Cancer immunotherapy is revolutionizing the treatment of many cancers. This revolution is being led by drugs that enhance the immune system’s T cell’s ability to kill cancer cells. This includes drugs such as Keytruda, an antibody that blocks a molecule called PD1 on T cells, and Kymriah, a living drug which is a product of using gene therapy to engineer a patient’s own T cells to better attack their cancer cells. Despite the amazing successes in some patients, unfortunately, not all patients respond to current immunotherapies.  

One of the cell types that appears to be responsible for the failure is a cell type called a macrophage. Macrophages are part of the immune system and have a function in protecting us from infections. However, tumors can reprogram macrophages to suppress other cells of the immune system, which benefits the tumor by preventing killer immune cells from entering the tumor and killing the cancer cells. Considerable evidence indicates that eliminating the macrophages of a tumor could improve patient outcomes and response to treatments, but traditional pharmacological approaches for doing this have not shown clinical benefit.  

To overcome the limitations of traditional drugs, we will harness the power of gene therapy and develop a new type of living drug in which we would gene engineer a patient’s own T cells to kill the immune suppressing macrophages in their tumors. This would eliminate a major barrier to immunotherapy treatment and help the patient’s immune system to eliminate cancer cells. This novel strategy will draw on the considerable advances in the gene therapy field that led to the development of Kymriah, and other drugs based on the use of chimeric antigen receptor (CAR).  

We will develop a CAR that specifically kills macrophages in a tumor, while sparing macrophages in healthy tissue. We will test our strategy in preclinical animal models of lung and breast cancer to determine if our tumor macrophage killing CAR can lead to the elimination of aggressive tumors. We will also evaluate further refinements to the therapy to make these CAR even more potent at helping the immune system permanently eliminate different cancer. This project will lead to the development of a new gene and cell immunotherapy with the potential to treat a wide variety of cancers and help a patient’s own immune system end their cancer. 

This Alliance for Cancer Gene Therapy Research Fellow is funded in part by Swim Across America. 

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.