B7 1 GENE MODIFIED TUMOR CELL VACCINE FOR RENAL CELL CA

University Of South Florida, Tampa FL

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Linked publications & trials

Abstract

There has been increasing interest in recent years in developing immunologic approaches to malignancies, and there is good evidence that the growth of renal cell carcinoma (RCC) can be modulated by the host's immune system. In fact the use of the immunomodulatory cytokine interleukin-2 (IL-2) is approved treatment for this disease. The efficacy of this approach remains low, and there is no other reasonable conventional therapy for patients with metastatic RCC. Therefore there is a need to develop novel treatment strategies. The development of autologous tumor cell vaccines, genetically modified to render them more immunogenic is one approach. One such genetic manipulation that is being studied by several groups is to everexpress B7-1 to provide costimulation to tumor-reactive T cells. The rationale for this is that in order to mount a cytotoxic response, T cells need two signals: the binding of the T cell receptor (TCR) to an antigenic peptide presented on MHC, and the binding of CD28 to B7-1. Since B7-1 is not normally expressed by RCC cells, the forced expression by transfection of an exogenous B7-1 gene could make the tumor cells more immunogenic. We recently completed accrual to a Phase I clinical trial where patients are being treated with autologous tumor cells modified to express B7-1 which functions as a tumor vaccine. Primary tumors or metastases were resected from patients with stage IV RCC. The tumor cells were adapted to in vitro culture; infected with a recombinant adenoviral vector containing the human B7-1 cDNA driven by the CMV promoter; radiated; and stored in liquid nitrogen. Aliquots of the B7-1 gene-modified tumor cells are being administered to the patients as a vaccine at varying intervals according to a dose escalation scheme. The patients also receive systemic IL-2 for the dual purpose of providing accepted therapy for this disease as well as expanding the tumor- reactive T cells activated by the vaccine. The immunogenicity and toxicity of the vaccine are in the process of being assessed in 12 patients. The Phase I trial will be completed with all of the data collected and analyzed in four months (January 2000). Once completed, we propose to conduct a Phase II trial involving 30 patients using this same approach. The primary objectives will be to determine tumor response rates. The immunogenicity of the treatment will be assessed by ELISPOT assays performed on the patients' peripheral blood lymphocytes and by immunohistochemical analysis of DTH skin test biopsies performed 48 hours after the intradermal injection of autologous, unmodified tumor cells.