High-affinity T cell receptors redirect cytokine-activated T cells (CAT) to kill cancer cells

Abstract

Cytokine-activated T cells (CATs) can be easily expanded and are widely applied to cancer immunotherapy. However, the good efficacy of CATs is rarely reported in clinical applications because CATs have no or very low antigen specificity. The low-efficacy problem can be resolved using T cell antigen receptorengineered CAT (TCR-CAT). Herein, we demonstrate that NY-ESO-1 157-165 HLA-A*02:01-specific high-affinity TCR (HAT)-transduced CATs can specifically kill cancer cells with good efficacy. With low micromolar range dissociation equilibrium constants, HAT-transduced CATs showed good specificity with no off-target killing. Furthermore, the high-affinity TCR-CATs delivered significantly better activation and cytotoxicity than the equivalent TCR-engineered T cells (TCR-Ts) in terms of interferon-g and granzyme B production and in vitro cancer cell killing ability. TCR-CAT may be a very good alternative to the expensive TCR-T, which is considered an effective personalized cyto-immunotherapy.

Decitabine enhances targeting of AML cells by NY-ESO-1-specific TCR-T cells and promotes the maintenance of effector function and the memory phenotype

“…Our previous study demonstrated that high-affinity 1G4 TCR-T cells (K D = 1.07 μM) showed enhanced killing activities than the wild-type 1G4 TCR-T cells (K D = 32 μM) [ 32 ]. We found here, in consistence with our previous study, high-affinity TCR-T (ha-TCR-T; thereafter referred to as TCR-T in other sections) cells in combing with DAC remains better killing than the wild-type TCR-T (wt-TCR-T) cells against AML.…”

“…The inhibition of target cells with an MHC-class I monoclonal antibody showed attenuated TCR activity with a significant reduction of TNF-α production by the NY-ESO-1-specific TCR-T cells. Our previous study demonstrated the effect of soluble high-affinity TCR (26 pM) in blocking melanoma and multiple myeloma cell lines, which could significantly reduce IFN-γ secretion [ 32 ]. Therefore, these data confirm that the enhanced anti-leukemia capacity of NY-ESO-1-specific TCR-T cells is MHC-dependent.…”

“…For example, NY-ESO-1 vaccination combined with DAC for the treatment of AML has established positive results in a phase I clinical study [ 27 ]. Although DAC-induced NY-ESO-1-specific cytotoxic T lymphocytes (CTLs) have been used in clinical settings, CTLs express wild-type TCRs, which have low affinity for their target under tumor-escaping conditions [ 31 , 32 ].…”

Neoantigens in precision cancer immunotherapy: from identification to clinical applications

“…Bajgain et al [93] showed that CAR T cells targeting a mucin1 neoantigen can expand selectively at the tumor site and achieve durable anti-tumor immunity. Neoantigen-specific TCR gene-engineered T-cells have been shown to be effective in multiple pre-clinical studies [94–96] . Many clinical trials have also shown that these TCR gene-engineered T cells mediate clinically meaningful anti-tumor immunity [97,98] …”

T Cell Reprogramming Against Cancer

“…TCRs with high affinity, not available in normal T cells because of negative selection in the thymus, may enhance the ability to kill target cells in the cancer environment [203]. Engineered T cells containing "high-affinity" TCRs showed efficiency in treating myeloma and synovial cell sarcomas [204,205]. Also, generation of synthetic TCRs able to recognize specific cancer neo-antigens or known cancer-specific antigen/MHC combinations can be advantageous for developing individualized anticancer therapy [206,207].…”