Enhancing CAR T-cell therapies against solid tumors: Mechanisms and reversion of resistance

Abstract

Chimeric antigen receptor (CAR) T-cell therapy, belonging to adoptive immune cells therapy, utilizes engineered immunoreceptors to enhance tumor-specific killing. By now new generations of CAR T-cell therapies dramatically promote the effectiveness and robustness in leukemia cases. However, only a few CAR T-cell therapies gain FDA approval till now, which are applied to hematologic cancers. Targeting solid tumors through CAR T-cell therapies still faces many problems, such as tumor heterogeneity, antigen loss, infiltration inability and immunosuppressive micro-environment. Recent advances provide new insights about the mechanisms of CAR T-cell therapy resistance and give rise to potential reversal therapies. In this review, we mainly introduce existing barriers when treating solid tumors with CAR T-cells and discuss the methods to overcome these challenges.

Challenges and solutions to superior chimeric antigen receptor‐T design and deployment for B‐cell lymphomas

“…Historically, the initial engineering efforts for CARs involved use of only the extracellular scFv and the intracellular CD3ζ activation domain—these comprised first‐generation CARs. These first‐generation CARs would depend solely on scFv for antigen binding and on CD3ζ activation domain for the effector response 2,3 . Further optimization of CAR design led to second‐generation constructs, which included the components of a first‐generation CAR and a co‐stimulatory domain such as CD28 and 4‐1BB.…”

“…The current Food and Drug Administration (FDA)-approved CAR-T therapies are mostly second-generation CARs. 2,3 In an effort to enhance immune effector function, third-generation CARs were eventually developed, and these have at least two co-stimulatory domains. Fourth-generation CARs contain cytokine inducers and involve NFAT activation.…”

“…These first-generation CARs would depend solely on scFv for antigen binding and on CD3ζ activation domain for the effector response. 2,3 Further optimization of CAR design led to second-generation constructs, which included the components of a first-generation CAR and a costimulatory domain such as CD28 and 4-1BB. The current Food and Drug Administration (FDA)-approved CAR-T therapies are mostly second-generation CARs.…”

“…The intracellular domain usually consists of CD3ζ (the intracellular portion of the CD3 complex), which mediates effector T cell function. 2,3 Historically, the initial engineering efforts for CARs involved use of only the extracellular scFv and the intracellular CD3ζ activation domain-these comprised first-generation…”

“…Finally, fifth-generation CARs contain a cytokine receptor within the construct, allowing for JAK-STAT activation. 3 Despite the success of CAR-T therapies, grade 3 and 4 toxicities are common with CAR-T products-these iatrogenic complications may sometimes lead to suboptimal outcomes. Cytokine release syndrome (CRS) and neurotoxicity are the most well-known toxicities of these therapies.…”