Current adoptive immunotherapy (AIT) requires cumbersome cell culture to generate adequate numbers of lymphocytes. The applicant has described a novel technique, namely stimulation of lymphocytes with bryostatin 1 and a calcium ionophore (B/1), which leads to the rapid expansion of tumor-sensitized T cells that have therapeutic activity in vivo. This has been translated to a Phase I clinical trial. To determine whether pharmacologic activation of T lymphocytes can be used to amplify weak immune responses and induce regression of weakly immunogenic tumors, without the need for prolonged cell culture, the applicant will determine: a) whether T cells activated only briefly in vitro with B/I mediate regression of very weakly immunogenic 4T1 mammary tumors; b) whether the anti-tumor effects of cytokines are involved in the anti-tumor effects of these drugs; c) whether Bryo, AS101, and/or IL-2 augment each other's anti-tumor effects; d) whether Bryo and AS101 augment the effect of gene-modified vaccines to induce protective immunity; and e) whether this approach can cause regression of established tumors. To understand the mechanisms underlying the efficacy of Bryo-activated T cells, the applicant will determine whether B/I selectively activates memory T cells, perhaps as a result of different patterns of protein kinase C expression and/or activation, and whether activation of DLN cells will preferentially expand certain TcR families compared to the starting population. To determine whether B/I-activated T lymphocytes from DLN of patients with breast cancer respond to a relevant tumor antigen, the applicant will test the following hypotheses: a) B/I-activated T cells from breast cancer patients respond to HER-2/neu-derived epitopes presented by HLA-A2; b) DLN cells are more likely to manifest responses to HER-2/neu than are peripheral blood lymphocytes from the same patients; c) T cell reactivity to HER-2/neu will be less likely or weaker in patients with metastases to the lymph nodes; and d) the responses of breast cancer patients' T cells to HER-2/neu are related to over-expression of HER-2/neu by their tumor cells.
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