Characterization and optimization of antigen-specific T cell responses during ex vivo expansion of melanoma tumor-infiltrating lymphocytes

摘要: Treatment of metastatic melanoma with tumor reactive T cells (adoptive cell therapy, ACT) is a promising approach associated high clinical response rate. However, further optimization this treatment modality required to increase the after therapy. ACT in involves an initial phase (pre-REP) tumor-infiltrating lymphocyte (TIL) expansion ex vivo from isolates followed by second phase, “rapid protocol” (REP) generating billions used as TIL infusion product. The main question addressed thesis was how currently REP affected responsiveness CD8 defined antigens. We hypothesized that drives differentiate and become hyporesponsive antigen restimulation, therefore, proper cytokine or other ways expand improve upon outcome. evaluated restimulation using MART-1 peptide-pulsed mature DC vitro. Post-REP TILs were mostly poor proliferation higher apoptosis. Phenotypic analysis revealed expression CD28 significantly reduced post-REP TILs. By sorting experiment microarray analysis, we confirmed few had superior survival capacity proliferated restimulation. then went on investigate methods maintain during responsiveness. Firstly, IL-15 IL-21 found synergize maintaining antigenic REP. Secondly, compared IL-2 supporting long-term antigen-specific