PD-1 blockade in combination with dasatinib potentiates induction of anti-acute lymphocytic leukemia immunity.

Immunotherapy, in the form of hematopoietic stem cell transplantation (HSCT), has been part of the standard of care in the treatment of acute leukemia for over 40 years. Trials evaluating novel immunotherapeutic approaches, such as targeting the programmed death-1 (PD-1) pathway, have unfortunately not yielded comparable results to those seen in solid tumors. Major histocompatibility complex (MHC) proteins are cell surface proteins essential for the adaptive immune system to recognize self versus non-self. MHC typing is used to determine donor compatibility when evaluating patients for HSCT. Recently, loss of MHC class II (MHC II) was shown to be a mechanism of immune escape in patients with acute myeloid leukemia after HSCT. Here we report that treatment with the tyrosine kinase inhibitor, dasatinib, and an anti-PD-1 antibody in preclinical models of Philadelphia chromosome positive B-cell acute lymphoblastic leukemia is highly active. The dasatinib and anti-PD-1 combination reduces tumor burden, is efficacious, and extends survival. Mechanistically, we found that treatment with dasatinib significantly increased MHC II expression on the surface of antigen-presenting cells (APC) in a tumor microenvironment-independent fashion and caused influx of APC cells into the leukemic bone marrow. Finally, the induction of MHC II may potentiate immune memory by impairing leukemic engraftment in mice previously cured with dasatinib, after re-inoculation of leukemia cells. In summary, our data suggests that anti-PD-1 therapy may enhance the killing ability of dasatinib via dasatinib driven APC growth and expansion and upregulation of MHC II expression, leading to antileukemic immune rewiring.
Competing Interests: Competing interests: PK reports advisory board fees from Novartis, Daiichi Sankyo, BMS, and Ascentage, the speaker’s bureau of Takeda and Novartis, reports participating in the data safety monitoring board with Treadwell Therapeutics, and honoraria with Clinical Care Targeted Communications. PW reports employment from Genentech. MAC reports grants and personal fees from ImmunoGenesis, Inc., personal fees from Alligator Bioscience, Inc., personal fees from ImmunOS, Inc., grants and personal fees from ImmunoMet, Inc., personal fees from Oncoresponse, Inc., personal fees from Pieris, Inc., personal fees from Nurix, Inc., personal fees from Aptevo, Inc., personal fees from Servier, Inc., personal fees from Kineta, Inc., personal fees from Salarius, Inc., personal fees from Xencor, Inc., personal fees from Agenus, Inc., personal fees from Mereo, Inc., personal fees from Amunix, Inc., personal fees from Adagene, Inc., outside the submitted work. In addition, MAC has a patent Methods and Composition for Localized Secretion of Anti-CTLA-4 Antibodies with royalties paid to multiple licensees, a patent Dual specificity antibodies which bind both PD-L1 and PD-L2 and prevent their binding to PD-1 with royalties paid to ImmunoGenesis, Inc., and a patent Cyclic Dinucleotides as Agonists of Stimulator of Interferon Gene Dependent Signaling licensed to ImmunoGenesis, Inc. MK reports grants from Ablynx, Agios, Ascentage, AstraZeneca, Calithera, Cellectis, Eli Lilly, Rafael Pharmaceutical, and Sanofi; grants and other support from AbbVie, F. Hoffman La-Roche, Forty-Seven, Genentech, and Stemline Therapeutics; and other support from Amgen, Kisoji, Reata Pharmaceutical outside the submitted work; and has a patent (US 7,795,305 B2: “CDDO-Compounds and Combination Therapie”) with royalties paid to Reata Pharm, a patent (“Combination Therapy With a Mutant IDH1 Inhibitor and a BCL-2”) licensed to Eli Lilly, and a patent (62/993,166: Combination of a MCL-1 Inhibitor and Midostaurin, Uses and Pharmaceutical Compositions Thereof”) pending to Novartis. Funding for this work was provided by the Advanced Scholar Program at MD Anderson (2018-2019, Koller), the University of Texas MD Anderson Cancer Center support Grant (CA016672), and the University of Texas MD Anderson–China Medical University and Hospital Sister Institution Network Fund.
(© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)