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Studies of T cell-mediated immune response against spontaneously arising autologous human tumors have been markedly facilitated by functional analyses of T cells at the clonal level (1-7). This particular approach has now provided a strong support for the long-held belief by some, although viewed skeptically by others, that T cell-mediated host responses do indeed exist in different types ofhuman cancers. The evidence for such T cell antitumor response has been particularly impressive in malignant melanoma (1-4, 6, 7). In this system, the existence of CTL response (1-4, 6, 7), proliferative T cell response (8, 9), suggestion for regulatory T cell response (10, 11), and delayed-type hypersensitivity response (12) have all been demonstrated. While this impressive body of evidence certainly represents a serious beginning in investigation on T cell responses against autologous cancer, a critical analysis ofT cell-immune responses against a large number ofautologous melanoma at clonal levels is necessary for a more comprehensive understanding of T cell-immune response in host defense against human cancers or, for that matter, against malignant melanoma .We have undertaken clonal analyses of T cell-immune response in a larger group of patients with melanoma . In this work, we present our observation of clonal analyses of CTL and regulatory responses in 31 autologous case studies. Here we show that T cell responses (CTL as well as regulatory T cell responses), taken together, are demonstrable in approximately half of this cohort of subjects. Results of our studies clearly document the involvement of the entire T cell repertoire in response to autologous melanoma . The melanoma-specific (CTL) responses show appropriate MHC class restriction, and the cytotoxic response in the PBL is subject to regulation by the helper and suppressor arms of the T cell network. The amplification of cytotoxic response by Th cell clones is mediated by the elaboration of IL-2 and IFN-y, and the T cell-mediated downregulatory responses can be specific as well as nonspecific.

Background. In a Phase II trial, surgical adjuvant active specific immunotherapy using a live vaccinia virus‐augmented allogeneic polyvalent melanoma cell lysate, vaccinia melanoma oncolysate (VMO), produced a significant disease free interval (DFI) in patients with International Union Against Cancer Stage II melanoma with positive lymph nodes. Therefore, a Phase III randomized prospective, double‐blind, multiinstitutional, surgical adjuvant VMO trial was performed to determine the efficacy of VMO to increase the DFI and the overall survival in this group of patients with Stage II disease. Methods. Two hundred and fifty patients with Stage II melanoma were divided into two postsurgical groups. One group received VMO (total protein equals 2 mg/ml) and the other received the placebo of live vaccinia vaccine virus (V) (105.4 TCID50/ml), an adjuvant component of the VMO. Patients initially received these biologies once a week for 13 weeks and then once every 2 weeks for an additional 39 weeks or until recurrence. All surviving patients have been followed for at least 30 months. Results. Statistical analysis of survival data (n = 217) for this first interim analysis shows that there is no statistically significant (P = 0.99) increase in DFI of patients treated with VMO (n = 104) when compared with V (n = 113). The median DFI is 38.0 months for patients treated with VMO and 37.0 months for patients treated with V. At 2‐ and 4‐year intervals, 70 and 38%, respectively, of patients treated with VMO vs. 66 and 36%, respectively, of patients treated with V were free of melanoma. The median overall survival is not available because the pa‐tients treated with VMO have not yet reached the 50% mark and the median overall survival is 45.0 months for patients treated with V. At 2‐ and 4‐year intervals, 70 and 38%, respectively, of VMO‐treated patients survived when compared with 66 and 36%, respectively, of pa‐tients treated with V. Although the overall survival of pa‐tients treated with VMO is not statistically significant (P = 0.88) at this point, there is an increasing trend in the overall survival of patients treated with VMO; a 10% increase at the 4‐year time point. Moreover, in the subset analysis, VMO‐treated male patients (n = 63) showed a 17% improvement in survival at 4‐year time point when compared with male patients treated with V (n = 67) (P = 0.19) at the same time point and male patients (n = 20) between the ages of 44 and 57 having 1‐5 positive lymph nodes showed a 37% difference in overall survival at the 4‐year time point when compared with those patients treated with V (n = 18) (P = 0.13) at the same time point. Conclusion. In this first interim analysis, active specific immunotherapy with VMO vs. V showed no difference in the disease free interval or overall survival. Subset analyses likewise showed no significant differences in outcome but the data suggest a potential difference in immunoreactivity between male and female patients with melanoma that awaits further follow up and may merit further inve...

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T cells (derived from peripheral blood lymphocytes [PBL], lymph nodes or tumor tissues and restimulated with autologous tumor cells and expanded in interleukin-2 [IL-2]), when cloned, produce three functional classes of clone. Class I T-cell clones exhibit the phenotype of alpha/beta cytotoxic T lymphocytes (CD3+, CD8+, CD4-, WT31+), use their CD3-alpha/beta complexes for cognate function, and lyse the autologous tumor cells specifically in a major histocompatibility complex (MHC) Class I-restricted manner. The second class of T cell clone expresses identical phenotype but exhibits a rather broad cytotoxic profile against the autologous and allogeneic tumor cells derived from tumors with similar and/or dissimilar histologies. Although these CTL clones can, at times, show MHC Class I-restricted killing and use their T-cell receptors (TCR) complexes for function, activation via certain accessory molecules, particularly lymphocyte-function associated (LFA-1) antigens, might induce their broad cytotoxic behavior. The nature of the tumor antigen recognized by the Class I antigen-specific CTL clones remains unknown. It is evident, however, that more than one antigen can be associated with a given tumor and they are recognized by different CTL clones from individual patients. The third class of T-cell clone is usually of CD4+ alpha/beta T cells (CD3+, CD4+, CD8-, WT31) and these T-cell clones exhibit no cytotoxicity toward the autologous or allogeneic target cells. When tested for potential regulatory property, one type of CD4+ T-cell clone exhibits the characteristics of helper T cells. This type induces or amplifies cytotoxic response in fresh PBL by elaborating interleukin-2 (IL-2) and interferon-gamma). These helper T-cell clones can proliferate against the autologous tumor cells and demonstrate functional specificity for the autologous tumor cells. The other type of CD4+ T-cell clone exhibits the phenotype of the helper T-cell clone (CD3+, CD4+, CD8-, WT31+) but suppresses the cytotoxic response of the autologous PBL in co-culture in the presence of the autologous tumor cells and exogenous IL-2. In some situations, these CD4+ suppressor T-cell clones exhibit considerable specificity for the autologous tumor cells. They do not suppress the cytotoxic response against allogeneic targets or against EBV-infected autologous lymphoblastoid cells. Furthermore, they specifically up-regulate their IL-2 receptors (IL-2R) when stimulated by the autologous tumor cells or with autologous tumor cell-pulsed antigen-presenting cells.(ABSTRACT TRUNCATED AT 400 WORDS)

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