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Posttransplant chimeric antigen receptor therapy

Melody Smith, Johannes Zakrzewski, Scott James and Michel Sadelain

Abstract

Therapeutic T cell engineering is emerging as a powerful tool 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. CAR T cells may also contribute to enhance allogeneic hematopoietic stem cell transplantation in selected settings. However, the use of allogeneic T cells poses unique challenges owing to their potential alloreactivity. We review here different approaches to overcome these challenges, 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 differentiation, and gene editing, are poised to enable the use of allogeneic CAR T cells without incurring graft-versus-host disease.

  • Submitted August 24, 2017.
  • Accepted December 18, 2017.