Abstract
Adoptive T-cell therapy (ACT) has proven to be a highly effective therapy option for melanoma and other immunogenic cancer types, however only a subset of 40% of the patients respond. Due to the intensive and costly regimen, it is important to find predictive biomarkers to identify patients that more likely respond to therapy.Melanoma-associated tissue antigens play an important role in melanoma immunotherapy, as they are expressed in the majority of tumors across different patients and can elicit T-cell recognition. Furthermore, such melanoma-associated T-cell responses may serve as a surrogate marker for T-cell reactivity in general and hence potentially also reflect the level of neoepitope reactivity. Several recent reports point towards the importance of mutation-derived neo-epitopes for cancer immunotherapy, as the mutational and putative neoantigen load correlates with therapeutically benefit of immune checkpoint blockade and ACT. In this study, we analyzed the impact of the number and size of T-cell responses against a library of shared antigens and predicted neoantigens to correlate the number of responses with the outcome of the ACT. We screened expanded tumor-infiltrating lymphocytes (TILs) from stage IV melanoma patients within a phase I/II clinical trial of ACT for CD8+ T-cell reactivity. A library of classical melanoma-associated shared antigens as well as a personalized library of predicted neoantigens for each patient was selected. CD8+ T-cell recognition in the TIL product was investigated by use of a novel technology based on DNA-barcode labeled MHC multimers, enabling high-throughput screening for >1,000 specific T-cell-populations in a single sample. Specific T-cell responses against shared antigens could be found and verified among the TIL samples. The number of CD8+ T-cells responses against tumor-associated shared antigens does not seem to correlate with progression-free or overall survival in this patient cohort, but further screenings have to be conducted. The analysis of neoantigen-reactive CD8+ T-cells within the TILs is ongoing.Identification of predictive biomarkers is an important step towards higher effectiveness of adoptive cell transfer as immunotherapeutic approach and the recognition pattern of melanoma by CD8+ T-cells associated with favorable clinical outcome provides mechanistic insights important for future developments.
Citation Format: Christina Heeke, Anne-Mette Bjerregaard, Amalie Kai Bentzen, Marco Donia, Rikke Andersen, Marie Stentoft Svane, Sine Reker Hadrup. T-cell recognition profiling of CD8+ T-cells in tumor-infiltrating lymphocytes expanded for adoptive cell transfer [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B015.
