CD7 CAR-T therapy: current developments, improvements, and dilemmas

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is an epoch-making immunotherapy for the treatment of relapsed or refractory (r/r) blood tumors, as demonstrated by its successful implementation in r/r B cell-derived malignancies. However, replicating this success in T-cell leukemia or lymphoma remains challenging. Among the various potential target antigens, CD7 has garnered attention as a promising candidate. CD7 CAR-T therapy is one of the most extensively studied approaches for treating r/r T-cell acute lymphoblastic leukemia/lymphoblastic lymphoma (T-ALL/LBL) and r/r acute myeloid leukemia (AML). Based on the source of T cells, CAR-T products can be categorized as autologous and allogeneic, both of which are being tested in clinical trials, each offering specific advantages. Allogeneic CD7 CAR-T cells outperform autologous cells in terms of reducing manufacturing costs, ensuring consistent quality, and improving affordability and availability. Despite these advantages, challenges like graft-versus-host disease (GVHD), host-versus-graft reaction (HVGR), and fratricide pose significant barriers to the clinical application of allogeneic CD7 CAR-T cells. However, innovative gene-editing techniques, such as CRISPR/Cas9 and base editing, and more promising cell sources, such as natural killer T (NKT) cells and induced pluripotent stem cells (iPSCs), are emerging as potential solutions. In this review, we discuss the different categories of CD7 CAR-T products, their application in clinical settings, and directions for refinement.

Keywords: AML; CAR-T; CD7; GVHD; clinical application; fratricide; r/r T-ALL/LBL.

Figure 1.

Commonly used techniques to avert fratricide, GVHD and HVGR. (A) CRISPR/Cas9: knock out CD7 to prevent fratricide, TRAC or TRBC1 or TRBC2 to avoid GVHD, B2M, or CIITA to circumvent HVGR. (B) Base editing: edit out CD7 to prevent fratricide, TRAC or TRBC1 or TRBC2 to avoid GVHD, B2M, or CIITA to circumvent HVGR. (C) PEBL: anchor CD7 in ER and/or Golgi apparatus to block CD7 trafficking to the T cell membrane. (D) Ibrutinib and dasatinib: inhibit the key kinases in CAR signaling pathway to block CAR cell activation. (E) CAR-NK cells: eliminate tumor cells with autocrine IL-15 to enhance persistence without causing GVHD. (F) CAR-γδT cells: eradicate tumor cells without causing GVHD. (G) iPSCs: reprogrammed from other cell types to differentiate into a wide range of cells for CAR cell production. (H) UCB cells: provide available HSPCs to manufacture CAR-cell products with advantageous phenotypes. B2M = β2 microglobulin, CAR = chimeric antigen receptor, CIITA = class II transactivator, ER = endoplasmic reticulum, GVHD = graft-versus-host disease, HNH = histidine-asparagine-histidine, HSPC HVGR = host versus graft reaction, IL = interleukin, iPSC = induced pluripotent stem cell, MHC = major histocompatibility complex, NK = natural killer, PAM = protospacer adjacent motif, PEBL = protein expression blocker, TRAC = T-cell receptor α, TRBC UCB = umbilical cord blood, βTCR = β T cell receptor.