Pilot studies using melanoma tumor-associated antigens (TAA) in specific-active immunochemotherapy of malignant melanoma

Abstract

Highly purified melanoma TAA which induce melanoma-related cellmediated immune responses have been further characterized using hyperimmune TAA antisera after affinity chromatography for double immunodiffusion-imrnunoelectrophoresis and indirect immunofluorescence studies. An additional study of antigenic modulation was performed in 23 nonanergic and seven anergic melanoma patients, tested simultaneously with melanoma TAA prepared from primary and metastatic tumors, which had been obtained from one patient a t different time periods. The results of pilot clinical trials are reported, including toxicity, timing and dosage studies in 20 patients and subsequent studies of patients with metastatic melanoma treated a t three separate centers, using a single lot of purified, allogeneic melanoma TAA. The results of these latter studies in 51 patients with Stage 111 (distantly metastatic) melanoma and in five patients with earlier stages of disease indicate that: (1) when the interval from primary therapy to recurrence is greater than one year and when liver, bone and brain are not involved, partial or total clinical regression may be noted in up to 25% of patients with metastatic disease receiving immunochemotherapy; (2) when total regression does occur, the effect usually lasts from one to three years; (3) cytoreductive (debulking) surgery, when possible, in cutaneous, nodal retroperitoneal, and visceral regions may enhance the response to specific active immunochemotherapy, although some debulked patients had less tumor burden and this factor alone may lead to an improved prognosis in patients undergoing any subsequent treatment; (4) when circulating inhibitory factors are modified through preimmunization chemotherapy, an enhanced host response may be seen; and (5) Cancer Serum Indices (CSI) may be useful in predicting recurrence and in following tumor load and response to therapy. Information obtained from these studies suggests the need for further trials to determine the effect of immunization on patients with earlier stages of disease where recurrence rates remain high, and to evaluate the mechanisms of tumor rejection or tumor progression in the face of immune stimulation.Cancer 49:1387-1404, 1982.OR several years, we have worked to identify sep-F arated cell membrane components which produce cell-mediated immune reactivrty. We have studied the separated soluble membrane components from malig- nant tissues and counterpart fetal, and benign and normal adult tissues. Our studies differed from those of others in that we started with carefully washed membrane preparations from washed, counted, viable cells for all of our initial work; and we attempted to find antigens appropriate for immunotherapy rather than immunodiagnosis by identifying only those separated components which induce cell-mediated immune responses in vivo and then in vitro.New advancements in technology have permitted us to perform experiments with a view to helping those who are interested in developing diagnostic or monitoring tests for melanoma. S...

Western blot analysis of serological responses following immunization with vaccinia viral lysates of melanoma cells

“…However, several phase-I1 studies of specific forms of immunotherapy have appeared promising. These include immunization with Newcastle-Disease-Virus (NDV)induced Iysates as adjuvant to surgical removal of lymph-node metastases (stage-I1 melanoma) (Cassel et a!., 1983), and a number of different vaccines in patients with stage-I1 (Slingluff et al, 1988;Bystryn et al, 1988;Humphrey et al, 1984) and disseminated disease (Hollinshead et al, 1982;Berd and Mastrangelo, 1988;Mitchell et al, 1988;Morton et al, 1987;Tallberg et al, 1986).…”

A proposal for a simple and inexpensive therapeutic cancer vaccine

“…Finally, and most recently, a series of remarkable trials reported by Hollinshead et al used tumour extracts emulsified in CFA. Phase II trials have been reported for melanoma 28 and for colon cancer 29 , 30 patients. Phase II and III trials have been carried out in lung cancer patients 29 , 31 , 32 , 33 .…”

State of the science 60th anniversary review

“…One of the first and most comprehensive reports was that of Hollinshead et al, who performed a series of studies in a multicenter collaboration. 176 In this report, the authors started by defining tumor-associated antigens from membrane preparations of primary or metastatic melanomas that induced delayed-type hypersensitivity reactions in patients with various stages of disease. They observed a positive reaction in nearly 90% of patients with early-stage melanoma who were disease-free at the time of testing, whereas only 1 of 3 of patients with advanced disease responded.…”

“…They reported a low response rate to chemotherapy and a very high response rate to ''chemoimmunotherapy'' (including a majority of patients who crossed over from the chemotherapy to the chemoimmunotherapy treatment) as well as the presence of inflammatory infiltrates in tumors that were biopsied during regression. 176 Further studies to identify tumor-associated antigens included efforts of the MemorialSloan Kettering group, which extensively investigated the immunogenicity of gangliosides found predominantly on melanoma by using antibodies 177 or ganglioside vaccinations. 178 Gene therapy as a component of immunotherapy for melanoma has appeared in the design of vaccines based on melanoma cells transduced to express a gene that renders them immunogenic, such as interferon-g. 179 Other current approaches to immunotherapy of melanoma are reflected in several recent Cancer publications describing the use of defined-sequence peptide fragments of melanoma antigens with known histocompatibility antigen restrictions, 180 and in some cases chemical modification of the amino acid sequence to enhance peptide binding to class I molecules and/or recognition by the T cell receptor.…”