Several phase I and II clinical trials have demonstrated an association between antibody induction in vaccinated cancer patients and clinical response (enhanced survival, tumor shrinkage) (Table 1). Sialyl-Tn-KLH vaccine induced IgG and IgM antibodies to the antigen in all vaccinated breast cancer patients, and antibody induction was associated with patients' survival (51). Anti-idiotypic antibodies binding to the antigen-combining site of antitumor antibodies may mimic tumor antigen. Anti-idiotypic antibody vaccine mimicking the high-molecular-weight melanoma-associated antigen (HMW-MAA) elicited anti-anti-idiotypic antibodies (Ab3; antibodies binding to anti-idiotype or Ab2) in melanoma patients, and the Ab3 responses were associated with patients' survival (52). However, in neither of the two studies were the antibodies shown to be associated with clinical responses demonstrated to bind to tumor cell-surface determinants, and, therefore, the role of these antibodies in the development of the clinical responses remains unclear. Both antibody and DTH responses induced by polyvalent melanoma cell vaccine in melanoma patients were associated with patients' survival (12). The antibodies were shown to bind to melanoma cell surfaces and may have destroyed these cells by ADCC or complement-dependent cytotoxicity (CDC) mechanisms, although this has not been directly demonstrated. In non-Hodgkin's lymphoma patients, antibody responses to idiotype protein induced by dendritic cells pulsed with keyhole limpet hemocyanin (KLH)-coupled idiotype were associated with clinical responses (53). An anti-idiotype vaccine trial in ovarian carcinoma patients has demonstrated an association between Ab3 response and survival of the vaccinated patients (54). The Ab3 mediated ADCC against antigen-positive ovarian carcinoma cells and may be related to the beneficial clinical responses observed in the vaccinated patients.
It needs to be emphasized that most of the studies described above, with few exceptions (7,12,52,55), have shown associations, but not statistically significant correlations, between humoral immune responses and beneficial clinical responses in vaccinated cancer patients. In the clinical trials conducted by Morton and colleagues in melanoma patients (7,12,55), immune responses to allogeneic tumor cell vaccine were significantly (p < 0.05) correlated with patients' survival. Similarly, a statistically significant (p < 0.0001) correlation between anti-HMW-MAA antibodies and survival has been demonstrated in melanoma patients vaccinated with anti-idiotype (52).
Table 1 also summarizes the clinical trials that have demonstrated associations between vaccine-induced cell-mediated immunity and beneficial clinical responses. Thus, induction of CTL responses by the vaccines was associated with beneficial clinical responses in patients with CRC, melanoma, and non-Hodgkin's lymphoma (5-7,9,10), and induction of DTH and proliferative lymphocyte responses was associated with clinical outcome in patients with melanoma, non-Hodgkin's lymphoma, and prostate carcinoma (2,4,7,8,11-14,55). The correlations between cellular immune responses and clinical immune responses were statistically significant in a few studies. Thus, CRC patients vaccinated with peptide-loaded dendritic cells demonstrated a significant (p = 0.002) correlation between CD8+ tetramer+ T-cell responses and tumor regression (5). A statistically significant correlation (p < 0.05) between DTH responses and survival was demonstrated in melanoma patients vaccinated with allogeneic tumor cells (8) or autologous, hapten-modified tumor cells (13).
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