Targeting acute myeloid leukemia through multimodal immunotherapeutic approaches

Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a dismal prognosis. Immunotherapeutic approaches using single agent checkpoint inhibitors have thus far shown limited success. We hypothesized that successful adaptive anti-AML specific immune responses require additional modulation of innate immunity. DMXAA exposure resulted in modest apoptosis of C1498 AML cells with a subtle increase in PD-L1 expression and limited production of IL-6 and IFN-β. In contrast, DMXAA + anti-PD-1 ab, but not either agent alone, significantly decreased in vivo disease burden and prolonged overall survival in C1498 engrafted leukemic mice. Combination-treated mice demonstrated increased memory T-cells and mature dendritic cells, lower numbers of regulatory T-cells and evidence of leukemia apoptosis. Furthermore, these effects were associated with markedly increased serum levels of type I interferon (IFN) and IFN gamma. We demonstrate that combining an innate immune agonist with a checkpoint inhibitor synergistically improved anti-tumor activity in a preclinical AML model.

Keywords:

• Immunotherapy
• AML
• PD-1
• innate immune agonist
• checkpoint inhibitor

Acknowledgements

We thank Dr. Bruce Blazar for kindly providing us with the stably transfected C1498FFDsR cell line, as well as Claire Fritz, Demi Lewis, and Dr. Kaitlyn Dykstra for technical assistance. We also thank the Roswell Park Flow Cytometry Core Lab for performing the Luminex assays and for the Roswell Park Pathology Core Lab for performing the immunohistochemistry.

Disclosure statement

Dr. Wang reports personal fees from Amgen, personal fees from Abbvie, personal fees from Astellas, personal fees from Jazz Pharmaceuticals, personal fees from Pfizer, personal fees from Daiichi Sankyo, personal fees from Arog/Dava Oncology, personal fees from PTC Therapeutics, personal fees from Macrogenics, personal fees from Stemline Therapeutics, personal fees from Kura Oncology, and personal fees from Immunogen. The other authors have no relevant conflicts of interest to disclose.

Additional information

Funding

This work is supported by the CCS Grant P30CA016056, Roswell Park Alliance Foundation, Jacquie Hirsch Leukemia Research Fund, and Roswell Park Cancer Institute.