Gene Augmentation and Editing to Improve TCR Engineered T Cell Therapy against Solid Tumors
| Autor: | Stefan Nierkens, Vania Lo Presti, Frank Buitenwerf, Niek P. van Til |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetic enhancement Transgene T cell Immunology adoptive T cell therapy lcsh:Medicine Review Cell therapy 03 medical and health sciences 0302 clinical medicine Immune system Genome editing Drug Discovery medicine Pharmacology (medical) Pharmacology gene editing business.industry lcsh:R T-cell receptor solid tumors Chimeric antigen receptor 030104 developmental biology Infectious Diseases medicine.anatomical_structure T cell receptor engineering 030220 oncology & carcinogenesis Cancer research business |
| Zdroj: | Vaccines, Vol 8, Iss 733, p 733 (2020) Vaccines |
| ISSN: | 2076-393X |
| DOI: | 10.3390/vaccines8040733 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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