CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity

Abstract

Chimeric Antigen Receptor (CAR)-T cell therapy has rapidly emerged as a groundbreaking approach in cancer treatment, particularly for hematologic malignancies. However, the application of CAR-T cell therapy in solid tumors remains challenging. This review summarized the development of CAR-T technologies, emphasized the challenges and solutions in CAR-T cell therapy for solid tumors. Also, key innovations were discussed including specialized CAR-T, combination therapies and the novel use of CAR-Treg, CAR-NK and CAR-M cells. Besides, CAR-based cell therapy have extended its reach beyond oncology to autoimmune disorders. We reviewed preclinical experiments and clinical trials involving CAR-T, Car-Treg and CAAR-T cell therapies in various autoimmune diseases. By highlighting these cutting-edge developments, this review underscores the transformative potential of CAR technologies in clinical practice.

Keywords: CAR-T cell therapy; CAR-Treg; autoimmune diseases; dual-CAR strategy; solid tumors.

Figure 1

Schematic of CAR-T cell therapy process. Peripheral blood mononuclear cells (PBMCs) are extracted from the patient’s blood. T cells are then concentrated, isolated, and activated. These activated T cells (TCRαβ⁺) are transduced with a recombinant lentivirus to express the chimeric antigen receptor (CAR). The CAR T cells (TCRαβ⁺) are subsequently expanded and multiplied in vitro. Finally, the amplified CAR T cells are infused back into the patient’s bloodstream to target and eliminate cancer cells.

Figure 2

The structure of chimeric antigen receptor (CAR). The CAR contains an ectodomain, usually a single-chain variable fragment (scFv) from an antibody, comprising a variable heavy chain region (VH) and a variable light chain region (VL), which is responsible for recognizing the antigen. The transmembrane domain anchors the CAR to the T cell membrane. The endodomain includes signaling elements such as the CD3ζ chain, which contains ITAMs, and the costimulatory domain (CM), which enhances T cell activation, proliferation, and persistence.

Figure 3

CAR development from the first to the fifth generation. First-generation CARs are characterized by the presence of a signaling domain originating from CD3ζ. Second-generation CARs encompass an additional co-stimulatory domain (CM1), such as CD28 or 4-1-BB. Building upon the second generation, third-generation CARs incorporate a second co-stimulatory domain (CM2). Fourth-generation CAR T cells, also known as T cells Redirected for Universal Cytokine-mediated Killing (TRUCKs), contain NFAT transcriptional elements, which can induce the expression of specific chemokines, such as IL-12, in the tumor microenvironment. Fifth-generation CARs are universal CAR-T cells. VH, variable heavy chain; VL, light chain; CM, co-stimulatory domain; IL, interleukin; CD, cluster of differentiation; NFAT, nuclear factor of activated T cells; ITAM, immunoreceptor tyrosine-based activation motify.

Figure 4

CAR-T cells in immunosuppressive TME. The immunosuppressive TME is a key factor that limits the efficacy of CAR-T cell therapy. The immunosuppressive tumor microenvironment is contributed by immunosuppressive cells including Treg cells, MDSCs, TAMs and immunosuppressive molecules like IL-10, TGF-0, IL-4 and VEGF. TME, tumor microenvironment; MDSCs, myeloid-derived suppressor cells; TAMs, tumor-associated macrophages.