Sidi Chen, PhD
Initial development of a novel CRISPRa-based immune gene therapy for pancreatic ductal adenocarcinoma (PDAC).
Major types of immunotherapy include checkpoint blockade, adoptive cell transfer, recombinant cytokines, and cancer vaccines. However, only a fraction of patients show sustained clinical responses.
These challenges demand new types of immunotherapies that are more potent and specific. Very recently, we have developed CRISPRa-mediated Multiplexed Activation of Endogenous Genes as an Immunotherapy (MAEGI) (Wang*, Chow* et al. 2019 Nature Immunology).
Neoantigen-targeting approaches demonstrated leveraging personalized neoantigens based on delivery of synthetic mutant peptides or transcripts. However, the efficacy and scalability of these approaches is limited. The CRISPR activation (CRISPRa) system uses a catalytically inactive Cas9 (dCas9), enabling simple and flexible gene expression regulation through dCas9-transcriptional activators paired with single guide RNAs (sgRNAs). This enables precise targeting of large gene pools of endogenous genes in a flexible manner. We demonstrate that MAEGI has therapeutic efficacy across three tumor types.
Pancreatic cancer is a challenging cancer type currently with few options. Based on the broad mechanism of action, we reason that MAEGI may apply to pancreatic cancer. We propose to develop MAEGI specifically for pancreatic cancer immune gene therapy at pre-clinical stage.
First, we will be generating lineage-specific expression vectors and CRISPRa libraries for targeting pancreatic cancer cells with MAEGI. Then, we will be testing PDAC-p-MAEGI’s in vivo efficacy in syngeneic pancreatic cancer models. Finally, we will be studying MAEGI’s mechanism of action in the tumor microenvironment in syngeneic pancreatic cancer models.
To our knowledge MAEGI is an entirely novel form of cancer immune gene therapy. Therefore, this is a high-risk, high-reward project. This project if successful may bring innovative treatment options, albeit at early stage, for pancreatic cancer and other forms of tough cancer types.
This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America.
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