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

1
Project for Vaccine and Immune Regulation, Graduate School of Pharmaceutical Sciences, Osaka University, Suita 565-0871, Japan
2
MEDINET Co. Ltd., Tokyo 143-0006, Japan
3
Department of Orthopaedic Surgery, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
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Department of Orthopaedics, Nozaki Tokusyukai Hospital, Daito 574-0074, Japan
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Department of Surgical Pathology, Hokkaido University Hospital, Sapporo 060-8648, Japan
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Research Division of Companion Diagnostics, Hokkaido University Hospital, Sapporo 060-8648, Japan
7
Clinical biobank, Clinical Research and Medical Innovation Center, Hokkaido University Hospital, Sapporo 060-8648, Japan
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Department of Orthopaedics, Osaka International Cancer Institute, Osaka 541-8567, Japan
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(10), 2735; https://doi.org/10.3390/cancers12102735
Received: 6 August 2020 / Revised: 15 September 2020 / Accepted: 21 September 2020 / Published: 23 September 2020
(This article belongs to the Section Cancer Therapy)
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 °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. View Full-Text
Keywords: TACTICs (tumor angiogenesis-specific CAR-T cells impacting cancers) therapy; anti-VEGFR2 CAR; mRNA electroporation; soft tissue sarcoma TACTICs (tumor angiogenesis-specific CAR-T cells impacting cancers) therapy; anti-VEGFR2 CAR; mRNA electroporation; soft tissue sarcoma
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MDPI and ACS Style

Fujiwara, K.; Sasawatari, S.; Nakai, S.; Imaeda, K.; Nagai, S.; Matsuno, Y.; Hatanaka, K.; Hatanaka, Y.; Takenaka, S.; Okada, N. Predicting the Efficacy and Safety of TACTICs (Tumor Angiogenesis-Specific CAR-T Cells Impacting Cancers) Therapy for Soft Tissue Sarcoma Patients. Cancers 2020, 12, 2735. https://doi.org/10.3390/cancers12102735

AMA Style

Fujiwara K, Sasawatari S, Nakai S, Imaeda K, Nagai S, Matsuno Y, Hatanaka K, Hatanaka Y, Takenaka S, Okada N. Predicting the Efficacy and Safety of TACTICs (Tumor Angiogenesis-Specific CAR-T Cells Impacting Cancers) Therapy for Soft Tissue Sarcoma Patients. Cancers. 2020; 12(10):2735. https://doi.org/10.3390/cancers12102735

Chicago/Turabian Style

Fujiwara, Kento, Shigemi Sasawatari, Sho Nakai, Keisuke Imaeda, Seina Nagai, Yoshihiro Matsuno, Kanako Hatanaka, Yutaka Hatanaka, Satoshi Takenaka, and Naoki Okada. 2020. "Predicting the Efficacy and Safety of TACTICs (Tumor Angiogenesis-Specific CAR-T Cells Impacting Cancers) Therapy for Soft Tissue Sarcoma Patients" Cancers 12, no. 10: 2735. https://doi.org/10.3390/cancers12102735

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