Donor T Cells Administered Over HLA Class II Barriers Mediate Antitumor Immunity without Broad Off-Target Toxicity in a NOD/Scid Mouse Model of Acute Leukemia

Abstract

Alloreactive (allo)-HLA-directed T cell responses after HLA-mismatched allogeneic hematopoietic stem cell transplantation and donor lymphocyte infusion are typically considered detrimental responses mediating graft-versus-host disease (GVHD). Allo-HLA-reactive T cells with beneficial and selective graft-versus-leukemia (GVL) reactivity, however, can also be identified within an HLA-mismatched context. We investigated whether allo-HLA class II-directed T cells with beneficial GVL reactivity induced in NOD/scid mice engrafted with human chronic myelogenous leukemia in lymphoid blast crisis after treatment with donor lymphocyte infusion - mediated detrimental xenogeneic GVHD as a result of broad off-target cross-reactivity. The results demonstrate that beneficial GVL reactivity and xenogeneic GVHD are mediated by separate T cells. GVL reactivity was mediated by human T cells recognizing allo-HLA class II molecules, whereas xenoreactivity was exerted by human T cells recognizing H-2 molecules. Taken together, our data indicate a limited risk for detrimental off-target effects by allo-HLA class II-directed T cells and thereby provide a basis for the development of strategies for selecting allo-HLA-restricted T cells with selective GVL reactivity for adoptive transfer after HLA-mismatched allogeneic hematopoietic stem cell transplantation.

Endogenous TCR promotes in vivo persistence of CD19-CAR-T cells compared to a CRISPR/Cas9-mediated TCR knockout CAR

“…Specificity of these responses might be infectious or allogeneic (xenogeneic in case of mouse tissue), since several studies have shown induction of GvHD when human T cells are injected into NSG mice. [26][27][28] Furthermore, in patients treated with HLAmismatched, allogeneic, TALEN-engineered, TCR-deficient CAR T cells, only a small fraction of contaminating TCR 1 CAR T cells persisted and induced GvHD. 8 Lapteva et al 10 could show that additional stimulation through a virus-specific TCR on CAR T cells led to enhanced proliferation and functionality in patients, underlining the important role of the TCR.…”

Loss of Mismatched HLA on the Leukemic Blasts of Patients With Relapsed Lymphoid Malignancies Following Bone Marrow Transplantation From Related Donors With HLA Class II Mismatches in the Graft Versus Host Direction

“…Stevanović et al have shown that HLA class II mismatched donor T cells displayed GVL effect in a lymphoid blast engrafted xenograft model. [12] Taken together, HLA class II antigens may be key molecules for relapse of ALL after partially HLA-mismatched related HSCT.…”

Mouse Models of Antigen Presentation in Hematopoietic Stem Cell Transplantation

“…NSG mice with intact murine MHC (H-2) and transgenic HLA-A*0201 expression develop accelerated lethality after transplantation with human PBMC, but equivalent histopathology (relative to HLA-A*0201-negative NSG mice) ( 83 ). In vitro assays demonstrate that multiple human CD4 + and CD8 + T cell clones are reactive to both murine MHC-I and II ( 84 ). In addition, highly aberrant CD4 + CD8 + T cell expansion within tissue has been seen after xenogeneic but not clinical transplantation and this likely reflects non-physiological antigen presentation ( 85 ).…”