hemagglutinin is not limited to the IHD strain of vaccinia virus, but occurs also with the Nelson and Levaditi strains.

Chapter 16 Long-Term Preservation of the Ehrlich Ascites Tumor

Publisher Summary Ascites tumors, particularly of mice, have been employed in a remarkably wide variety of research endeavors, and a major symposium attests to their usefulness. Prominent among these tumors is the Ehrlich ascites tumor of the mouse, which has become to mammalian cell research that Escherichia coli is to microbiology. Associated with its extensive use is a need for availability, in a preserved state. Soon after cell preservation techniques began to be developed, it was concluded that a cooling rate of 1°C per minute is best and that a temperature below - 130°C is indicated for long-term storage. Implicit in this is the requirement for elaborate cryophilic equipment. This chapter presents a simple method, within the reach of most laboratories, by which the Ehrlich ascites tumor can be preserved in a frozen state for many years.

An hypothesis for the mechanism by which an hemagglutinin inhibitor affects vaccinia virus.

Summary A study was made of the loss of hemagglutinin by vaccinia virus under the influence of an hemagglutinin inhibitor originating from a mouse ascites tumor. It was found that the inhibitor reacted with the hemagglutinin by forming a dissociable complex. In examining the possible mechanisms by which stable, hemagglutinin-negative virus is formed, it was noted that the inhibitor exhibited no neutralizing action against hemagglutinin-positive virus, that hemagglutinin negative virus could not be found in cloned populations of hemagglutinin-positive virus, and that there was no obvious growth advantage shown by the hemagglutinin-negative virus in the presence of inhibitor. For these and other reasons the hypothesis is presented that the inhibitor facilitates the emergence of stable, hemagglutinin-negative virus by complexing with and gradually eliminating the hemagglutinin, which might be necesary as a template for the formation of more hemagglutinin.