Vaccination with an ISCOM-based tumor vaccine and a TLR ligand overcomes tumor-induced immune suppression and leads to the eradication of established pancreatic carcinomas

Introduction: Pancreatic carcinoma is associated with a poor prognosis and new therapies are warranted. Tumor vaccination aims at inducing cytotoxic T cells capable of killing tumors. However, immune responses are severely impaired in cancer patients. Overcoming immune suppression is a challenge for new generation tumor vaccines.

Methods: An ISCOM vaccine containing the model antigen OVA was generated. Mice were challenged s.c. with OVA-expressing pancreatic carcinoma cells (Panc02-OVA) either after (prophylactic) or before (therapeutic) vaccination with OVA/ISCOM alone or in combination with the TLR9 ligand CpG. In an orthotopic model, tumor cells were injected into the pancreas of anaesthetized mice. OVA-specific CD8+ T cell responses were analyzed in peripheral blood by intracellular IFN-gamma staining.

Results: Two vaccinations with OVA/ISCOM resulted in a 100% protection from subsequent Panc02-OVA tumor challenge. However, the T cell response was severely reduced in tumor bearing mice. Furthermore, tumor growth of ISCOM vaccinated mice did not differ from control mice, indicative of tumor-mediated immune suppression. By adding CpG to the ISCOM vaccine, the T cell response was restored to the level seen in tumor free mice and even large tumors disappeared. Mice stayed tumor free for up to 3 month and rejected new tumors in 100% after Panc02-OVA re-challenge. When challenged with parental Panc02 cells (no OVA expression) 4/7 of long-term survivors rejected tumors and 3/7 showed delayed tumor growth, indicative of epitope spreading. We next assessed this vaccination strategy in an orthotopic tumor model. Again, mice vaccinated with the ISCOM vaccine and CpG survived long-term without evidence of tumor, whereas untreated or mice treated with ISCOM alone died.

Conclusions: ISCOM vaccines are efficient in inducing cytotoxic T cell responses. However, mice with pancreatic cancer have a compromised immune system rending vaccination ineffective. By combining the ISCOM vaccine with a TLR9 ligand, tumor-induced immune suppression can be broken resulting in the eradication of large pancreatic cancers. This strategy may hold promise for the development of a cancer vaccine against human pancreatic cancer.