title: Chemo-immunotherapy mediates durable cure of orthotopic KrasG12D/p53-/-pancreatic ductal adenocarcinoma.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, exhibiting a five-year overall survival (OS) of only 7% despite aggressive standard of care. Recent advances in immunotherapy suggest potential application of immune-based treatment approaches to PDAC. To explore this concept further, we treated orthotopically established K-rasG12D/p53-/-PDAC tumors with gemcitabine and a cell-based vaccine previously shown to generate durable cell-mediated (TH1) immunity. Tumor progression was monitored by IVIS. The results indicated that the combination of chemotherapy and dendritic cell (DC) vaccination was effective in eliminating tumor, preventing metastasis and recurrence, and significantly enhancing OS. No animal that received the combination therapy relapsed, while mice that received gemcitabine-only or vaccine-only regimens relapsed and progressed. Analysis of circulating PBMC demonstrated that mice receiving the combination therapy exhibited significantly elevated levels of CD8+IFNγ+CCR7+NK1.1+T-cells with significantly reduced levels of exhausted GITR+CD8+T-cells after the cessation of treatment. Retro-orbital tumor re-challenge of surviving animals at six-months post-treatment demonstrated durable antitumor immunity only among mice that had received the combination therapy. CD8+splenocytes derived from surviving mice that had received the combination therapy were sorted into NK1.1posand NK1.1negpopulations and adoptively transferred into naive recipients. Transfer of only 1,500 CD8+NK1.1posT-cells was sufficient to mediate tumor rejection whereas transfer of 1,500 CD8+NK1.1negT-cells imparted only minimal effects. The data suggest that addition of a TH1 DC vaccine regimen as an adjuvant to existing therapies can mediate eradication of tumors and offer durable protection against PDAC.
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX, USA.
authors.forename: Vanaja
authors.initials: V
authors.lastname: Konduri
authors.affiliation: Michael E. Debakey Department of Surgery, Baylor College of Medicine , Houston, TX, USA.
authors.forename: Dali
authors.initials: D
authors.lastname: Li
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Halpert
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Liang
authors.affiliation: Michael E. Debakey Department of Surgery, Baylor College of Medicine , Houston, TX, USA.
authors.forename: Zhengdong
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine , Houston, TX, USA.
authors.forename: Yunyu
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Elkins Pancreas Center, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Fisher
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Center for Human Immunobiology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Silke
authors.initials: S
authors.lastname: Paust
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Scott Department of Urology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Levitt
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Michael E. Debakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA; Elkins Pancreas Center, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey VA Medical Center, Houston, TX, USA.
authors.forename: Qizhi Cathy
authors.initials: QC
authors.lastname: Yao
authors.affiliation: Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Decker
keywords: Adjuvant therapy; PDAC; tumor immunology; vaccination