Harnessing the potential of CAR-T cell therapy: progress, challenges, and future directions in hematological and solid tumor treatments

Abstract

Traditional cancer treatments use nonspecific drugs and monoclonal antibodies to target tumor cells. Chimeric antigen receptor (CAR)-T cell therapy, however, leverages the immune system's T-cells to recognize and attack tumor cells. T-cells are isolated from patients and modified to target tumor-associated antigens. CAR-T therapy has achieved FDA approval for treating blood cancers like B-cell acute lymphoblastic leukemia, large B-cell lymphoma, and multiple myeloma by targeting CD-19 and B-cell maturation antigens. Bi-specific chimeric antigen receptors may contribute to mitigating tumor antigen escape, but their efficacy could be limited in cases where certain tumor cells do not express the targeted antigens. Despite success in blood cancers, CAR-T technology faces challenges in solid tumors, including lack of reliable tumor-associated antigens, hypoxic cores, immunosuppressive tumor environments, enhanced reactive oxygen species, and decreased T-cell infiltration. To overcome these challenges, current research aims to identify reliable tumor-associated antigens and develop cost-effective, tumor microenvironment-specific CAR-T cells. This review covers the evolution of CAR-T therapy against various tumors, including hematological and solid tumors, highlights challenges faced by CAR-T cell therapy, and suggests strategies to overcome these obstacles, such as utilizing single-cell RNA sequencing and artificial intelligence to optimize clinical-grade CAR-T cells.

Keywords: Antigen escape; CAR-T cell therapy; Cytokine release syndrome; Hematological malignancy; Immunotherapy; Solid tumor; Tumor antigens.

Fig. 1

Structural design of different generations of CARs. A First-generation CARs with ScFv, Hinge, Transmembrane, and CD3ζ domains. B Second-generation CARs with all first-generation domains and an additional CD28/4-1BB costimulatory domain. C Third-generation CARs with all first-generation domains and two additional costimulatory domains (CD28 and 4-1BB). D Two different types of fourth-generation CARs with additional cytokine and co-stimulatory ligand domains to address challenges of tumor microenvironments. E Fifth-generation CARs with one intracellular domain more than the fourth-generation CAR-T cells, which include truncated intracellular domains of cytokine receptors (e.g., IL-2R chain fragment), with an additional domain for binding transcription factors such as STAT-3/5. CARs, Chimeric antigen receptors; ScFv, single-chain variable fragment

Fig. 2

CAR-T cell therapy challenges and their mitigation strategies. A Cytokine Release Syndrome (CRS) (1) Choice of costimulatory domain CD28 or 41BB as well as the length of the hinge domain influence CRS (2) Cytokines released by macrophages and Inflammatory cytokines and immunostimulatory alarmins released during pyroptosis can be mitigated by using specific drugs for each cytokine (e.g., Etanecerpt, Tocilizumab, Corticosteroids, Dasatinib, Emapalumab) B Tumor-associated antigen escape (1) CAR-T cell-mediated killing of target cell if the target antigen is present on the surface (2) Tumor antigen escape in the absence of surface antigen of the CAR-T cell and potential strategies to abet it by using DUAL CARs and BiTE CARs. C Trafficking and tumor infiltration (1) Schematic diagram to demonstrate reduced homing of CAR-T cells to tumor microenvironments due to the presence of different cellular components (2) Improving homing of CAR-T cells to TME by using armored anti-angiogenic CARs as well as self-driving CARs, which express multiple anti-angiogenic factors. D On-target Off-tumor/Lack of reliable TAAs. Schematic diagram to demonstrate targeting of the normal cell by CAR-T cells if the antigen is expressed on normal cells, which can be mitigated by a selection of reliable tumor-associated antigen by integration of artificial intelligence with big data mining. E Immunosuppressive tumor microenvironment (1) Diagram to illustrate suppressive tumor microenvironment comprising different cellular components including low oxygen, cancer-associated fibroblast, high ROS and other components that diminish proliferation of CAR-T cells (2) CAR-T expressing anti-checkpoint inhibitors to promote the growth of T cells in tumor microenvironments (3) HIF1α-inducible CARs, which get activated in hypoxic tumor microenvironment. HIF1α to promote T cell growth (4) Catalase-expressing CAR to scavenge reactive oxygen species in tumors to promote T cell growth. CARs, Chimeric antigen receptors; BiTE, bispecific T-cell engagers; TAAs, tumor-associated antigens; TME, tumor microenvironment; ROS, reactive oxygen species; HIF1α, hypoxia inducible factor 1 alpha

Fig. 3

Artificial intelligence-based machine learning model for predicting CAR-T cell therapy outcome. The model can be trained using different-omics and medical imaging datasets as input. The input data are processed by the deep learning algorithm, and results are passed to the output for classification

Fig. 4

Building better CAR-T cells. A Off-the-shelf/Universal CAR-T cells, Generation of universal CAR-T cells from an allogenic donor by deletion of MHC and TCRs using CRISPR/Cas-9 technology. B Tailor-made CAR-T cells for different TME. Multidomain and Armored CAR-T cells to tackle different tumor microenvironments to stimulate CAR-T cell growth. C Molecular Switches to control CAR-T cell cytotoxicity, Programming of CAR-T cells with degron (degradation) sequence and iCasp9 (Inducible caspase 9) to induce their destruction upon life-threatening toxicity in treated patients. D Alternate to ScFv. Potential alternative to bulky ScFv like DARPin based CARs and Fn3 recognition domain CAR-T cells. E Making CAR-T cells financially viable therapeutic modality. Reduction cost of production and introduction of universal CAR-T cells, which can be produced in bulk. F Novel CAR-T cell based combination therapies. Combination CAR-T cell therapy with novel immunomodulatory agents will help in achieving a durable therapeutic response in cancer patients