Heterologous vaccination and checkpoint blockade synergize to induce anti-leukemia immunity

Checkpoint blockade-based immunotherapies are effective in cancers with high numbers of non-synonymous mutations. In contrast, current paradigms suggest that such approaches will be ineffective in cancers with few non-synonymous mutations. To examine this issue we made use of a murine model of BCR-ABL + B-lineage Acute Lymphoblastic Leukemia. Using a principal component analysis, we found that robust MHC-II expression, coupled with appropriate costimulation, correlated with lower leukemic burden. We next assessed whether checkpoint blockade or therapeutic vaccination could improve survival in mice with pre-established leukemia. Consistent with the low mutation load in our leukemia model, we found that checkpoint blockade alone had only modest effects on survival. In contrast, robust heterologous vaccination with a peptide derived from the BCR-ABL fusion (BAp), a key driver mutation, generated a small population of mice that survived long-term. Checkpoint blockade strongly synergized with heterologous vaccination to enhance overall survival in mice with leukemia. Enhanced survival did not correlate with numbers of BAp:I-A b -specific T cells, but rather with increased expression of IL10, IL17, and Granzyme B and decreased expression of Programmed Death 1 on these cells. Our findings demonstrate that vaccination to key driver mutations cooperates with checkpoint blockade and allows for immune control of cancers with low non-synonymous mutation loads.