Checkpoint blockade with anti-CTLA-4 monoclonal antibodies has emerged as an exciting new therapeutic modality for patients with metastatic melanoma. At our center, we have participated in 5 clinical trials using ipilimumab, a fully human IgG1 monoclonal antibody developed by Medarex and Bristol-Myers Squibb. Similar studies are being conducted elsewhere, using tremelimumab, an IgG2 developed by Pfizer. Initial studies of both of these agents have shown clinical activity as monotherapy with a unique pattern of controllable immune related adverse events (irAEs). At MSKCC, we have enrolled a significant number of patients on the phase II ipilimumab trials for patients who have not responded to prior therapy. In these studies, we have made some intriguing observations concerning patterns of response and progression, as well as association with immunologic correlates.
In general, patients demonstrate clinical benefit to ipilimumab at a later time point than would be expected for standard cytotoxic chemotherapy. Pooled data from prior phase I and II trials suggest an objective (partial + complete) response rate of approximately 15% at 12 weeks after initiation of therapy. However, a significant number of patients demonstrate long-term stabilization of disease, which can evolve into an objective response after time periods as long as 5 or 6 months. Even more curious is the observation that patients may have radiologic imaging suggestive of overt progression before eventually showing true clinical response many months later. This suggests that a unique set of criteria need to be developed for accurate classification of response to immunotherapy.
We have also noted that several patients treated with ipilimumab have undergone lymphoid reconstitution during anti-CTLA-4 therapy. Prior lymphopenia, which is frequently induced by temozolomide therapy, was corrected with ipilimumab and this immune reconstitution correlated with clinical response. The underlying biology is currently a topic of investigation and we are actively attempting to model this in mice. One hypothesis is that homeostatic proliferation, present in the context of lymphopenia, is accelerated by checkpoint blockade with anti-CTLA-4. Clearly, this has implications for the design of future clinical trials combining cytotoxic therapies with anti-CTLA-4 antibodies.
As part of the clinical trials, investigators within the Ludwig Center at MSKCC have developed a comprehensive immune monitoring plan for patients receiving anti-CTLA-4 therapy. This includes phenotypic characterization of T-cell subsets pre- and post-treatment, antigen-specific immune responses (both serologic and T-cell) and analyses of T-cell repertoire spectratyping.
This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.
- Copyright © 2008 by Jedd D. Wolchok