cyclophosphamide on D-1. On D0 the CAR groups received 1.5-2x10 6 CAR T cells with aPDL1 continuing until W12. Mice were bled every two weeks starting D+7 from CAR T cells to assess CLL load, CAR/T cell subsets and groups were culled together when they got sick or peripheral blood (PB) CLL>70%. Results: Compared to WT CAR T cells, AT CAR T cells proliferate less in culture, skew towards CD8 cells, exhibit significantly lower transduction efficiencies in CD8 cells and have higher expression of PD1 + in both CD4 and CD8 cells. All mice treated with CAR T cells cleared their CLL and normal B cells at D+7, and those mice treated with WT CAR T cells all remained in remission until W18, whereas 50-60% of mice treated with AT CAR T cells slowly relapsed from D+21. Spleen weights in WT CAR treated mice were equivalent to age matched controls whilst AT CAR treated mice had variable size by W18. The addition of aPDL1 to AT CAR T cells did not alter their performance from AT CAR T cells alone in any parameter examined. CAR T cell expansion in all groups was greatest at D+7 and the majority of CAR + cells were CD8 + and PD1 + . PD1 + expression was significantly higher in AT compared to WT CAR T cells at D+7. Summary/Conclusion: CD19+ relapse post CAR T cells is determined byT cell fitness as WT CAR T cells can prevent relapse and can normalise PD1+ expression and spleen size. CAR T cells derived from CLL T cells are less able to prevent CD19+ relapse and this is not improved using concurrent aPDL1, which also seems to have limited activity in treatment alone of AT TCL1 CLL. Ongoing studies using CAR plus immunotherapy and BTK inhibitor combinations are addressing which steps are necessary to optimize CAR T cell fitness.

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