Engineering naturally occurring CD7 ⁻ T cells for the immunotherapy of hematological malignancies

Key Points

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  Naturally occurring CD7 negative T cells are functional effector T cells that can be used for chimeric antigen receptor therapy.

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  CD7 negative T cells expressing a CD7-CAR have robust antitumor activity and bypass fratricide.

Visual Abstract

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-CAR ^CD7−) T cells. CD7-CAR ^CD7− 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-CAR ^CD7− T cells revealed that CD19-CAR ^CD7− 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 ( CD7 ^lo) 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-CAR ^CD7lo 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 CD7 ^lo expression. Additionally, samples from patients responsive to therapy had a higher proportion of CD7 ^lo T cells than nonresponders (NCT03573700). Thus, CAR ^CD7− 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.

Abstract

CD7 is expressed on many T-cell malignancies and is an attractive target for CAR T-cell therapy for T-cell leukemia/lymphoma, but concurrent CD7 expression on CAR T cells predisposes to cell loss through fratricide. Freiwan and colleagues report on selection to enrich CD7-negative T cells as targets for CAR T-cell engineering and demonstrate that they have enhanced antitumor activity, suggesting a potentially attractive strategy for optimizing CAR T-cell therapy for T-cell malignancies.