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 - 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 -