Influencing factors and solution strategies of chimeric antigen receptor T-cell therapy (CAR-T) cell immunotherapy

Abstract

Chimeric antigen receptor T-cesll therapy (CAR-T) has achieved groundbreaking advancements in clinical application, ushering in a new era for innovative cancer treatment. However, the challenges associated with implementing this novel targeted cell therapy are increasingly significant. Particularly in the clinical management of solid tumors, obstacles such as the immunosuppressive effects of the tumor microenvironment, limited local tumor infiltration capability of CAR-T cells, heterogeneity of tumor targeting antigens, uncertainties surrounding CAR-T quality, control, and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy. These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach. In this paper, we comprehensively analyze recent preclinical and clinical reports on CAR-T therapy while summarizing crucial factors influencing its efficacy. Furthermore, we aim to identify existing solution strategies and explore their current research status. Through this review article, our objective is to broaden perspectives for further exploration into CAR-T therapy strategies and their clinical applications.

Keywords: Chimeric antigen receptor T-cell therapy (CAR–T); Influencing factor; Solution strategies; Tumor targeting therapy.

Figure 1. The efficacy of CAR-T targeting on tumor is mainly affected by the following aspects: The quality control of CAR-T preparation is a double-edged sword that affects the efficacy, and high-quality CAR-T can significantly improve tumor prognosis; The degree of tumor infiltration by CAR-T determines whether tumor cells can be directly targeted and eliminated. Heterogeneity of tumor-associated antigens leads to loss or mismatch of targeted antigens, resulting in drug resistance; The inhibitory effect of various immunosuppressive factors on the expansion and function of CAR-T cells in TME, as well as various adverse reactions of targeted tumor removal during CAR-T targeted therapy, resulted in the decline of patient compliance and affected the therapeutic effect.

Figure 2. Summary diagram illustrating the developmental trajectory and ongoing optimization of CAR–T cell design. The figure portrays the evolution of structural designs from initial generation to current iterations, with varying design timelines that do not follow a sequential order. Preclinical research holds intrinsic value, but long-term examination is essential for assessing actual clinical efficacy.