Development of a Novel Anti-CD19 CAR Containing a Fully Human scFv and Three Costimulatory Domains
Issued Date
2022-01-18
Resource Type
eISSN
2234943X
Scopus ID
2-s2.0-85123872156
Journal Title
Frontiers in Oncology
Volume
11
Rights Holder(s)
SCOPUS
Bibliographic Citation
Frontiers in Oncology Vol.11 (2022)
Suggested Citation
Wutti-in Y., Sujjitjoon J., Sawasdee N., Panya A., Kongkla K., Yuti P., Yongpitakwattana P., Thepmalee C., Junking M., Chieochansin T., Poungvarin N., Yamabhai M., Yenchitsomanus P.T. Development of a Novel Anti-CD19 CAR Containing a Fully Human scFv and Three Costimulatory Domains. Frontiers in Oncology Vol.11 (2022). doi:10.3389/fonc.2021.802876 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/83858
Title
Development of a Novel Anti-CD19 CAR Containing a Fully Human scFv and Three Costimulatory Domains
Author's Affiliation
Other Contributor(s)
Abstract
Second-generation anti-CD19-chimeric antigen receptor T cells (anti-CD19-CAR2 T cells) are effective for treating B-cell malignancies; however, anti-CD19-CAR2 T cells can induce human anti-mouse immune responses because anti-CD19 single-chain variable fragment (scFv) in the CAR molecules is derived from a murine FMC63 (mFMC63) monoclonal antibody. Consequently, the persistence of mFMC63-CAR2 T cells and their therapeutic efficiency in patients are decreased, which results in tumor relapse. In an attempt to remedy this shortcoming, we generated a new anti-CD19-CAR T cells containing fully human anti-CD19 scFv (Hu1E7-CAR4 T cells) to pre-clinically evaluate and compare with mFMC63-CAR4 T cells. The human anti-CD19 scFv (Hu1E7) was isolated from a human scFv phage display library and fused to the hinge region of CD8α, the transmembrane domain of CD28, three intracellular costimulatory domains (CD28, 4-1BB, and CD27), and a CD3ζ signaling domain (28BB27ζ). Compared to mFMC63-CAR2 T cells (BBζ) and mFMC63-CAR3 (BB27ζ), the mFMC63-CAR4 T cells (28BB27ζ) exerted superior anti-tumor activity against Raji (CD19+) target cell. The Hu1E7-CAR4 and mFMC63-CAR4 T cells demonstrated comparable cytotoxicity and proliferation. Interestingly, compared to mFMC63-CAR4 T cells, the Hu1E7-CAR4 T cells secreted lower levels of cytokines (IFN-γ and TNF-α), which may be due to the lower binding affinity of Hu1E7-CAR4 T cells. These findings demonstrated the successfulness in creation of a new CAR T cells containing a novel fully human-derived scFv specific to CD19+ cancer cells. In vivo studies are needed to further compare the anti-tumor efficacy and safety of Hu1E7-CAR4 T cells and mFMC63-CAR4 T cells.