Feasibility and preclinical efficacy of CD7-unedited CD7 CAR T cells for T cell malignancies

Mol Ther. 2023 Jan 4;31(1):24-34. doi: 10.1016/j.ymthe.2022.09.003. Epub 2022 Sep 9.


Chimeric antigen receptor (CAR)-mediated targeting of T lineage antigens for the therapy of blood malignancies is frequently complicated by self-targeting of CAR T cells or their excessive differentiation driven by constant CAR signaling. Expression of CARs targeting CD7, a pan-T cell antigen highly expressed in T cell malignancies and some myeloid leukemias, produces robust fratricide and often requires additional mitigation strategies, such as CD7 gene editing. In this study, we show fratricide of CD7 CAR T cells can be fully prevented using ibrutinib and dasatinib, the pharmacologic inhibitors of key CAR/CD3ζ signaling kinases. Supplementation with ibrutinib and dasatinib rescued the ex vivo expansion of unedited CD7 CAR T cells and allowed regaining full CAR-mediated cytotoxicity in vitro and in vivo on withdrawal of the inhibitors. The unedited CD7 CAR T cells persisted long term and mediated sustained anti-leukemic activity in two mouse xenograft models of human T cell acute lymphoblastic leukemia (T-ALL) by self-selecting for CD7-, fratricide-resistant CD7 CAR T cells that were transcriptionally similar to control CD7-edited CD7 CAR T cells. Finally, we showed feasibility of cGMP manufacturing of unedited autologous CD7 CAR T cells for patients with CD7+ malignancies and initiated a phase I clinical trial (ClinicalTrials.gov: NCT03690011) using this approach. These results indicate pharmacologic inhibition of CAR signaling enables generating functional CD7 CAR T cells without additional engineering.

Keywords: CD7; T cell lymphoma; T cell malignancies; T-ALL; adoptive cell therapy; chimeric antigen receptor; engineered T cells; fratricide.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dasatinib / metabolism
  • Feasibility Studies
  • Humans
  • Immunotherapy, Adoptive / methods
  • Mice
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*
  • Receptors, Chimeric Antigen* / genetics
  • Receptors, Chimeric Antigen* / metabolism
  • T-Lymphocytes


  • Dasatinib
  • Receptors, Chimeric Antigen

Associated data

  • ClinicalTrials.gov/NCT03690011