Advances in Universal CAR-T Cell Therapy

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy achieved extraordinary achievements results in antitumor treatments, especially against hematological malignancies, where it leads to remarkable, long-term antineoplastic effects with higher target specificity. Nevertheless, some limitations persist in autologous CAR-T cell therapy, such as high costs, long manufacturing periods, and restricted cell sources. The development of a universal CAR-T (UCAR-T) cell therapy is an attractive breakthrough point that may overcome most of these drawbacks. Here, we review the progress and challenges in CAR-T cell therapy, especially focusing on comprehensive comparison in UCAR-T cell therapy to original CAR-T cell therapy. Furthermore, we summarize the developments and concerns about the safety and efficiency of UCAR-T cell therapy. Finally, we address other immune cells, which might be promising candidates as a complement for UCAR-T cells. Through a detailed overview, we describe the current landscape and explore the prospect of UCAR-T cell therapy.

Keywords: CRISPR/Cas9; cellular immunotherapy; chimeric antigen receptor T cell therapy; gene editing; universal chimeric antigen receptor T cell therapy.

Figure 1

The structure of conventional CAR and modular CAR: (A) the first generation of CAR consists of an extracellular antigen-binding domain (usually the single chain variable fragment, scFv), a transmembrane domain, and an intracellular signaling domain of the CD3ζ chain. Then, a costimulator is added in the (B) second generation and more in the (C) third generation. (D) The fourth generation of CAR is modified further to secret a cytokine to enhance the function. (E) The modular CAR is split into two interactive parts, the signaling module on T cells and the switching module to recognize targets.

Figure 2

Multiple gene or non-gene editing on UCAR-T cells. In addition to transducing a CAR into T cells, the TCR can be knocked out or inhibited to prevent GVHD. Genetic ablation of MHC-I and/or MHC-II diminish immunogenicity. Destruction of CD52 can make cells resistant to alemtuzumab. CD7 is edited to prevent the fratricide in CD7 UCAR-T cells. In addition, inhibitory checkpoints (e.g., PD-1) can be knocked out to enhance the function of cells.

Figure 3

The logic gatings in modular CAR. (A) OR logic: the modular CAR-T cell can eliminate different cancer cells with various switching modules, which are recognized by the same CAR-T cell but target different antigens on cancer cells. (B) AND logic: the antigen-binding domain and costimulator are separated into two CARs targeting different antigens and cotransduced into T cells. Only when tumor cells express two antigens simultaneously can they be recognized and attacked by these CAR-T cells. (C) NOT logic: a tumor-associated antigen is expressed on cancer cells and normal cells simultaneously, while another antigen is expressed on normal cells only. The two modules binding to them are complementary in the site recognized by the signaling module. The extra target works as a safety label to prevent the “on-target, off-tumor” toxicity of CAR-T cells.