Feasibility and Preclinical Efficacy of CD7-Unedited CD7 Car T Cells for T Cell Malignancies

Authors

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
LaQuisa C Hill
Helen E Heslop
Chonghui Cheng
Malcolm K Brenner
Maksim Mamonkin

Publication Date

1-4-2023

Journal

Molecular Therapy

DOI

10.1016/j.ymthe.2022.09.003

PMID

36086817

PMCID

PMC9840107

PubMedCentral® Posted Date

9-9-2022

PubMedCentral® Full Text Version

Post-Print

Published Open-Access

yes

Keywords

Mice, Animals, Humans, T-Lymphocytes, Immunotherapy, Adoptive, Dasatinib, Feasibility Studies, Receptors, Chimeric Antigen, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, chimeric antigen receptor, engineered T cells, adoptive cell therapy, CD7, T cell malignancies, T-ALL, T cell lymphoma, fratricide

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.

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