IFN-γ and donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation
Sawa Ito, Emily Geramita, Kedwin Ventura, Biswas Neupane, Shruti Bhise, Erika M. Moore, Scott Furlan, Warren D. Shlomchik
Sawa Ito, Emily Geramita, Kedwin Ventura, Biswas Neupane, Shruti Bhise, Erika M. Moore, Scott Furlan, Warren D. Shlomchik
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Clinical Research and Public Health Hematology Transplantation

IFN-γ and donor leukocyte infusions for relapsed myeloblastic malignancies after allogeneic hematopoietic stem cell transplantation

Abstract

BACKGROUND The graft-versus-leukemia (GVL) effect contributes to the efficacy of allogeneic stem cell transplantation (alloSCT). However, relapse, indicative of GVL failure, is the greatest single cause of treatment failure. Based on preclinical data showing that IFN-γ is important to sensitize myeloblasts to alloreactive T cells, we performed a phase I trial of IFN-γ combined with donor leukocyte infusions (DLIs) in myeloblastic malignancies that relapsed after HLA-matched alloSCT.METHODS Patients with relapsed acute myeloid leukemia or myelodysplastic syndrome after alloSCT were eligible. Patients self-administered IFN-γ for 4 weeks (cohort 1) or 1 week (cohort 2), followed by DLI and concurrent IFN-γ for a total of 12 weeks. Bone marrow samples were analyzed by single-cell RNA sequencing (scRNA-Seq) to assess in vivo responses to IFN-γ by malignant myeloblasts.RESULTS IFN-γ monotherapy was well tolerated by all participants (n = 7). Treatment-related toxicities after DLI included grade I–II graft-versus-host disease (n = 5), immune effector cell–associated neurotoxicity syndrome (n = 2), and idiopathic pulmonary syndrome (n = 1), all of which resolved with corticosteroids. Four of 6 DLI recipients achieved minimal residual disease-negative complete remissions and full donor hematopoietic recovery. Median overall survival was 579 days (range, 97–906) in responders. scRNA-Seq validated in vivo activation of the IFN-γ response pathway in hematopoietic stem cell–like or myeloid progenitor cells after IFN-γ in analyzed samples.CONCLUSION IFN-γ was safe and well tolerated in this phase I study of IFN-γ for relapsed acute myeloid leukemia and myelodysplastic syndrome after alloSCT, with a promising efficacy signal when combined with DLI. Larger studies are needed to formally test the efficacy of this approach.TRIAL REGISTRATION ClinicalTrials.gov NCT04628338.FUNDING UPMC Hillman Cancer Center Cancer Immunology and Immunotherapy Program Pilot Award and Cure Within Reach: Drug Repurposing Clinical Trials to Impact Blood Cancers.

Authors

Sawa Ito, Emily Geramita, Kedwin Ventura, Biswas Neupane, Shruti Bhise, Erika M. Moore, Scott Furlan, Warren D. Shlomchik

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Figure 3

IFN-γ responsiveness of leukemia myeloblasts.

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IFN-γ responsiveness of leukemia myeloblasts. In vitro p-STAT1 quantitat...
In vitro p-STAT1 quantitation of BM cells after in vitro culture with or without IFN-γ (1 or 50 ng/mL) for 15 minutes (A). Shown is anti–p-STAT1 staining gating on cells that were CD34+, CD13+CD11b–, CD4+, CD8+, or CD19+. (B) Expression of HLA-ABC, HLA-DR, HLA-DP, ICAM-1, and PD-L1 on myeloblasts (see Supplemental Figure 1 for gating strategies) after culture for 48 hours without or with IFN-γ (1 ng/mL or 50 ng/mL). FMO (fluorescence minus 1) samples were cultured with 50 ng/mL IFN-γ. (C) BM samples from participants were collected between 2 and 14 days prior to and 48–60 hours after in vivo IFN-γ. Shown is expression of HLA-ABC, HLA-DR, HLA-DP, ICAM-1, and PD-L1 on myeloblasts. p-STAT1 and HLA-DR expression of an array of primary AML samples (n = 60) before and after in vitro IFN-γ stimulation (D and E). Shown is fold-induction with IFN-γ (y axis) for p-STAT1 (D) and HLA-DR (E) grouped by ELN classification (x axis). (F) Representative flow cytometry plots of p-STAT1 and IFN-γ–inducible molecules after in vitro culture with or without IFN-γ. Shown are data (from top to bottom) of samples that manifest IFN-γ induction of p-STAT1 and HLA-DR, only p-STAT1, or neither.