Targeting the Microbiome to Enable Immunotherapeutic Efficacy in Pancreatic Carcinoma
Abstract
The PRCRP Topic Area to be addressed is Pancreatic Cancer. The PRCRP Military Relevance Focus Area is Gaps in cancer treatment. Systemic chemotherapy remains the standard of care therapy for advanced pancreatic ductal adenocarcinoma (PDA); however, it has limited efficacy. Immunotherapy has developed into a transformative oncologic treatment option in several malignancies, but PDA has proven resistant to this approach in the clinic. This resistance has been attributed to PDA having a distinctive inflammatory environment, harboring a preponderance of immune-suppressive cells and biochemical signals that transmit immunologic tolerance. The sum of bacteria inhabiting the human body, collectively known as the microbiome, is emerging as an important regulator in the balance between health and disease. We hypothesized that the microbiome plays an important role in shaping the immune-suppressive environment in PDA. Accordingly, we recently reported that the cancerous pancreas harbors a markedly more abundant and distinctive microbiome compared to normal pancreas in humans and in mouse models. We showed that the microbiome exerts potent immune-suppressive influences on PDA and can be targeted to improve outcomes in mice. We also found that by reversing immune suppression, targeting the microbiome enabled efficacy for immunotherapy that otherwise failed in PDA. Our ultimate goal (Aim 3) is to perform a clinical trial in PDA patients testing strategies to modulate the microbiome to enhance the efficacy for immunotherapy. However, the optimal regimen to advance to clinical trial has not been defined. In Aims 1 and 2 we propose to perform experiments in both mouse models and in human 3D cancer models that are aimed at defining the most efficacious microbiome modulatory regimens – either antibiotics and/or probiotics – to combine with immunotherapy. Collectively, these foundational studies will provide rationale for the transformative clinical trial that will lead to a new treatment paradigm for PDA patients that involves reconfiguring the microbiome to enable immunotherapeutic responsiveness in PDA patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910603
Entities
People
- George Miller
Organizations
- Grossman School of Medicine
- United States Army