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Theranostics 2023; 13(14):5099-5113. doi:10.7150/thno.84946 This issue Cite

Research Paper

A dendritic/tumor fusion cell vaccine enhances efficacy of nanobody-based CAR-T cells against solid tumor

Shuyang Sun^1#, Ziqiang Ding^1#, Li Gao^1#, Bruce D. Hammock², Xianing Huang¹, Zhi Ping Xu³, Xuan Wang⁴, Qihong Cheng⁴, Fengzhen Mo¹, Wei Shi¹, Shenxia Xie¹, Aiqun Liu¹, Haixia Li¹, Xiaomei Yang^1✉, Xiaoling Lu^1✉

1. College of Stomatology/ Hospital of Stomatology/ School of Basic Medical Sciences/ Guangxi Key Laboratory of Nanobody Research/ Guangxi Nanobody Engineering Research Center/ Laboratory Animal Center/ Pharmaceutical College/ Affiliated Tumor Hospital, Guangxi Medical University, Nanning, 530021, China.
2. UCD Comprehensive Cancer Center, Department of Entomology and Nematology, University of California, Davis, CA 95616, USA.
3. Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, QLD 4072, Australia.
4. Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
# These authors contributed equally to this work.

✉ Corresponding authors: Xiaoling Lu (luxiaolingedu.cn) and Xiaomei Yang (yxmedu.cn).

Abstract

Background: Chimeric antigen receptor (CAR) T-cell therapy is practical in treating cancers of hematopoietic origin, but of that in solid tumors compromises efficacy for the loss of the antigen recognized by the CAR. However, dendritic cell (DC)/tumor fusion vaccines present a spectrum of known or unknown tumor antigens to stimulate T cell expansion and enhanced T cell response. Developing a new strategy of enhanced nanobody-based CAR-T (Nb-CAR-T) cells antitumor activity by DC/tumor fusion vaccines stimulation would provide guidance for more effective CAR-T cell therapies.

Methods: Considering the therapeutic potential of nanobody (Nb), we first screened EGFRvIII Nb, then constructed and verified the function of EGFRvIII Nb-CAR-T cells in vitro and in vivo. We further combined DC/tumor fusion vaccines to boost EGFRvIII Nb-CAR-T cells antitumor effect, which was evaluated in vitro Nb-CAR-T cell function and in the tumor-bearing xenograft mouse models.

Results: We had for the first time successfully selected EGFRvIII Nb for the generation of the novel EGFRvIII Nb-CAR-T cells. Importantly, our results suggested that DC/tumor fusion vaccines stimulate Nb-CAR-T cells response not only in improving T cell proliferation, T cell activation, cytokine secretion and tumor-specific cytotoxicity in vitro, but also significantly reducing tumor burden, prolonging survival and improving Nb-CAR-T cells infiltration.

Conclusions: We have innovatively shown that DC/tumor fusion vaccines significantly enhance the efficacy of Nb-CAR-T cells against solid tumors. This new strategy has provided a promising therapeutic platform for promoting the clinical treatment of CAR-T cells therapy.

Keywords: nanobody, CAR-T cells, DC/tumor fusion vaccines, EGFRvIII, solid tumor

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