Optimal Pairing of Chemotherapy With Immunotherapy for Pancreatic Cancer
Recent evidence indicates that human pancreatic ductal adenocarcinoma (PDAC) is vulnerable to immune recognition and rejection. This raises the challenge of identifying immunotherapy strategies for pancreatic ductal adenocarcinoma that are not excessively labor intensive, that consistently prolong survival and that ideally are curative.
In an effort to develop effective off-the-shelf immunotherapy against PDAC, SPORE researchers discovered that repetitive administration of cyclophosphamide (CY) alternating with TLR agonists (TLRa) is therapeutically as effective as or more effective than the classically synergistic combination of cyclophosphamide and T cell adoptive therapy.
Off-the-shelf CY+TLRa treatment is much less labor intensive than is adoptive therapy, is well-tolerated and is often sufficient to cure syngeneic wild-type mice of advanced PDAC tumors.
Remarkably, CY+TLRa's therapeutic efficacy is fully abrogated by depleting host CD4+ and CD8+ T cells and NK cells, indicating that CY+TLRa successfully maintains an endogenous anti-tumor immune response even in the absence of adoptive therapy or vaccine maneuvers.
An additional unique therapeutic feature is CY+TLRa's ability to convert rebounding myeloid progenitors into tumoricidal macrophages, thereby preventing tumors from differentiating them into myeloid-derived suppressor cells.
Aims of the Optimal Pairing of Chemotherapy With Immunotherapy for Pancreatic Cancer research project are to:
- Fully delineate the mechanism by which CY+TLRa treatment is therapeutically effective against mouse PDAC models to maximize translatability
- Conduct phase I to II trials that will promptly evaluate this strategy in patients with PDAC, using the novel TLR8 agonist VentiRx-2337
- Complete development of a vaccine strategy capable of priming T cell responses as well as reverse T cell tolerance to MUC1, which is hyperexpressed by more than 90 percent of human PDAC MUC1. This will be incorporated in the CY+TLRa strategy with the goal of rendering this treatment uniformly effective for PDAC.
Leaders of this Pancreatic Cancer SPORE project are:
The project collaborators are:
- Mary L. Disis, M.D., University of Washington School of Medicine
- Geert-Jan Boons, Ph.D., University of Georgia
- Mitesh J. Borad, M.D.