Table 1 Some examples of the application of TCR-like CARs and TCR-CARs in human cancers.
From: TCR-like CARs and TCR-CARs targeting neoepitopes: an emerging potential
Target antigen | Epitope type | HLA type | CAR ECD | CAR ICDs | Highlights of the study | Refs. |
|---|---|---|---|---|---|---|
MELAN-A, TGFβR2 | Wild-type, mutated | HLA-A2 | TCR domains | CD28/CD3ζ | - Stable expression of TCR-CARs, even in CD3-free system such as the NK cells (for TGFβR2-specific TCR-CAR) - Efficient targeting and killing activity of TCR-CARs | [4] |
NY-ESO-1, MAGE-A3 | Wild-type, mutated | HLA-A*0201 | Single variable domain of TCRβ chain | CD28/4-1BB/CD3ζ | - Stable expression of TCR-CARs on T cells - Selective binding of TCR-CAR to pMHC - Triggering T cells in the same manner as full TCRs | [36] |
NY-ESO-1 | Wild-type, mutated | HLA-A*0201 | scFv | CD28/CD3ζ | - Despite soluble Fab specificity, CARs expressing the same scFv caused moderate lysis of targets independent of antigen - Lowering the affinity of the CAR for HLA-A2 restored the TCR-like CAR T cell’s epitope specificity and improved its cytolytic activity | [39] |
WT1 | Mutated | HLA-A*2402 | scFv | CD3ζ/GITR | - TCR-like CAR T cells showed therapeutic efficacy - DCs loaded with the cognate antigen enhanced CAR T cells efficacy | [40] |
WT1 | Wild-type | HLA-A2 | scFv | CD28/FcRγ | - In contrast to low-affinity αβ-TCRs, the high-affinity TCR-like CAR exhibited reduced activity and loss of specificity - Combination of high affinity and avidity of a TCR-like CAR displayed dramatic effects on the specificity | [41] |
NY-ESO-1 | Wild-type | HLA-A*0201 | scFv | CD28/CD3ζ | - TCR-like CAR T cells had a predominant effector memory phenotype, and lysed target cells in an antigen-specific manner | [44] |
HA-1H | Mutated | HLA-A*0201 | scFv | CD28/CD3ζ | - High-affinity TCR-like CARs (Kd = 19.9 nM) exerted lower cytotoxicity in target cells with low-density peptide/MHC complexes (~100 per cell), when compared to the scFvs with moderate to low affinity (Kd = 446 nM) - CD8+ TCR-like CAR T cells were not necessarily CD8-dependent probably due to failure to form stable complexes with CD3 | [47] |
AFP | Mutated | HLA-A*0201 | scFv | CD28/CD3ζ | - TCR-like CAR T cells selectively activated, released cytokines, and killed AFP+ target cells in vitro and in vivo. | [56] |
WT1 | Wild-type | HLA-A2 | scFv | 4-1BB/CD3ζ | - Affinity-enhanced scFv showed exquisite specificity towards WT1 epitope - Bivalent scFv-huIgG1-Fc fusion protein showed higher avidity to the epitope and induced cytolytic function of TCR-like CAR T/NK cells | [42] |
PR1 | Wild-type | HLA-A2 | scFv | CD28/CD3ζ | - Efficient transduction and function of TCR-like CARs into PBMCs as well as T cells generated from umbilical cord blood (more permissive for HLA-mismatching) - TCR-like CAR T cells displayed preferential cytotoxicity against PR1+ leukemia cells | [57] |
