TIM3 blockade with hypomethylating therapy restores NK and cytotoxic CD4+ T cell activity in patients with AML or MDS

Occasional complete responses to immune checkpoint inhibitor therapies suggest that acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are immune-sensitive when appropriately targeted. Here, we analyzed AML/MDS patients treated with anti-TIM3 sabatolimab and decitabine in a phase Ib clinical trial (NCT03066648) using single-cell RNA and T cell receptor (TCR) sequencing and functional co-culture assays. Unlike T cell restricted CTLA4 and PD1, TIM3 was broadly expressed across natural killer (NK), myeloid, and T cell populations. Therapy induced expansion of cytotoxic NK cell subsets and enhanced type I interferon signaling. Less than 1% of bone marrow CD8+ T cells showed canonical exhaustion phenotypes, and the treatment preferably expanded small CD8+ T cell clones in responders. Responders had more cytotoxic CD4+ T and B cells which was exemplified by a patient with an outstanding complete response of 23-months. Over >20% of this patients lymphocytes were CD4+ T-cell large granular lymphocyte leukemia (T-LGLL) cells that expressed a TCR capable of recognizing autologous blasts. SignificanceAnti-TIM3+decitabine offers a distinct mechanism compared to anti-PD1 and anti-CTLA4: it preferentially enhances innate and unconventional cytotoxic lymphocyte populations. Furthermore, our findings suggest that clonal expansion of self-antigen-specific T cells, such as T-LGLL, may augment anti-leukemic immunity in the context of immunotherapy.