Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies. However graft-versus-host disease (GVHD) and relapse after allo-HSCT remain major causes of morbidity and mortality following transplant. Chimeric antigen receptors (CARs) are non-MHC-restricted T cell receptor-like constructs that confer novel antigen recognition capabilities to T cells, allowing them to proliferate and mediate anti-cancer activity in response to tumor cells. Clinical studies have shown that adoptive transfer of autologous T cells transduced with CARs targeting CD19, which is expressed on normal B cells and several B cell malignancies, is effective against CD19+ malignancies.

To assess the potential of allogeneic CD19-CAR T cells to prevent relapse after allo-HSCT, we are investigating the immunobiology of donor-derived CD19-CAR T cells in preclinical allo-HSCT and lymphoma models. We have generated retroviral vectors encoding mouse CD19-specific CARs, similar to those currently in clinical trials. We have identified that donor CD19-CAR T cells exhibit potent graft-versus-lymphoma (GVL) activity but reduced GVHD activity — a finding that has also been demonstrated in clinical application of allogeneic donor T cells modified with CARs. These findings support the administration of donor CD19-CAR T cells to prevent relapse of CD19+ malignancies after allo-HSCT without increasing the risk for GVHD. Our future directions include delineating the mechanism of reduced GVHD potential of alloreactive T cells bearing CD19-specific CARs and generation of novel receptor constructs that have the potential to inhibit GVHD while retaining GVL.

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