CAR-T cell therapy for hematological malignancies: Limitations and optimization strategies

Abstract

In the past decade, the emergence of chimeric antigen receptor (CAR) T-cell therapy has led to a cellular immunotherapy revolution against various cancers. Although CAR-T cell therapies have demonstrated remarkable efficacy for patients with certain B cell driven hematological malignancies, further studies are required to broaden the use of CAR-T cell therapy against other hematological malignancies. Moreover, treatment failure still occurs for a significant proportion of patients. CAR antigen loss on cancer cells is one of the most common reasons for cancer relapse. Additionally, immune evasion can arise due to the hostile immunosuppressive tumor microenvironment and the impaired CAR-T cells in vivo persistence. Other than direct antitumor activity, the adverse effects associated with CAR-T cell therapy are another major concern during treatment. As a newly emerged treatment approach, numerous novel preclinical studies have proposed different strategies to enhance the efficacy and attenuate CAR-T cell associated toxicity in recent years. The major obstacles that impede promising outcomes for patients with hematological malignancies during CAR-T cell therapy have been reviewed herein, along with recent advancements being made to surmount them.

Keywords: CAR-T cell therapy; hematological malignancies; immune evasion; toxicity; tumor microenvironment.

Figure 1

Immunosuppressive effects of the TME on CAR-T cells and strategies to overcome them. The activity of CAR-T cells can be severely impaired by the tumor microenvironment (TME). The immunosuppressive effects of the TME are due to increased level of immune checkpoints/inhibitors and immunosuppressive factors/cells. Strategies to overcome them include: (1) removing or modifying related signaling pathways; (2) eliminating or remodeling immunosuppressive cells and (3) enhancing the activation of CAR-T cells. PD-1, Programmed death-1; PD-L1, Programmed death-1 ligand-1; CAF, cancer-associated fibroblasts; MDSC, myeloid-derived suppressor cells; TAM, tumor associated macrophages; Treg, regulatory T cells; TGF-β, transforming growth factor -β; D2HG, D-2-hydroxyglutarate.

Figure 2

Approaches to promote CAR-T cell persistence in vivo. The persistence of CAR-T cells during treatment is crucial to achieve a durable and long-lasting outcome. CAR-T cell persistence can be extended via (1) the promotion of CAR-T cell activation or expansion; (2) enhanced CAR-T cell fitness; (3) proper CAR construct design and (4) increased CAR-T cells stemness. TM, transmembrane; ROS, reactive oxygen species.

Figure 3

Major causes of CAR-T cell treatment failure and strategies to avoid them. The main reasons for CAR-T cell treatment failure are (1) loss of antigen relapse, (2) the immunosuppressive TME, (3) poor CAR-T cell poor persistence in vivo and (4) severe toxicity. Numerous efforts have been made to propose strategies to overcome these obstacles. The efficacy of CAR-T cell therapy can be enhanced by addressing these factors. TCR, T-cell receptor; TME, tumor microenvironment; PD-1, Programmed death-1; TGF-β, transforming growth factor -β; MDSC, myeloid-derived suppressor cells; TAM, tumor associated macrophages; Treg, regulatory T cells; CRS, cytokine release syndrome; iCasp9, inducible caspase9; SMAsh, Small molecule–assisted shutoff; ADCC, antibody-dependent cellular cytotoxicity.