4.6 Article

Predicting the Efficacy and Safety of TACTICs (Tumor Angiogenesis-Specific CAR-T Cells Impacting Cancers) Therapy for Soft Tissue Sarcoma Patients

期刊

CANCERS
卷 12, 期 10, 页码 -

出版社

MDPI
DOI: 10.3390/cancers12102735

关键词

TACTICs (tumor angiogenesis-specific CAR-T cells impacting cancers) therapy; anti-VEGFR2 CAR; mRNA electroporation; soft tissue sarcoma

类别

资金

  1. JSPS KAKENHI [18H04018, 16K15160, 19H05552]
  2. SENSHIN Medical Research Foundation
  3. Takeda Research Support 2019
  4. Takeda Science Foundation
  5. Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED [JP19am0101084]
  6. Grants-in-Aid for Scientific Research [16K15160, 18H04018] Funding Source: KAKEN

向作者/读者索取更多资源

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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