Abstract A33: Tumor derived T cell clones for evaluation of check point inhibitor therapeutics

Abstract

Improving clinical outcomes using immunotherapeutics in cancer treatments will depend on a variety of factors including the composition and phenotype of effector T cell in tumors, the inhibitory factors from myeloid, tumor and stromal compartments of the tumor and selection of efficacious combination of therapeutic immunomodulatory agents that either neutralize immune checkpoint inhibitors or activate T cell costimulatory pathways. To address the issue of selecting optimal combinations of immune modulating agents we developed an in-vitro culture system for allo-stimulating and expanding tumor infiltrating lymphocytes (TILS) from tumor digests with an MHC Class II alloantigen expressing cell line. We selected allo-specific CD4 and CD8 clones from expanded TILS with an exhausted phenotype confirmed by cell surface expression of PD-1, LAG3 and TIGIT. T cell clones were incubated with the alloantigen expressing cell lines transduced with different combinations of immodulatory ligands and compared the effect of single agent versus combinations of checkpoint inhibitory monoclonal antibodies on T cell proliferation and cytokine production. Taqman and flow cytometry analysis was performed on several clones following allo-stimulation. A decrease in TIL clonality with repeated allo-stimulation was confirmed by TcR beta chain sequencing. In-vitro IFN gamma and Granzyme B production was enhanced with anti-PD-1 antibodies in combination with either anti-LAG3 or anti-TIGIT antibodies. This in-vitro system has the potential of screening combinations of immodulatory antibodies in a variety of TILS from different tumor types and can improve our understanding of new checkpoint inhibitor combinations. Citation Format: Robert L. Shields, Sabine Le Saux, Sophie Li, Manjiri Sathe, Terri McClanahan, Rene De Waal Malefyt. Tumor derived T cell clones for evaluation of check point inhibitor therapeutics [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A33.