Awardees

Chaitanya Parikh  |  Ruscetti Research Group  |  Pancreatic Cancer Alliance Fellowship Award

Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer, with a mere 13% average 5-year survival rate. Conventional chemotherapy and immunotherapy regimens have limited effectiveness, and surgical resection of the tumor is not viable for the majority of PDAC patients diagnosed with advanced metastatic disease. Our previous research has shown therapeutic induction of cellular senescence with RAS pathway targeting therapies can induce cytokine and chemokine production through the senescence-associated secretory phenotype (SASP) that can effectively activate anti-tumor T cell immunity and responses to anti-PD-1 immune checkpoint blockade. To build on these findings and overcome limitations associated with senescence-inducing therapy toxicity, here we leveraged mRNA technology to deliver specific SASP cytokines and chemokines we have found to stimulate immune responses into the suppressive PDAC TME as an immune oncology platform. We created an in vitro transcription pipeline for mRNA production and have successfully demonstrated delivery of multiple mRNAs simultaneously into the TME of transplanted and autochthonous PDAC mouse models, stimulating the local production of cytokines normally absent in PDAC. We further characterized a novel combination of five cytokines and chemokines that can effectively recruit and activate both innate and adaptive immune responses against PDAC. Considering the recent success of off-the-shelf neoantigen mRNA vaccines in early human PDAC patient trials, we have now developed mRNAs that encode PDAC-specific antigens. By integrating our cytokine mRNA platform with antigen mRNAs, we observe a significant increase in intratumoral antigen-presenting dendritic cell populations, leading to substantially enhanced T-cell-mediated anti-tumor immune response. Long-term studies in autochthonous PDAC mouse models demonstrate that combining cytokine and antigen mRNAs can completely eradicate tumors in select cases, resulting in significantly extended survival. Overall, this study not only unveils pivotal insights into the cytokines absent in PDAC that are crucial for promoting anti-tumor immunity but also pioneers an innovative immunotherapy approach.