Limitations in the Design of Chimeric Antigen Receptors for Cancer Therapy

Abstract

Cancer therapy has entered a new era, transitioning from unspecific chemotherapeutic agents to increasingly specific immune-based therapeutic strategies. Among these, chimeric antigen receptor (CAR) T cells have shown unparalleled therapeutic potential in treating refractory hematological malignancies. In contrast, solid tumors pose a much greater challenge to CAR T cell therapy, which has yet to be overcome. As this novel therapeutic modality matures, increasing effort is being invested to determine the optimal structure and properties of CARs to facilitate the transition from empirical testing to the rational design of CAR T cells. In this review, we highlight how individual CAR domains contribute to the success and failure of this promising treatment modality and provide an insight into the most notable advances in the field of CAR T cell engineering.

Keywords: CAR T cell; adoptive cell therapy; chimeric antigen receptor; immunotherapy.

Figure 1

Limitations of chimeric antigen receptor (CAR) T cells. Tonic signaling, exhaustion and activation-induced cell death (AICD) limit T cell functionality, proliferation and persistence. Trafficking of CAR T cells to the tumor site may be limited due to an inadequate chemokine receptor profile. Antigen loss can lead to tumor escape, while cytokine release syndrome (CRS) constitutes a frequently observed adverse event. Abbreviations: PD-1, programmed cell death protein 1; LAG-3, lymphocyte activation gene 3; TIM-3, T cell immunoglobulin mucin 3.

Figure 2

Summary of CAR-intrinsic and CAR-extrinsic factors of CAR T cell design. Depicted is a representation of a CAR molecule with its respective domains. The table lists the most notable contributions of individual domains to CAR T cell functionality. The zoom-in illustrates how the length of the spacer domain may influence the immunological synapse distance and confer flexibility for optimal target recognition. Abbreviations: Ig, immunoglobulin; ICOS, inducible T cell costimulator; CRISPR, clustered regularly interspaced short palindromic repeats.

Figure 3

(A) Novel CAR formats. (1) Tandem CAR T cells can recognize either tumor antigen A or B and may prevent antigen escape. (2) CARs with separated signaling domains display attenuated off-tumor toxicity. (3) Synthetic Notch receptors can induce the transcription of another transgene, such as a conventional CAR, upon antigen recognition. (4) SUPRA CAR T cell activity may be tuned at multiple levels to ensure maximal effectiveness and minimal toxicity. (B) Add-ons to CARs. (1) CARs may be combined with chemokine receptors to increase CAR T cell trafficking to the tumor site. (2) Switch receptors can convert negative stimuli into positive ones. (3) CAR T cells can be engineered to secrete chemokines, cytokines and matrix-degrading enzymes to potentiate their anti-tumor efficacy. (4) Inhibitory CARs may be used to protect healthy tissue from CAR T cell-mediated destruction. Abbreviations: SUPRA CAR, split, universal and programmable CAR; TAA, tumor-associated antigen.