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.
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.
|Kim, Jungsun; Bamlet, William R; Oberg, Ann L et al. (2017) Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. Sci Transl Med 9:|
|Espindola-Netto, Jair Machado; Chini, Claudia C S; Tarragó, Mariana et al. (2017) Preclinical efficacy of the novel competitive NAMPT inhibitor STF-118804 in pancreatic cancer. Oncotarget 8:85054-85067|
|Pathangey, Latha B; McCurry, Dustin B; Gendler, Sandra J et al. (2017) Surrogate in vitro activation of innate immunity synergizes with interleukin-7 to unleash rapid antigen-driven outgrowth of CD4+ and CD8+ human peripheral blood T-cells naturally recognizing MUC1, HER2/neu and other tumor-associated antigens. Oncotarget 8:10785-10808|
|Javeed, Naureen; Mukhopadhyay, Debabrata (2017) Exosomes and their role in the micro-/macro-environment: a comprehensive review. J Biomed Res 31:386-394|
|Blackburn, Patrick R; Tischer, Alexander; Zimmermann, Michael T et al. (2017) A Novel Kleefstra Syndrome-associated Variant That Affects the Conserved TPLX Motif within the Ankyrin Repeat of EHMT1 Leads to Abnormal Protein Folding. J Biol Chem 292:3866-3876|
|Walz, Amy; Ugolkov, Andrey; Chandra, Sunandana et al. (2017) Molecular Pathways: Revisiting Glycogen Synthase Kinase-3? as a Target for the Treatment of Cancer. Clin Cancer Res 23:1891-1897|
|Yellow, Winta; Bamlet, William R; Oberg, Ann L et al. (2017) Association between Alcohol Consumption, Folate Intake, and Risk of Pancreatic Cancer: A Case-Control Study. Nutrients 9:|
|Luo, Kuntian; Li, Yunhui; Yin, Yujiao et al. (2017) USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling. EMBO J 36:1434-1446|
|Liou, Geou-Yarh; Bastea, Ligia; Fleming, Alicia et al. (2017) The Presence of Interleukin-13 at Pancreatic ADM/PanIN Lesions Alters Macrophage Populations and Mediates Pancreatic Tumorigenesis. Cell Rep 19:1322-1333|
|Cho, Dong Seong; Doles, Jason D (2017) Single cell transcriptome analysis of muscle satellite cells reveals widespread transcriptional heterogeneity. Gene 636:54-63|
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