Posttransplant chimeric antigen receptor therapy

Abstract

Therapeutic T-cell engineering is emerging as a powerful approach to treat refractory hematological malignancies. Its most successful embodiment to date is based on the use of second-generation chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas. Remarkable complete remissions have been obtained with autologous T cells expressing CD19 CARs in patients with relapsed, chemo-refractory B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Allogeneic CAR T cells may also be harnessed to treat relapse after allogeneic hematopoietic stem cell transplantation. However, the use of donor T cells poses unique challenges owing to potential alloreactivity. We review different approaches to mitigate the risk of causing or aggravating graft-versus-host disease (GVHD), including CAR therapies based on donor leukocyte infusion, virus-specific T cells, T-cell receptor-deficient T cells, lymphoid progenitor cells, and regulatory T cells. Advances in CAR design, T-cell selection and gene editing are poised to enable the safe use of allogeneic CAR T cells without incurring GVHD.

Figure 1.

Cell engineering strategies to provide allogeneic CAR T cells in the posttransplant setting. (A) Dual TCR/CAR T cell: The TCR may be alloreactive (DLI) or virus-specific (VST). There is a risk of signaling overload in bispecific T cells. (B) TCR-less CAR T cell: The endogenous TCR can be disrupted in mature T cells to abrogate GVHD potential (UCART19, TRAC-CAR). (C) Pro-CAR: Mismatched lymphoid progenitors can yield host tolerant CAR T cells, but require successful engraftment, development, and selection (precursor T cells).