In Response: We wish to thank Drs. Schultes, Smith, and Nicodemus for their questions about our characterization of oregovomab as passive immunotherapy, the potential interference of human anti-mouse antibody (HAMA) in the Luminex assay used in our studies, and clarification on the induction of CA125-specific B- and T-cell responses (1).
(a) We agree that published studies indicate that oregovomab is capable of inducing CA125-specific immune responses via the idiotypic network and cross-presentation (2, 3). We were attempting to provide contrasts between passive immunity provided by traditional antibody approaches and those capable of provoking antigen-specific CTL and T-helper cell responses as well as antibodies. They correctly state that both oregovomab and abagovomab should be considered in the latter group.
(b) Regarding the possible influence of HAMA on the antihuman cytokine Luminex beads, there is no direct experimental evidence either way. In our study, we found that samples with high HAMA and low HAMA gave the same order of increase in IFN-γ, suggesting that the cytokine data are unlikely to be due to HAMA artifact.
(c) We agree with our colleagues that Ab3 responses should not be equated with anti-CA125 antibody induction. As they have noted with oregovomab, other studies of abagovomab have reported that a significant proportion of Ab3 antibodies do not bind to the original antigen. Ab1′ antibodies (CA125 specific) were found in only 54% of patients in the study by Pfisterer et al. (4) and in 50.4% of patients in the prior study by Reinertz et al. (5). Interestingly, in the latter study, the association between immune variables and survival showed a consistent survival advantage of the Ab3 responder over the nonresponder, suggesting that the Ab3 response could be considered as a surrogate for clinical vaccine “activity.” In fact, patients with a positive HAMA, Ab1′, or antibody-dependent cell cytotoxic response all had a longer median overall survival when compared with those nonresponders in each group. Whereas further analysis of the antibody response and its specificity is important in learning to optimize this vaccine approach, we opted to consider the Ab3 titer as the primary immune study end point with the intention of proceeding to a phase III trial if the construct was immunogenic based on Ab3 titers coupled with an acceptable safety profile. In our study, we showed Ab1′ activity in 3 of 30 patients with posttreatment samples available for testing.
(d) We agree that it would be informative if the responses were shown separately for ACA125- (antibody) and CA125- (antigen) specific components of our in vitro stimulation assay. However, we only carried out in vitro stimulation in the presence of sequentially added ACA125 and CA125. We did not dissect out the specific components responsible for our observations. This experimental design was based on the notion that both ACA125 and CA125 are likely to be circulating in the ovarian tumor–bearing host, and the results would more likely reflect the in vivo responses to abagovomab.
Our colleagues have recently completed randomization of an additional phase III front-line remission ovarian cancer trial with oregovomab using the characteristics of the successful front-line subgroup in their initial phase III study (6). These results, in conjunction with those of the ongoing phase III front-line abagovomab study, will hopefully provide benefits to patients with ovarian cancer in remission and will, in any case, provide insights as we plan future strategies targeting the CA125 antigen.
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