PHASE I STUDY--ADOPTIVE CELLULAR THERAPY WITH BRYOSTATIN

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A major obstacle to the development of successful adoptive cellular therapy for the treatment of human cancer has been the inability to expand specific tumor-reactive immune cells to therapeutic numbers within a relevant time frame. Lymphokine activate killer cells can be generated from peripheral blood mononuclear cells in sufficient numbers in a matter of days, but these are not specifically sensitized to a patient's patients's tumor and have not been shown to enhance the activity of high dose interleukin-2 with which they are routinely coadministered. Tumor infiltrating T lymphocytes can be shown to be specifically tumor sensitized, but these are only available in limited number. Previous efforts to activate and expand tumor-sensitized T lymhocytes have involved either in vitro stimulation with autologous tumor or antigen mimicry, for example, with anti-CD3 monoclonal antibodies, and results to date have been unsatisfactory. The hypothesis which underlies this application is that T lymphocytes previously sensitized to tumor by virtue of residence in tumor-draining lymph nodes can be activated an expanded in vitro via pharmacological activation of the signal transduction pathway that is normally triggered by antigen binding to the T cell receptor. In a series of preclinical studies, we have demonstrated that this can be accomplished through the use of the protein kinase C activator, bryostatin 1, a calcium ionophore, and low dose interleukin-2. Adoptive cellular transfer of these activated and expanded draining lymph node lymphocytes in conjunction with systemic interleukin=-2 can cure established animal tumors and confer long-lasting, tumor-specific immunity. We propose a phase I study to demonstrate the clinical feasibility, safety, and toxicity of this approach. Beyond setting the stage for subsequent phase II investigations, this study potentially will have broad implications for emerging approaches to adoptive cellular therapy in which antigenically defined T cell populations available in small numbers are targeted as therapeutic agents.