Recent evidence indicates that human pancreatic ductal adenocarcinoma (PDA) is vulnerable to immune recognition and rejection. This raises the challenge of identifying immunotherapy strategies for PDA that are not excessively labor intensive, that consistently prolong survival, and that ideally are curative. In our effort to develop effective off-the-shelf immunotherapy against PDA, we discovered that repetitive administration of cyclophosphamide (CY) alternating with TLR agonists (TLRa) is therapeutically as or more effective than the classically synergistic combination of CY and T cell adoptive therapy. Off-the-shelf CY+TLRa treatment is much less labor intensive than adoptive therapy, is well tolerated, and is often sufficient to cure syngeneic wildtype mice of advanced PDA 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.
Our Specific Aims are (1) to fully delineate the mechanism by which CY+TLRa treatment is therapeutically effective against mouse PDA models, to maximize translatability;(2) to perform Phase I-II clinical trials which will promptly evaluate this strategy in PDA patients, using the novel TLR8 agonist VentiRx-2337;and (3) to complete development of a vaccine strategy capable of priming T cell responses as well as reversing T cell tolerance to MUC1, which is hyperexpressed by >90% of human PDA MUC1. This will be incorporated in the CY+TLRa strategy with the goal of rendering this treatment uniformly effective for PDA.

Public Health Relevance

It was recently demonstrated that pancreatic cancer can be attacked by the immune system. This project studies a combination treatment-chemotherapy and toll-like receptor agonists-which tricks the body into perceiving cancer as a life threatening infection so that the immune system will fight harder. The treatment already cures pancreatic cancer in mice, and the project brings the treatment to patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
Razidlo, Gina L; Burton, Kevin M; McNiven, Mark A (2018) Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J Biol Chem 293:11143-11153
Chaker, Mahmoud; Minden, Audrey; Chen, Suzie et al. (2018) Rho GTPase effectors and NAD metabolism in cancer immune suppression. Expert Opin Ther Targets 22:9-17
Sugimoto, Motokazu; Farnell, Michael B; Nagorney, David M et al. (2018) Decreased Skeletal Muscle Volume Is a Predictive Factor for Poorer Survival in Patients Undergoing Surgical Resection for Pancreatic Ductal Adenocarcinoma. J Gastrointest Surg 22:831-839
Danai, Laura V; Babic, Ana; Rosenthal, Michael H et al. (2018) Altered exocrine function can drive adipose wasting in early pancreatic cancer. Nature 558:600-604
Paradise, Brooke D; Barham, Whitney; Fernandez-Zapico, Martín E (2018) Targeting Epigenetic Aberrations in Pancreatic Cancer, a New Path to Improve Patient Outcomes? Cancers (Basel) 10:
Hogan, Kelly A; Cho, Dong Seong; Arneson, Paige C et al. (2018) Tumor-derived cytokines impair myogenesis and alter the skeletal muscle immune microenvironment. Cytokine 107:9-17
Tarragó, Mariana G; Chini, Claudia C S; Kanamori, Karina S et al. (2018) A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline. Cell Metab 27:1081-1095.e10
Chini, Eduardo N; Chini, Claudia C S; Espindola Netto, Jair Machado et al. (2018) The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging. Trends Pharmacol Sci 39:424-436
Antwi, Samuel O; Bamlet, William R; Pedersen, Katrina S et al. (2018) Pancreatic Cancer Risk is Modulated by Inflammatory Potential of Diet and ABO Genotype: A Consortia-based Evaluation and Replication Study. Carcinogenesis :
Klein, Alison P; Wolpin, Brian M; Risch, Harvey A et al. (2018) Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. Nat Commun 9:556

Showing the most recent 10 out of 336 publications