Recent developments in gene engineering technologies have drastically improved the therapeutic treatment options for cancer patients. The use of effective chimeric antigen receptor T (CAR-T) cells and recombinant T cell receptor engineered T (rTCR-T) cells has entered the clinic for treatment of hematological malignancies with promising results. However, further fine-tuning, to improve functionality and safety, is necessary to apply these strategies for the treatment of solid tumors. The immunosuppressive microenvironment, the surrounding stroma, and the tumor heterogeneity often results in poor T cell reactivity, functionality, and a diminished infiltration rates, hampering the efficacy of the treatment. The focus of this review is on recent advances in rTCR-T cell therapy, to improve both functionality and safety, for potential treatment of solid tumors and provides an overview of ongoing clinical trials. Besides selection of the appropriate tumor associated antigen, efficient delivery of an optimized recombinant TCR transgene into the T cells, in combination with gene editing techniques eliminating the endogenous TCR expression and disrupting specific inhibitory pathways could improve adoptively transferred T cells. Armoring the rTCR-T cells with specific cytokines and/or chemokines and their receptors, or targeting the tumor stroma, can increase the infiltration rate of the immune cells within the solid tumors. On the other hand, clinical “off-tumor/on-target” toxicities are still a major potential risk and can lead to severe adverse events. Incorporation of safety switches in rTCR-T cells can guarantee additional safety. Recent clinical trials provide encouraging data and emphasize the relevance of gene therapy and gene editing tools for potential treatment of solid tumors.

Equine rhinitis A virus (ERAV), a picornavirus closely related to foot-and-mouth disease virus, causes respiratory infections in horses. We performed a HEK293T CRISPRi screen and identified integrin α2β1 as a protein receptor for ERAV. Using knock-out cells and pretreating cells with an antibody or soluble receptor, we confirmed the importance of this integrin for infection of multiple cell types, including equine fibroblasts. Cryo-EM and glycoproteomics analyses revealed that ERAV binds integrin α2β1 in its closed conformation by attaching to the β-propeller of the α2 chain, independent of divalent cations, as well as to a high-mannose glycan on α2 N112 and a sialylated glycan on β1 N269. Using glycan knockout and knock-in cells and by reconstituting integrin α2β1-depleted cells with mutant receptors, we demonstrated the importance of these glycans for virus entry. Our results identify a hitherto unseen combination of protein and glycan interactions between a virus and its receptor.