Chemo-immunotherapy mediates durable cure of orthotopic K ras^G12D/p53^-/- pancreatic ductal adenocarcinoma

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-ras^G12D/p53^-/- PDAC tumors with gemcitabine and a cell-based vaccine previously shown to generate durable cell-mediated (T_H1) 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 NK1.1^pos and NK1.1^neg populations and adoptively transferred into naive recipients. Transfer of only 1,500 CD8⁺NK1.1^pos T-cells was sufficient to mediate tumor rejection whereas transfer of 1,500 CD8⁺NK1.1^neg T-cells imparted only minimal effects. The data suggest that addition of a T_H1 DC vaccine regimen as an adjuvant to existing therapies can mediate eradication of tumors and offer durable protection against PDAC.