Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia
Meghali Goswami, Gege Gui, Laura W Dillon, Katherine E Lindblad, Julie Thompson, Janet Valdez, Dong-Yun Kim, Jack Y Ghannam, Karolyn A Oetjen, Christin B Destefano, Dana M Smith, Hanna Tekleab, Yeusheng Li, Pradeep Dagur, Thomas Hughes, Jennifer L Marté, Jaydira Del Rivero, Joanna Klubo-Gwiezdzinksa, James L Gulley, Katherine R Calvo, Catherine Lai, Christopher S Hourigan, Meghali Goswami, Gege Gui, Laura W Dillon, Katherine E Lindblad, Julie Thompson, Janet Valdez, Dong-Yun Kim, Jack Y Ghannam, Karolyn A Oetjen, Christin B Destefano, Dana M Smith, Hanna Tekleab, Yeusheng Li, Pradeep Dagur, Thomas Hughes, Jennifer L Marté, Jaydira Del Rivero, Joanna Klubo-Gwiezdzinksa, James L Gulley, Katherine R Calvo, Catherine Lai, Christopher S Hourigan
Abstract
Background: The powerful 'graft versus leukemia' effect thought partly responsible for the therapeutic effect of allogeneic hematopoietic cell transplantation in acute myeloid leukemia (AML) provides rationale for investigation of immune-based therapies in this high-risk blood cancer. There is considerable preclinical evidence for potential synergy between PD-1 immune checkpoint blockade and the hypomethylating agents already commonly used for this disease.
Methods: We report here the results of 17 H-0026 (PD-AML, NCT02996474), an investigator sponsored, single-institution, single-arm open-label 10-subject pilot study to test the feasibility of the first-in-human combination of pembrolizumab and decitabine in adult patients with refractory or relapsed AML (R-AML).
Results: In this cohort of previously treated patients, this novel combination of anti-PD-1 and hypomethylating therapy was feasible and associated with a best response of stable disease or better in 6 of 10 patients. Considerable immunological changes were identified using T cell receptor β sequencing as well as single-cell immunophenotypic and RNA expression analyses on sorted CD3+ T cells in patients who developed immune-related adverse events (irAEs) during treatment. Clonal T cell expansions occurred at irAE onset; single-cell sequencing demonstrated that these expanded clones were predominately CD8+ effector memory T cells with high cell surface PD-1 expression and transcriptional profiles indicative of activation and cytotoxicity. In contrast, no such distinctive immune changes were detectable in those experiencing a measurable antileukemic response during treatment.
Conclusion: Addition of pembrolizumab to 10-day decitabine therapy was clinically feasible in patients with R-AML, with immunological changes from PD-1 blockade observed in patients experiencing irAEs.
Keywords: adaptive immunity; immunotherapy; investigational; lymphocyte activation; therapies; translational medical research.
Conflict of interest statement
Competing interests: CSH receives research support from Merck Sharpe & Dohme and SELLAS Life Sciences Group AG. CL is on the Speakers’ Bureau for Astellas, Jazz Pharma and serves in a consulting or advisory role for Daiichi, Jazz Pharma, Amgen, Abbvie, Macrogenics, and Agios. The remaining authors declare no competing interests.
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.
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