Abstract SY32-02: Update on clinical results and correlative immunologic analysis of ipilimumab in patients with melanoma
Authors: Wolchok Jedd D. 
Published: August 2012

Abstract
Immunotherapy for cancer has moved into a more mainstream role given the recent approval of the CTLA-4 blocking antibody ipilimumab for treatment of metastatic melanoma. Results of two large randomized trials have shown that immunologic checkpoint blockade mediate durable disease control in a subset of patients with melanoma, leading to improvement in overall survival. Observations of heterogeneous response kinetics have necessitated the development of proposed revisions in standard imaging response criteria which incorporate the biologic of the host response into such assessments. A unique pattern of mechanism-based immune related adverse events is observed in patients receiving ipilimumab and these toxicities are generally manageable with immunosuppressive medications. Intriguingly, the anti-tumor effect of ipilimumab does not seem to be dampened with the use of corticosteroids and other immune suppressing medications, suggesting that toxicities can be uncoupled from response.
Given that only a subset of melanoma patients benefits from ipilimumab, much attention has been paid to investigation of predictive and pharmacodynamic biomarkers of response and toxicity. As of now, changes in absolute lymphocyte count over time appears to be a reasonable and mechanism-associated pharmacodynamic marker while pre-existing immunity to the NY-ESO-1 cancer testis antigen has some predictive value. Patients with baseline antibody responses to NY-ESO-1 have approximately twice the likelihood of experiencing disease control at 24 weeks compared to patients who are seronegative, implying that a patient whose immune system has been trying, albeit unsuccessfully to mount an immune response to a tumor, may be more likely to respond. Patients who mount a CD8+ T cell response to this representative antigen during ipilimumab therapy have an even higher likelihood of benefit. This fits well in the context of tumor expression data suggesting that presence of FoxP3+ cells and IDO+ cells at the tumor site, indicative of regulated inflammation, are associated with higher chance of clinical benefit. Analysis of bladder tumor specimens after CTLA-4 blockade revealed that a population of ICOShi CD4+ T cells is induced, which has the capacity for IFN gamma secretion in the context of cognate antigen. A similar induction of ICOS on CD4+ T cells in the peripheral blood has been observed in a large cohort of melanoma patients and persistent elevation of ICOS expression has been correlated with clinical outcome. Biomarkers for toxicity are also under active investigation and elevated levels of serum IL-17 are temporally associated with symptomatic enterocolitis. Studies are underway to determine the role of the microbiome in the development of both clinical response as well as toxicity, especially in the gut.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY32-02. doi:1538-7445.AM2012-SY32-02