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

Norihiro Watanabe, Feiyan Mo, Rong Zheng, Royce Ma, Vanesa C. Bray, Dayenne G. van Leeuwen, Juntima Sritabal-Ramirez, Hongxiang Hu, Sha Wang, Birju Mehta, Madhuwanti Srinivasan, Lauren D. Scherer, Huimin Zhang, Sachin G. Thakkar, La Quisa C. Hill, Helen E. Heslop, Chonghui Cheng, Malcolm K. Brenner, Maksim Mamonkin

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StateAccepted/In press - 2022

Keywords

  • CD7
  • T cell lymphoma
  • T cell malignancies
  • T-ALL
  • adoptive cell therapy
  • chimeric antigen receptor
  • engineered T cells
  • fratricide

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint

Dive into the research topics of 'Feasibility and preclinical efficacy of CD7-unedited CD7 CAR T cells for T cell malignancies'. Together they form a unique fingerprint.

Cite this