Engineering Naturally Occurring CD7- T Cells for the Immunotherapy of Hematological Malignancies

Authors

Abdullah Freiwan
Jaquelyn T Zoine
Jeremy Chase Crawford
Abishek Vaidya
Stefan A Schattgen
Jacquelyn A Myers
Sagar L Patil
Mahsa Khanlari
Hiroto Inaba
Jeffery M Klco
Charles G Mullighan
Giedre Krenciute
Peter J Chockley
Swati Naik
Deanna M Langfitt
Maksim Mamonkin
Esther A Obeng
Paul G Thomas
Stephen Gottschalk
M Paulina Velasquez

Language

English

Publication Date

12-22-2022

Journal

Blood

DOI

10.1182/blood.2021015020

PMID

35914226

PMCID

PMC9935551

PubMedCentral® Posted Date

8-3-2022

PubMedCentral® Full Text Version

Post-print

Abstract

Chimeric antigen receptor (CAR) T-cell therapy targeting T-cell acute lymphoblastic leukemia (T-ALL) faces limitations such as antigen selection and limited T-cell persistence. CD7 is an attractive antigen for targeting T-ALL, but overlapping expression on healthy T cells leads to fratricide of CD7-CAR T cells, requiring additional genetic modification. We took advantage of naturally occurring CD7- T cells to generate CD7-CAR (CD7-CARCD7-) T cells. CD7-CARCD7- T cells exhibited a predominantly CD4+ memory phenotype and had significant antitumor activity upon chronic antigen exposure in vitro and in xenograft mouse models. Based on these encouraging results, we next explored the utility of CD7- T cells for the immunotherapy of CD19+ hematological malignancies. Direct comparison of nonselected (bulk) CD19-CAR and CD19-CARCD7- T cells revealed that CD19-CARCD7- T cells had enhanced antitumor activity compared with their bulk counterparts in vitro and in vivo. Lastly, to gain insight into the behavior of CD19-CAR T cells with low levels of CD7 gene expression (CD7lo) in humans, we mined single-cell gene and T-cell receptor (TCR) expression data sets from our institutional CD19-CAR T-cell clinical study. CD19-CARCD7lo T cells were present in the initial CD19-CAR T-cell product and could be detected postinfusion. Intriguingly, the only functional CD4+ CD19-CAR T-cell cluster observed postinfusion exhibited CD7lo expression. Additionally, samples from patients responsive to therapy had a higher proportion of CD7lo T cells than nonresponders (NCT03573700). Thus, CARCD7- T cells have favorable biological characteristics and may present a promising T-cell subset for adoptive cell therapy of T-ALL and other hematological malignancies.

Keywords

Humans, Mice, Animals, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptors, Antigen, T-Cell, Immunotherapy, Adoptive, Hematologic Neoplasms, Immunotherapy, Antigens, CD19

Published Open-Access

yes

Recommended Citation

Freiwan, Abdullah; Zoine, Jaquelyn T; Crawford, Jeremy Chase; et al., "Engineering Naturally Occurring CD7- T Cells for the Immunotherapy of Hematological Malignancies" (2022). Faculty and Staff Publications. 5659.
https://digitalcommons.library.tmc.edu/baylor_docs/5659