Abstract LB-223: ATLASTMreveals a dominant inhibitory antigen in melanoma patients, and a reduced breadth of tumor-associated antigen-specific T cells in non-responders to checkpoint blockade

Broadly reinvigorating the T cell response by blocking immune-inhibitory receptors can produce durable clinical benefit in 20-40% of melanoma patients. Due to low response rates and potential toxicity of checkpoint therapy, identification of biomarkers to predict response to immune checkpoint inhibitors (ICIs) has the potential to stratify patients and increase the efficacy of ICI therapy in treated patients. However, to date, the significant effort to identify biomarkers has yielded unreliable predictors. To better understand ICI response and resistance, we profiled T cell responses to a panel of known tumor-associated antigens (TAAs). The ex vivo ATLAS™ technology enables comprehensive profiling of a patient’s antigen-specific T cells, with putative antigens expressed as individual clones, processed by the subject’s own antigen presenting cells and presented to autologous CD4+ or CD8+ T cells for measurement of recall responses. A unique feature of ATLAS is the ability to identify stimulatory and inhibitory T cell responses based on cytokine secretion that statistically exceeds or is reduced, respectively, relative to baseline controls. Pre- and post-treatment CD4+ and CD8+ T cell responses to a library of 56 known TAAs were profiled from 16 patients with metastatic melanoma undergoing ICI therapy. Consistent with previous studies, a low frequency of responses was observed from both T cell subsets. Overall, there were fewer responses detected in non-responders than in responders both pre- and post-treatment; in fact, no stimulatory CD8+ T cell responses were identified in non-responders prior to ICI therapy. Surprisingly, one TAA elicited only inhibitory responses across most subjects, independently of clinical outcome and predominantly from the CD8+ T cell subset. Hierarchical clustering showed that patient responses are similar to themselves across visits, but the antigen profiles across patients did not cluster by visit or treatment response. ATLAS provides a powerful, non-invasive, blood-based platform for the interrogation of peripheral T cell responses. Our data show that melanoma patients who are non-responsive to ICI therapy have a limited T cell response to TAAs. In addition, one TAA elicited a dominant inhibitory response across patients. Upon further refinement, patient-specific responses may allow for prediction of advanced melanoma patients for whom checkpoint therapy would prove successful. Citation Format: Louisa Dowal, Anna Lyubetskaya, Crystal Cabral, Mariya Croll, Christopher Warren, James Perry, Melissa Hayes, James Loizeaux, James Foti, Jessica B. Flechtner, Jason R. Dobson, F. Stephen Hodi, Wendy Broom. ATLASTMreveals a dominant inhibitory antigen in melanoma patients, and a reduced breadth of tumor-associated antigen-specific T cells in non-responders to checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-223.