The diagnosis of pancreatic cancer continues to be one of grim prognosis with a complicated medical and surgical course. Patients with locally advanced and unresectable pancreatic cancer have a median survival of up to 1 year while patients with metastatic disease only have up to 6 months. Clearly, the current chemotherapeutic regimens are not effective enough, and new pathways need to be explored in order to provide improved efficacy in such a deadly malignancy. One such pathway in pancreatic cancer could include the body’s own immune system—in the form of immunotherapy.
Immunotherapy is a relatively new treatment modality that focuses on enhancing the body’s natural response to cancer cells. Data released earlier in 2012 showed positive phase 1 results for a programmed death (PD-1) receptor antibody in renal cell carcinoma, melanoma, and non-small cell lung cancer patients. A more specific immunotherapeutic target in pancreatic cancer is MUC1, a transmembrane glycoprotein that has increased expression in pancreatic cancer cells. MUC1 improves invasiveness of cancer cells and has been implicated in the activation of T-cells. In preclinical models, mice with a MUC1 gene deletion have been shown to have decreased transcription of the proteins associated with metastasis. Anti-MUC1 antibodies targeting pancreatic cancer cells have successfully been conjugated to immune adjuvants such as CpG oligodeoxynucleotide in order to bolster antibody-dependent cellular cytotoxicity (ADCC).
An additional immune target in pancreatic cancer is indoleamine 2,3-dioxygenase (IDO). IDO is an enzyme involved in the breakdown of tryptophan which, when induced to high levels by pancreatic cancer cells, can deplete T cells of its tryptophan requirement. This leads to immunosuppression and decreased surveillance of the tumor cells by the patient’s immune system. The IDO inhibitor D-1-methyl-tryptophan (D-1-MT) is currently being studied both with and without standard chemotherapy regimens, including gemcitabine. There is also a potential role for pharmacogenomics in the IDO pathway. IDO2, another enzyme that contributes to the breakdown of tryptophan, has two identified genetic polymorphisms that can lead to enzymatic deactivation. With further research, screening patients to identify those who have the susceptible genotype and would respond best to IDO inhibitor therapy becomes a possibility.
Pancreatic cancer continues to be one of the most deadly malignancies encountered by our patients. The evolution of immunotherapy in the form of MUC1-antibodies and IDO inhibitors hopefully represents the new cutting edge technology needed to provide pancreatic cancer patients with a more optimistic prognosis.
Questions to Readers:
- What additional immunotherapeutic agents do you think show promise in pancreatic cancer?
- What are the potential pitfalls with immunotherapies as a drug class?