Targeted Chemotherapy and Checkpoint Blockade Mediate Synergistic Protection Against BCR-ABL+ B Cell Leukemia

Abstract Immunotherapy using anti-PDL1/anti-CTLA4 checkpoint blockade has been successfully employed for cancers with many non-synonymous mutations. Whether checkpoint blockade-based approaches can be adapted to cancers with low mutational burden, such as BCR-ABL+ B cell leukemia, is still unclear. We have previously demonstrated that the endogenous anti-tumor T cell response, although important for initial control of leukemia, is unable to control leukemia by itself. We show here that leukemia induces an exhaustion phenotype in activated T cells, as well as an associated loss of effector function, that could contribute to the inability to clear leukemia. However, checkpoint blockade therapy using aPDL1 and aCTLA4 by themselves had no impact on survival in leukemic mice. Combining aPDL1 blockade with targeted chemotherapy using the BCR-ABL inhibitor nilotinib had a significant synergistic therapeutic effect. The effectiveness of the aPDL1-nilotinib dual therapy was primarily dependent on CD4 T cells, indicating a key role for endogenous anti-tumor CD4 T cells in leukemia clearance. Indeed, a significant proportion of long-term surviving nilotinib + aPDL1-treated mice were protected against a secondary leukemia re-challenge; indicative of an effective memory T cell responses. Thus, combination therapeutic approaches involving checkpoint blockade can elicit potent anti-tumor CD4 T cell responses that induce long-term protection against leukemia. Future studies will explore the mechanisms by which CD4 T cells orchestrate protective anti-leukemia responses.