Patient outcomes after allogeneic bone marrow transplant (allo-BMT) depend on the balance between graft-versus-tumor effect (GvT, effective treatment) and GvHD (toxicity). Following allo-, but not syngeneic BMT, bone marrow CD8+ T cells displayed an exhausted phenotype (e.g., TIGIT, PD-1, TOX) even in the absence of tumor, likely driven by host allo-antigens. Cyclophosphamide depleted exhausted and enriched stem-like CD8+ T cells, whose efficacy could be boosted with a decoy-resistant IL-18 cytokine to promote GvT, minimize GvHD, and extend mouse survival in a major-mismatch BMT leukemia model.
Contributed by Alex Najibi
ABSTRACT: Some hematological malignancies such as multiple myeloma are inherently resistant to immune-mediated antitumor responses, the cause of which remains unknown. Allogeneic bone marrow transplantation (alloBMT) is the only curative immunotherapy for hematological malignancies due to profound graft-versus-tumor (GVT) effects, but relapse remains the major cause of death. We developed murine models of alloBMT where the hematological malignancy is either sensitive [acute myeloid leukemia (AML)] or resistant (myeloma) to GVT effects. We found that CD8(+) T cell exhaustion in bone marrow was primarily alloantigen-driven, with expression of inhibitory ligands present on myeloma but not AML. Because of this tumor-independent exhaustion signature, immune checkpoint inhibition (ICI) in myeloma exacerbated graft-versus-host disease (GVHD) without promoting GVT effects. Administration of post-transplant cyclophosphamide (PT-Cy) depleted donor T cells with an exhausted phenotype and spared T cells displaying a stem-like memory phenotype with chromatin accessibility present in cytokine signaling genes, including the interleukin-18 (IL-18) receptor. Whereas ICI with anti-PD-1 or anti-TIM-3 remained ineffective after PT-Cy, administration of a decoy-resistant IL-18 (DR-18) strongly enhanced GVT effects in both myeloma and leukemia models, without exacerbation of GVHD. We thus defined mechanisms of resistance to T cell-mediated antitumor effects after alloBMT and described an immunotherapy approach targeting stem-like memory T cells to enhance antitumor immunity.
Author Info: (1) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (2) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (3) Cl
Author Info: (1) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (2) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (3) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (4) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (5) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (6) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (7) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (8) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (9) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (10) QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. (11) Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA. (12) Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA. (13) QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. (14) Department of Medicine, University of Washington, Seattle, WA 98109, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (15) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington, Seattle, WA 98109, USA. (16) Australian Center for Blood Diseases, Monash University/the Alfred Hospital, Melbourne, VIC 3004, Australia. Malignant Haematology and Stem Cell Transplantation, the Alfred Hospital, Melbourne, VIC 3004, Australia. Department of Clinical Haematology, Monash University, Melbourne, VIC 3800, Australia. (17) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (18) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington, Seattle, WA 98109, USA. (19) QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia. (20) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington, Seattle, WA 98109, USA. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (21) Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA. (22) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Pediatrics, University of Washington, Seattle, WA 98105, USA. (23) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. Department of Medicine, University of Washington, Seattle, WA 98109, USA.
