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

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 non-selected (bulk) CD19-CAR and CD19-CARCD7- T cells revealed that CD19-CARCD7- T cells had enhanced antitumor activity compared to 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 post-infusion. Intriguingly, the only functional CD4+ CD19-CAR T-cell cluster observed post-infusion exhibited CD7lo expression. Additionally, samples from patients responsive to therapy had a higher proportion of CD7lo T cells than in non-responders. 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.

Naturally selected CD7 CAR-T therapy without genetic editing demonstrates significant antitumour efficacy against relapsed and refractory acute myeloid leukaemia (R/R-AML)

“…The above study demonstrated the persistence of naturally selected CD7 CAR T cells in the in vitro phase of the study. However, further validation of its durability in comparison with other reported CD7 CAR-T cells and in clinical trials of R/R-AML needs to be performed [15,[51][52][53][54].…”

“…In addition, CD7 CAR-Ts may be less costly and exhibit lower risks associated with gene editing. In addition, in recent years, the construction of CAR-T cells by isolating CD7-negative cell populations or the use of ibrutinib and dasatinib to inhibit fratricide has demonstrated good potential value [52,54]. Hai-Ping Dai et al demonstrated the safety and efficacy of CD7 CAR-T cells using protein expression blockers to block CD7 expression at the CAR-T-cell membrane for the treatment of R/R early T-cell precursor lymphoblastic leukaemia/lymphoma (ETP-ALL/LBL) in patients with TP53 mutations [51].…”

The emerging scenario of immunotherapy for T-cell Acute Lymphoblastic Leukemia: advances, challenges and future perspectives

“…Indeed, they are predominantly CD4+ effector memory and CD4+ and terminally differentiated effector memory cells with a preserved expansion activity and viability. Moreover CD7 CAR-T cells are characterized by an effective antitumor immune response, as demonstrated by their ability to kill both CD7 and CD19 expressing haematological malignant cells [ 103 ].…”

Chimeric antigen receptor T-cell therapy for T-ALL and AML

“…In another study, Freiwan et al. sorted CD7- T cells from PBMC before transducing them with CD7 CAR, the CD7- CAR-T cells contained more CD4+ memory phenotype and have a robust antitumor activity to CD7+ cell lines CCRF-CEM and MOLT3 in vitro and eliminated CCRF-CEM cells in the mouse model, as well as bypass fratricide ( 89 ). Li et al.…”