Composite CD79A/CD40 co-stimulatory endodomain enhances CD19CAR-T cell proliferation and survival
Julamanee J, Terakura S, Umemura K, Adachi Y, Miyao K, Okuno S, Takagi E, Sakai T, Koyama D, Goto T, Hanajiri R, Hudecek M, Steinberger P, Leitner J, Nishida T, Murata M, Kiyoi H (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 29
Pages Range: 2677-2690
Journal Issue: 9
DOI: 10.1016/j.ymthe.2021.04.038
Abstract
Adoptively transferred CD19 chimeric antigen receptor (CAR) T cells have led to impressive clinical outcomes in B cell malignancies. Beyond induction of remission, the persistence of CAR-T cells is required to prevent relapse and provide long-term disease control. To improve CAR-T cell function and persistence, we developed a composite co-stimulatory domain of a B cell signaling moiety, CD79A/CD40, to induce a nuclear translocating signal, NF-κB, to synergize with other T cell signals and improve CAR-T cell function. CD79A/CD40 incorporating CD19CAR-T cells (CD19.79a.40z) exhibited higher NF-κB and p38 activity upon CD19 antigen exposure compared with the CD28 or 4-1BB incorporating CD19CAR-T cells (CD19.28z and CD19.BBz). Notably, we found that CD19.79a.40z CAR-T cells continued to suppress CD19+ target cells throughout the co-culture assay, whereas a tendency for tumor growth was observed with CD19.28z CAR-T cells. Moreover, CD19.79a.40z CAR-T cells exhibited robust T cell proliferation after culturing with CD19+ target cells, regardless of exogenous interleukin-2. In terms of in vivo efficiency, CD19.79a.40z demonstrated superior anti-tumor activity and in vivo CAR-T cell proliferation compared with CD19.28z and CD19.BBz CD19CAR-T cells in Raji-inoculated mice. Our data demonstrate that the CD79A/CD40 co-stimulatory domain endows CAR-T cells with enhanced proliferative capacity and improved anti-tumor efficacy in a murine model.
Involved external institutions
Nagoya University / 名古屋大学
Japan (JP)
Universitätsklinikum Würzburg
Germany (DE)
Medizinische Universität Wien
Austria (AT)
Japan (JP)
Universitätsklinikum Würzburg
Germany (DE)
Medizinische Universität Wien
Austria (AT)
How to cite
APA:
Julamanee, J., Terakura, S., Umemura, K., Adachi, Y., Miyao, K., Okuno, S.,... Kiyoi, H. (2021). Composite CD79A/CD40 co-stimulatory endodomain enhances CD19CAR-T cell proliferation and survival. Molecular Therapy, 29(9), 2677-2690. https://doi.org/10.1016/j.ymthe.2021.04.038
MLA:
Julamanee, Jakrawadee, et al. "Composite CD79A/CD40 co-stimulatory endodomain enhances CD19CAR-T cell proliferation and survival." Molecular Therapy 29.9 (2021): 2677-2690.
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