Abstract
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.
Highlights
Introduction of Chemokines Receptors to PromoteMigration and InfiltrationMigration, infiltration, and homing of T cells into solid tumors are often hampered by the presence of a suppressive environment
This review summarizes the most recent developments, with a strong focus on genetic approaches, that have been applied in the field of recombinant T cell receptor engineered T (rTCR-T) cells and the treatment of solid tumors
Transient expression of inducible constructs of IL-12 (iIL-12) showed to be sufficient to inhibit the growth of B16F10 melanoma tumors and to increase the number of tumor-infiltrating recombinant TCRs (rTCRs)-T cells, without showing toxicity compared with the use of the nuclear factor of activated T cell (NFAT)-promoter [83]
Summary
Increasing affinity and avidity of the TCRs have a reflection on the safety of the T cell therapy This has been demonstrated in clinical trials with a high affinity rTCR-T cells against melanoma antigen recognized by T cells 1 (MART-1) causing severe toxicities of the skin, eye, and ears [34]. To preserve the safety of the therapy, an extensive analysis of the expression of the antigen on healthy tissue and the possible cross-reactivity against non-cognate peptide is essential before using rTCR in the clinic. (HA2) specific TCR using a 9-mer combinatorial peptide library (CPL) screening This technique was able to recognize cross-reactivity toward a Cadherin 13 (CDH13)-derived peptide, not detected using the most frequent test (alanine scanning mutagenesis). Afterwards the rTCR-T cells were found to be cross-reactive to a similar epitope derived from the striated muscle-specific protein titin, expressed by cardiac cells [18]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
