Neoantigen-augmented iPSC cancer vaccine combined with radiotherapy promotes antitumor immunity in poorly immunogenic cancers

Kevin Chih-Yang Huang; William Tzu-Liang Chen; Jia-Yi Chen; Chien-Yueh Lee; Chia-Hsin Wu; Chia-Ying Lai; Pei-Chen Yang; Ji-An Liang; An-Cheng Shiau; K S Clifford Chao; Tao-Wei Ke

doi:10.1038/s41541-024-00881-5

Neoantigen-augmented iPSC cancer vaccine combined with radiotherapy promotes antitumor immunity in poorly immunogenic cancers

NPJ Vaccines. 2024 May 31;9(1):95. doi: 10.1038/s41541-024-00881-5.

Authors

Kevin Chih-Yang Huang^{1

2

3}, William Tzu-Liang Chen^{4

5

6}, Jia-Yi Chen⁷, Chien-Yueh Lee^{8

9

10}, Chia-Hsin Wu^{7

11}, Chia-Ying Lai^{12

7}, Pei-Chen Yang⁷, Ji-An Liang^{13

14}, An-Cheng Shiau^{12

7

13}, K S Clifford Chao^{15

16

17}, Tao-Wei Ke^{18

19}

Affiliations

¹ Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 406040, Taiwan, ROC. chihyang0425@mail.cmu.edu.tw.
² Translation Research Core, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. chihyang0425@mail.cmu.edu.tw.
³ Cancer Biology and Precision Therapeutics Center, China Medical University, Taichung, 406040, Taiwan, ROC. chihyang0425@mail.cmu.edu.tw.
⁴ Department of Surgery, School of Medicine, China Medical University, Taichung, 406040, Taiwan, ROC.
⁵ Department of Colorectal Surgery, China Medical University HsinChu Hospital, China Medical University, HsinChu, 302, Taiwan, ROC.
⁶ Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC.
⁷ Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC.
⁸ Innovation Frontier Institute of Research for Science and Technology, National Taipei University of Technology, Taipei, 106344, Taiwan, ROC.
⁹ Department of Electrical Engineering, National Taipei University of Technology, Taipei, 106344, Taiwan, ROC.
¹⁰ Department of Biomedical Engineering, China Medical University, Taichung, 406040, Taiwan, ROC.
¹¹ Bioinformatics and Biostatistics Core, Centers of Genomic and Precision Medicine, National Taiwan University, Taipei, 10055, Taiwan, ROC.
¹² Department of Biomedical Imaging and Radiological Science, China Medical University, Taichung, 406040, Taiwan, ROC.
¹³ Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC.
¹⁴ Department of Radiotherapy, School of Medicine, China Medical University, Taichung, 406040, Taiwan, ROC.
¹⁵ Proton Therapy and Science Center, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. d94032@mail.cmuh.org.tw.
¹⁶ Department of Radiation Oncology, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. d94032@mail.cmuh.org.tw.
¹⁷ Department of Radiotherapy, School of Medicine, China Medical University, Taichung, 406040, Taiwan, ROC. d94032@mail.cmuh.org.tw.
¹⁸ Department of Colorectal Surgery, China Medical University Hospital, China Medical University, Taichung, 404327, Taiwan, ROC. d18047@mail.cmuh.org.tw.
¹⁹ School of Chinese Medicine and Graduate Institute of Chinese Medicine, China Medical University, Taichung, 406040, Taiwan, ROC. d18047@mail.cmuh.org.tw.

Abstract

Although irradiated induced-pluripotent stem cells (iPSCs) as a prophylactic cancer vaccine elicit an antitumor immune response, the therapeutic efficacy of iPSC-based cancer vaccines is not promising due to their insufficient antigenicity and the immunosuppressive tumor microenvironment. Here, we found that neoantigen-engineered iPSC cancer vaccines can trigger neoantigen-specific T cell responses to eradicate cancer cells and increase the therapeutic efficacy of RT in poorly immunogenic colorectal cancer (CRC) and triple-negative breast cancer (TNBC). We generated neoantigen-augmented iPSCs (NA-iPSCs) by engineering AAV2 vector carrying murine neoantigens and evaluated their therapeutic efficacy in combination with radiotherapy. After administration of NA-iPSC cancer vaccine and radiotherapy, we found that ~60% of tumor-bearing mice achieved a complete response in microsatellite-stable CRC model. Furthermore, splenocytes from mice treated with NA-iPSC plus RT produced high levels of IFNγ secretion in response to neoantigens and had a greater cytotoxicity to cancer cells, suggesting that the NA-iPSC vaccine combined with radiotherapy elicited a superior neoantigen-specific T-cell response to eradicate cancer cells. The superior therapeutic efficacy of NA-iPSCs engineered by mouse TNBC neoantigens was also observed in the syngeneic immunocompetent TNBC mouse model. We found that the risk of spontaneous lung and liver metastasis was dramatically decreased by NA-iPSCs plus RT in the TNBC animal model. Altogether, these results indicated that autologous iPSC cancer vaccines engineered by neoantigens can elicit a high neoantigen-specific T-cell response, promote tumor regression, and reduce the risk of distant metastasis in combination with local radiotherapy.

Abstract

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