Journal
CANCERS
Volume 12, Issue 10, Pages -Publisher
MDPI
DOI: 10.3390/cancers12102735
Keywords
TACTICs (tumor angiogenesis-specific CAR-T cells impacting cancers) therapy; anti-VEGFR2 CAR; mRNA electroporation; soft tissue sarcoma
Categories
Funding
- JSPS KAKENHI [18H04018, 16K15160, 19H05552]
- SENSHIN Medical Research Foundation
- Takeda Research Support 2019
- Takeda Science Foundation
- Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED [JP19am0101084]
- Grants-in-Aid for Scientific Research [16K15160, 18H04018] Funding Source: KAKEN
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Simple Summary Sarcomas have few effective treatment options due to the rarity and diversity and have a high risk of recurrence and metastasis. Therefore, the development of new therapeutics that can meet their medical needs is required. Our adoptive immunotherapy strategy using T cells to express the chimeric antigen receptor (CAR) against vascular endothelial growth factor receptor 2 (VEGFR2), which is highly expressed on tumor vascular endothelial cells, has the potential to be a novel treatment against diverse sarcomas with abundant vascular invasion. Here, we optimized the manufacturing and transportation of anti-VEGFR2 CAR-mRNA-transfected T cells and collected information that allowed the extrapolation of their efficacy and safety potential for sarcoma patients. Our results support the development of a first in humans study to evaluate the potential of our anti-VEGFR2 CAR-T cell therapy as a new treatment option for sarcoma patients. Soft tissue sarcomas (STSs) are heterogeneous and aggressive malignancies with few effective therapies available. We have developed T cells expressing a vascular endothelial growth factor receptor 2 (VEGFR2)-specific chimeric antigen receptor (CAR) to establish a tumor angiogenesis-specific CAR-T cells impacting cancers (TACTICs) therapy. In this study, we optimized the manufacturing and transportation of mRNA-transfected anti-VEGFR2 CAR-T cells and collected information that allowed the extrapolation of the efficacy and safety potential of TACTICs therapy for STS patients. Although 5-methoxyuridines versus uridines did not improve CAR-mRNA stability in T cells, the utilization of CleanCap as a 5 ' cap-structure extended the CAR expression level, increasing VEGFR2-specific cytotoxicity. Furthermore, 4 degrees C preservation conditions did not affect the viability/cytotoxicity of CAR-T cells, contrarily to a freeze-thaw approach. Importantly, immunohistochemistry showed that most of the STS patients' specimens expressed VEGFR2, suggesting a great potential of our TACTICs approach. However, VEGFR2 expression was also detected in normal tissues, stressing the importance of the application of a strict monitoring schedule to detect (and respond to) the occurrence of adverse effects in clinics. Overall, our results support the development of a first in humans study to evaluate the potential of our TACTICs therapy as a new treatment option for STSs.
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