We have developed a novel approach to immunotherapy of human cancer: autologous tumor cells modified with the hapten, dinitrophenyl (DNP). Administration of DNP-vaccine to patients with metastatic melanoma induces a unique response - the development of inflammation in metastatic masses. Histologically, this response is characterized by infiltration of activated T cells that are predominantly CD8+. Moreover, molecular analysis of the T cell receptor (TCR) structures within metastases indicates that the T cell infiltration consists, at least in part, of novel T cell clones not found in pre-treatment metastases. Occasionally, administration of DNP-vaccine results in regression of established metastases; small lung metastases are most likely to respond. Moreover, administration of DNP-vaccine to melanoma patients with bulky regional node metastases following lymphadenectomy results in a remarkably high relapse-free (about 45 percent) and overall (about 58 percent) survival at five years. Now we propose to extend the work in the following directions: 1)Determine whether comparable immunological and clinical results can be obtain with a second tumor type - adenocarcinoma of the ovary. Preliminary experiments suggest that patients with stage III ovarian cancer develop delayed-type hypersensitivity (DTH) to autologous tumor cells following administration of DNP-vaccine. We will expand these studies to determine whether the positive immunological response is associated with tumor regression and/or prolonged survival. 2)Determine whether modification with a second hapten, sulfanilic acid, further augments the immunogenicity of melanoma cells. The use of a second hapten, one that modifies peptide residues that are different from those modified by DNP, is based on extensive animal data. We will test the immunogenicity of tumor cells modified with sulfanilic acid and with a combination of DNP and sulfanilic acid. 3)Determine whether haptenized cell membranes can substitute for intact melanoma cells as test materials and immunogen. The substitution of haptenized cell membranes for intact cells has theoretical and practical advantages. We will prepare cell membranes from hapten-modified tumor cells and test their ability to elicit DTH and to immunize patients against intact cells. 4)Characterize the T cell repertoire of lymphocytes infiltrating metastases following hapten-modified vaccine. We will build on the data obtained during the last grant period showing that the lymphocytic infiltration induced by the vaccine represents clonal T cell expansion. Using established molecular techniques, we will characterize the TCR structures found in inflamed and/or regressing metastases. This work may lead to the development of reagents useful in identifying the target antigens.
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