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.
