Journal
NATURE IMMUNOLOGY
Volume 20, Issue 11, Pages 1494-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41590-019-0500-4
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Funding
- Yale SBI/Genetics Startup Fund
- National Institutes of Health/National Cancer Institute (NIH/NCI) [DP2CA238295, R01CA231112, R33CA225498, U54CA209992-8697, RF1DA048811, P50CA196530-A10805, P50CA121974-A08306]
- Damon Runyon Dale Frey Award [DFS-13-15]
- Melanoma Research Alliance [412806, 16-003524]
- St Baldrick's Foundation [426685]
- Breast Cancer Alliance
- Cancer Research Institute
- American Association for Cancer Research [499395, 17-20-01-CHEN]
- Mary Kay Foundation [017-81]
- V Foundation [V2017-022]
- Ludwig Family Foundation, DoD [W81XWH-17-1-0235]
- Sontag Foundation
- Chenevert Family Foundation
- NIH/NCI Cancer Center Support Grant [3P30CA016359]
- CRI Irvington Postdoctoral Fellowship
- NIH [T32GM007499, T32GM007205]
- C Revson Postdoctoral Fellowship
- RJ Anderson Postdoctoral Fellowship
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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.
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