Abstract A14: Neoepitope-specific CD8+ T cells in adoptive T-cell transfer

Abstract

Adoptive T-cell therapy (ACT) relies on expansion of tumor-infiltrating lymphocytes and infusion into patients following lymphodepletion, which have yielded complete responders in up to 25% of treated patients suffering from metastatic melanoma. However, a large proportion of patients have no clinical benefit (50-60%). Previous studies have found that clinical outcome correlates with tumor mutational and putative neoantigen load. Furthermore, expression of core antigen-presentation pathways including MHC class I genes in tumors correlates with clinical benefit. Based on these findings, we hypothesize that the presence of neoepitope-specific CD8+ T cells within the infusion product of ACT is a key determinant of clinical benefit. We apply in silico prediction of neoepitopes along with DNA-barcoded dextran multimer libraries to screen for personal neoepitope-specific CD8+ T cells. We show persistence of neoepitope-specific CD8+ T cells within patient peripheral blood for up to 24 months after therapy. Furthermore, we show an almost complete lack of neoepitope-specific CD8+ T cells within the infusion products of patients with progressive disease. However, patients with stable disease and long-term responses only have a modest increase in the number of targeted neoepitopes, as wells as the total frequency of neoepitope-specific CD8+ T cells. For future experimentation, we therefore aim to include more patients as well as study the phenotypical differences within the pool neoepitope-specific CD8+ T cells, the ultimate goal being a better understanding of what parameters from neoepitope-specific CD8+ T cells correlate with clinical efficacy of ACT. Citation Format: Nikolaj Pagh Kristensen, Christina Heeke, Siri A. Tvingsholm, Anne-Mette Bjerregaard, Arianna Draghi, Amalie Kai Bentzen, Rikke Andersen, Marco Donia, Inge Marie Svane, Sine Reker Hadrup. Neoepitope-specific CD8+ T cells in adoptive T-cell transfer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A14.

Mechanisms of Immunosuppressive Tumor Evasion: Focus on Acute Lymphoblastic Leukemia

“…ACT aims to generate a robust immune-mediated antitumor response via infusion of ex vivo -manipulated T cells. Studies have suggested that clinical outcomes correlate with tumor mutational and neoantigen load ( 217 – 219 ). Although ALL has been described as a malignancy with low mutational load, a recent analysis reported that it is possible to obtain immunodominant neoantigens that could be used to develop neoepitope-CD8+ T cells and treat patients with ALL ( 83 , 220 ).…”