T-Cell Receptor Gene Therapy: Critical Parameters for Clinical Success

Abstract

T-cell receptor (TCR) gene therapy aims to induce immune reactivity against tumors by introducing genes encoding a tumor-reactive TCR into patient T cells. This approach has been extensively tested in preclinical mouse models, and initial clinical trials have demonstrated the feasibility and potential of TCR gene therapy as a cancer treatment. However, data obtained from preclinical and clinical studies suggest that both the therapeutic efficacy and the safety of TCR gene therapy can be and needs to be further enhanced. This review highlights those strategies that can be followed to develop TCR gene therapy into a clinically relevant treatment option for cancer patients.

The CD3-Zeta Chimeric Antigen Receptor Overcomes TCR Hypo-Responsiveness of Human Terminal Late-Stage T Cells

“…Therefore our data strongly suggest, that a transgenic CAR, which utilizes a CD3-zeta chain for signal transduction, is not hampered by galectin-3 interaction with the TCR signal transduction machinery after antigen recognition. Life imaging moreover implies that the TCR and the CAR independently form synapses that is in contrast to the transgenic expression of a recombinant TCR that can form heterodimers with the physiological TCR [24], [25]. Even a modified transgenic TCR that does not pair with the endogenous TCR localizes in close vicinity to the endogenous TCR/CD3 in Jurkat T cells [13].…”

The three main stumbling blocks for anticancer T cells

“…Enhanced potency of adoptively transferred T cells comes with increased risk of toxicity, mainly because healthy cells and organs may be recognized and destroyed by the transferred T cells [66]. Novel methods of inserting TCRs, combined with blocking the expression of endogenous TCR chains have shown increased efficacy and reduced toxicity due to a reduced probability of mispairing with endogenous TCR a-and bchains [67][68][69]. In addition, promising new techniques have been developed that enable the destruction of transferred cells in vivo, in case of otherwise uncontrolled tissue damage [70].…”

Mechanism of immune evasion in breast cancer

“…In addition, the expression of its extracellular domain is significantly higher in the sera of BC patients compared with tumor-free individuals, and its expression levels are positively correlated with histological tumor grade, suggesting that HER2/neu is overexpressed in and leads to the poor prognosis of Her2-positive BC 14. The low expression of HER2/neu might restrict the immune-cell-mediated destruction of tumor cells; thus, TCR gene therapy that encodes for TCR and enhances the immune response has been profoundly studied and tested in clinical trials 13,15. Additionally, a specially designed nanobody can selectively bind to TAA receptors 16.…”