A randomized phase II trial comparing two different sequence combinations of autologous vaccine and human recombinant interferon gamma and human recombinant interferon alpha 2b therapy in patients with metastatic renal cell carcinoma: Clinical outcome and analysis of immunological parameters

Purpose: The clinical observation of spontaneous regression in patients wit h renal cell carcinoma (RCC) and the response to various immunotherapeutic therapies strongly suggest a role for the host immune system in this diseas e. Prior studies showed that sequential administration of interferon (IFN) gamma and IFN alpha to RCC patients was safe. Clinical responses as well as immune changes in the peripheral blood mononuclear cell compartment were o bserved. Autologous tumor cell vaccines (AV) have also demonstrated activit y in renal cell carcinoma. We hypothesize that the addition of AV to sequen tial IFN gamma and alpha therapy might improve the tumor-specific immune re sponse by providing an appropriate source of antigen in the appropriate cyt okine environment. To our knowledge, this is the first trial using AV combi ned with IFN alpha and IFN gamma. The purpose of this study was to evaluate the feasibility of manufacturing and administering (AV) from resected tumo r samples, and administration of AV with combination IFN gamma and IFN alph a therapy. Finally, the impact on immunological parameters of these treatme nt options was assessed. Materials and Methods: Patients with metastatic RCC were randomly assigned to receive AV plus bCG along with a sequential administration of IFN gamma and alpha either together or after initiation of vaccine. Toxicity and clin ical responses were evaluated. Modulations of the immune system were invest igated by analyzing phenotype, cytokine mRNA expression, T cell proliferati on and cytotoxicity in the peripheral blood mononuclear cell compartment. Results: Fourteen patients with metastatic renal cell carcinoma were enroll ed in this study; 9 were available for response evaluation. In a 70 day per iod, 3 (33%) showed mixed responses, 5 (56%) stable disease and 1 (11%) pro gression of disease. Toxicities were consistent with previous clinical repo rts. In the flow-cytometry phenotype analysis, stimulation of distinct subs ets of circulating T-lymphocytes and a decrease of CD8+ T cell subsets was demonstrated. T-cell proliferation to allogeneic tumor cell stimulation imp roved following treatment. IL-4 and IL-5 mRNA levels were reduced in all pa tients after treatment. Patients who responded to treatment did not produce any IL-4 mRNA at all, before or after treatment. Conclusions: AV with IFN gamma and IFN alpha therapy might induce a MHC cla ss-mediated cytotoxic T lymphocyte (CTL) response. We suggest that adequate therapy might direct T cell response toward a Th1 type response. We hypoth esize a state of improved immune readiness in patients who might eventually respond to immunotherapy.