Immunotherapy: The future in pancreatic cancer treatment?
Researchers are setting their sights high on immunotherapy as a promising strategy in advanced pancreatic cancer, with several agents currently in development.
“There is excitement in the use of immunotherapy for cancer treatment because of their mechanism in targeting the tumour microenvironment,” said Dr Thomas Yau of The University of Hong Kong, who spoke at the Asian Pacific Digestive Week 2017 in Hong Kong.
For patients with advanced pancreatic cancer, few treatment options are available and chemotherapy-based regimens remain the standard of care. Newer strategies such as nab-paclitaxel, a combination of paclitaxel and albumin used in combination with gemcitabine to enhance drug delivery to the tumour microenvironment, have demonstrated some survival benefit vs gemcitabine alone in both the first- and second-line settings. However, the median overall survival for these patients remains less than 1 year. [J Natl Cancer Inst 2015, doi: 10.1093/jnci/dju413]
Research into targeted therapeutic approaches over the last 10 years have yielded only marginal benefits. “Erlotinib is the first and only targeted therapy approved for treatment of advanced pancreatic cancer,” said Yau. “However, its use is associated with increased toxicity and most oncologists don’t regard erlotinib as a clinically meaningful treatment option in advanced pancreatic cancer.”
Targeting the immunosuppressive microenvironment of the pancreatic tumour may be the key to overcoming the high resistance to treatment in pancreatic tumours, suggested Yau. Within the typical microenvironment, an immune response would elicit activated T cells to remove the cancerous cells. However, pancreatic tumours are able to activate various immune-suppressive pathways to evade this immune response. Immunotherapies act on these various mechanisms to restore T cell activity against the tumour.
“Pancreatic tumours can evade the immune system by causing ineffective presentation of the tumour antigens to the immune system. They can also recruit immunosuppressive cells, release immunosuppressive factors or cause T cell checkpoint dysregulation,” explained Yau. “The most important components of this tumour microenvironment are the myeloid-derived suppressor cells and T regulatory cells.”
“Immunotherapies currently in development for pancreatic cancer include checkpoint inhibitors, immune modulators, monoclonal antibodies, therapeutic vaccines and adoptive T cell therapies such as chimeric antigen receptor T cell therapy,” he continued.
More recently, the PD-1 inhibitor nivolumab, used in combination with nab-paclitaxel and gemcitabine, demonstrated encouraging clinical activity with low toxicity in patients with metastatic pancreatic cancer in a phase I study. [J Clin Oncol 2017;35(suppl 4S): abstract 412]
However, Yau warns that immunotherapies are not without side effects. “PD-1 inhibitors, for example, are associated with rash that sometimes requires systemic steroid treatment,” he noted. “Other adverse effects of immunotherapies include diarrhoea, colitis and pneumonitis.”
Until further data on immunotherapies become available, Yau recommends treating advanced pancreatic cancer with a gemcitabine-based regimen (gemcitabine alone or in combination with nab-paclitaxel or erlotinib) or FOLFIRINOX (5-FU, leucovorin, irinotecan, and oxaliplatin) in the first-line setting, followed by FOLFIRINOX or a gemcitabine-based regimen, respectively, upon disease progression.