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Development of T-cell immunotherapy for hematopoietic stem cell transplantation recipients at risk of leukemia relapse

Robson G. Dossa, Tanya Cunningham, Daniel Sommermeyer, Indira Medina-Rodriguez, Melinda A. Biernacki, Kimberly Foster and Marie Bleakley

Key Points

  • A new T-cell immunotherapy has been developed to prevent or manage relapse of leukemia following HCT.

  • Memory CD8+ and CD4+ T cells are engineered with a minor histocompatibility antigen–targeting TCR, CD8 coreceptor, and safety switch.

Publisher's Note: There is a Blood Commentary on this article in this issue.

Abstract

Leukemia relapse remains the major cause of allogeneic hematopoietic stem cell transplantation (HCT) failure, and the prognosis for patients with post-HCT relapse is poor. There is compelling evidence that potent selective antileukemic effects can be delivered by donor T cells specific for particular minor histocompatibility (H) antigens. Thus, T-cell receptors (TCRs) isolated from minor H antigen–specific T cells represent an untapped resource for developing targeted T-cell immunotherapy to manage post-HCT leukemic relapse. Recognizing that several elements may be crucial to the efficacy and safety of engineered T-cell immunotherapy, we developed a therapeutic transgene with 4 components: (1) a TCR specific for the hematopoietic-restricted, leukemia-associated minor H antigen, HA-1; (2) a CD8 coreceptor to promote function of the class I–restricted TCR in CD4+ T cells; (3) an inducible caspase 9 safety switch to enable elimination of the HA-1 TCR T cells in case of toxicity; and (4) a CD34-CD20 epitope to facilitate selection of the engineered cell product and tracking of transferred HA-1 TCR T cells. The T-cell product includes HA-1 TCR CD4+ T cells to augment the persistence and function of the HA-1 TCR CD8+ T cells and includes only memory T cells; naive T cells are excluded to limit the potential for alloreactivity mediated by native TCR coexpressed by HA-1 TCR T cells. We describe the development of this unique immunotherapy and demonstrate functional responses to primary leukemia by CD4+ and CD8+ T cells transduced with a lentiviral vector incorporating the HA-1 TCR transgene construct.

  • Submitted July 14, 2017.
  • Accepted October 1, 2017.
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