To boost antitumor immunity by enhancing antigen expression, Wang and Chow et al. utilized targeted gene activating CRISPRa methodology and built multiplexed genomic and precision mutant (targeting 1116 mutated genes) CRISPRa libraries from TNBC E0771 tumors. When delivered as cell-based vaccines (prophylactic and therapeutic) or i.t. using AAV, potent antitumor efficacy was seen with all modes of delivery. Therapeutic i.t. AAV delivery was effective in three tumor types and in distant uninjected sites. Antitumor responses were T cell dependent and associated with increases in TCR diversity, T cell infiltration, and effector function.
Contributed by Katherine Turner
Immunotherapy has transformed cancer treatment. However, current immunotherapy modalities face various limitations. In the present study, we developed multiplexed activation of endogenous genes as an immunotherapy (MAEGI), a new form of immunotherapy that elicits antitumor immunity through multiplexed activation of endogenous genes in tumors. We leveraged CRISPR activation (CRISPRa) to directly augment the in situ expression of endogenous genes, and thereby the presentation of tumor antigens, leading to dramatic antitumor immune responses. Deploying this as a cell-based vaccination strategy showed efficacy in both prophylactic and therapeutic settings. Intratumoral adeno-associated virus delivery of CRISPRa libraries elicited strong antitumor immunity across multiple cancer types. Precision targeting of mutated gene sets eradicated a large fraction of established tumors at both local and distant sites. This treatment modality led to alterations in the tumor microenvironment, marked by enhanced T cell infiltration and antitumor immune signatures. Multiplexed endogenous gene activation is a versatile and highly scalable strategy to elicit potent immune responses against cancer, distinct from all existing cancer therapies.
Author Info: (1) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biolog
Author Info: (1) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. (2) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. MD-PhD Program, Yale University, New Haven, CT, USA. (3) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. Department of General Surgery, Beijing Friendship Hospital of Capital Medical University, Beijing, China. (4) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. (5) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. (6) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. (7) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. MD-PhD Program, Yale University, New Haven, CT, USA. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA. Immunobiology Program, Yale University, New Haven, CT, USA. (8) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. (9) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. (10) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA. (11) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. MD-PhD Program, Yale University, New Haven, CT, USA. (12) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. (13) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. System Biology Institute, Yale University, West Haven, CT, USA. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. (14) Department of Medicine, Yale University School of Medicine, New Haven, CT, USA. Smilow Cancer Hospital, New Haven, CT, USA. Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA. (15) Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. sidi.chen@yale.edu. System Biology Institute, Yale University, West Haven, CT, USA. sidi.chen@yale.edu. Center for Cancer Systems Biology, Yale University, West Haven, CT, USA. sidi.chen@yale.edu. MD-PhD Program, Yale University, New Haven, CT, USA. sidi.chen@yale.edu. Immunobiology Program, Yale University, New Haven, CT, USA. sidi.chen@yale.edu. Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA. sidi.chen@yale.edu. Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA. sidi.chen@yale.edu. Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA. sidi.chen@yale.edu. Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA. sidi.chen@yale.edu. Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA. sidi.chen@yale.edu. Yale Center for Biomedical Data Science, Yale University School of Medicine, New Haven, CT, USA. sidi.chen@yale.edu.
