Schematic of a CAR and three CAR engineering approaches.
© lisa clark

(1) A chimeric antigen receptor (CAR) is a modular, synthetic receptor that endows T cells with different targeting abilities. Several emerging engineering approaches aim to improve the safety, specificity, and efficacy of CAR therapies.1,2

(2) Engineered CAR T cells expressing therapeutic payloads can transform the immunosuppressive environment of solid tumors, such as through producing and secreting proinflammatory cytokines.3,4

(3) CAR T cells that perform combinatorial logic operations help cells discriminate between healthy and cancerous cells and hone their attack, thus reducing toxicity. For example, activation of a synthetic Notch (synNotch) receptor that binds one antigen can trigger the expression of a CAR targeting another antigen.5

(4) A CAR controlled remotely via drugs and other small molecules puts the brakes on T cell activation and prevents exhaustion.6,7

          Schematic of a TCR and four CAR engineering approaches.
© lisa clark

(5) The T cell receptor (TCR) is a protein complex that recognizes different peptides and triggers T cell activation. A TCR genetically engineered to bind specific peptide-HLA complexes can improve targeting specificity.8

(6) Soluble TCR and TCR mimics are small proteins that bind peptides and engage with the CD3ε subunit of the endogenous TCR to create a synthetic immunological synapse.9,10

(7) A T cell antigen coupler (TAC) and a TCR fusion construct (TRuC) also engage endogenous TCR signaling, but, similar to a CAR, they bind to tumor antigens. This can increase receptor sensitivity while reducing cytotoxicity and T cell exhaustion observed with a CAR.11,12

(8) Synthetic TCR antigen receptor/HLA-independent TCR (STAR/HIT) constructs retain the full complex of CD3 signaling but also have high antigen sensitivity via the fusion of an antibody binding domain. This hybrid receptor design combines the strengths of a CAR and a TCR.13


  1. Irvine DJ, et al. The future of engineered immune cell therapies. Science. 2022;378:853-858.
  2. Rafiq S, et al. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat Rev Clin Oncol. 2020;17:147-167.
  3. Yeku OO, et al. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci Rep. 2017;7:10541. 
  4. Hu B, et al. Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18. Cell Rep. 2017;20(13):P3025-P3033. 
  5. Choe JH, et al. SynNotch-CAR T cells overcome challenges of specificity, heterogeneity, and persistence in treating glioblastoma. Sci Transl Med. 2021;13(591):eabe7378.
  6. Wu C-Y, et al. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science. 2015;350(6258):eaab4077.
  7. Jan M, et al. Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide. Sci Transl Med. 2021;13(575):eabb6295.
  8. Klebanoff CA, et al. T cell receptor therapeutics: Immunological targeting of the intracellular cancer proteome. Nat Rev Drug Discov. 2023;22:996-1017.
  9. Liddy N, et al. Monoclonal TCR-redirected tumor cell killing. Nat Med. 2012;18:980-987.
  10. Hsiue E, et al. Targeting a neoantigen derived from a common TP53 mutation. Science. 371(6533):eabc8697.
  11. Helsen CW, et al. The chimeric TAC receptor co-opts the T cell receptor yielding robust anti-tumor activity without toxicity. Nat Commun. 2018;9:3049.
  12. Hassan R, et al. Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: Phase 1/2 trial interim results. Nat Med. 2023;29:2099-2109.
  13. Mansilla-Soto J, et al. HLA-independent T cell receptors for targeting tumors with low antigen density. Nat Med. 2022;28:345-352.

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