TY - JOUR
T1 - Pembrolizumab and decitabine for refractory or relapsed acute myeloid leukemia
AU - Goswami, Meghali
AU - Gui, Gege
AU - Dillon, Laura W.
AU - Lindblad, Katherine E.
AU - Thompson, Julie
AU - Valdez, Janet
AU - Kim, Dong Yun
AU - Ghannam, Jack Y.
AU - Oetjen, Karolyn A.
AU - Destefano, Christin B.
AU - Smith, Dana M.
AU - Tekleab, Hanna
AU - Li, Yeusheng
AU - Dagur, Pradeep
AU - Hughes, Thomas
AU - Marté, Jennifer L.
AU - Del Rivero, Jaydira
AU - Klubo-Gwiezdzinksa, Joanna
AU - Gulley, James L.
AU - Calvo, Katherine R.
AU - Lai, Catherine
AU - Hourigan, Christopher S.
N1 - Funding Information:
Funding This work was supported by the Intramural Research Program of the
Funding Information:
Acknowledgements We appreciate the technical expertise of the NHLBI Flow Cytometry and DNA Sequencing Cores. Thank you to Steven Soldin (NIH Clinical Center) for technical guidance. We thank the NIH HPC Biowulf cluster for their computational resources (http://hpc.nih.gov). This work is supported in part by a research grant from Investigator-Initiated Studies Program of Merck Sharp & Dohme.
Publisher Copyright:
©
PY - 2022/1/11
Y1 - 2022/1/11
N2 - 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.
AB - 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.
KW - adaptive immunity
KW - immunotherapy
KW - investigational
KW - lymphocyte activation
KW - therapies
KW - translational medical research
UR - http://www.scopus.com/inward/record.url?scp=85123461068&partnerID=8YFLogxK
U2 - 10.1136/jitc-2021-003392
DO - 10.1136/jitc-2021-003392
M3 - Article
C2 - 35017151
AN - SCOPUS:85123461068
SN - 2051-1426
VL - 10
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 1
M1 - e003392
ER -