Study authors Masakazu Hashimoto, Stephanie Perrino, Andrew M. Lowy and Pnina Brodt
A combinatorial immunotherapy may provide significant therapeutic benefit in managing pancreatic ductal adenocarcinoma liver metastases, preclinical research shows
Recently published in Molecular Cancer Therapeutics, work by researchers from the Research Institute of the McGill University Health Centre (RI-MUHC) may open the door for new treatments for an aggressive cancer known as pancreatic ductal adenocarcinoma (PDAC).
PDAC is currently the fourth leading cause of cancer-related deaths in the industrialized world. The prognosis for PDAC patients is currently very poor, with a high incidence of postoperative recurrence, mainly in the liver. Promising advances in cancer immunotherapies such as the PD-1 blocking antibody have not so far proven effective in the treatment of PDAC. This is due, at least in part, to the presence of specific cells that suppress the immune response to this therapy, including myeloid-derived suppressor cells (MDSC). Therapeutic approaches targeting these immunosuppressive cells, particularly in the liver, could enhance the efficacy of immunotherapy and improve prognosis.
A team led by Pnina Brodt, PhD, senior scientist in the Cancer Research Program at the RI‑MUHC, approached the problem by using a newly bioengineered inhibitor, the IGF-Trap, which blocks type 1 insulin-like growth factor receptor (IGF-IR) signaling. Her team and others had previously shown that immunosuppression within the tumour microenvironment is enhanced by the IGF signaling pathway. The researchers therefore asked whether this novel inhibitor could reverse the suppressive effect of IGF and allow immune cells to act against the tumour, thus enhancing the efficacy of immunotherapy for PDAC.
“We found that by targeting the IGF system, we were able to profoundly alter the immune landscape of PDAC metastases in the liver,” says Dr. Brodt. “As a result, the effect of a PD-1 blocking antibody was enhanced, causing a marked reduction in metastatic tumour growth.”
“Using a murine model, we treated microscopic PDAC liver metastases with the IGF-Trap,” explains first author Masakazu Hashimoto, PhD, a postdoctoral fellow with Pnina Brodt at the time of this study. “We found that this treatment reprogrammed the local immunosuppressive tumour microenvironment in the liver.”
Measuring the impact of the treatment on different types of cells in the immune system, the researchers found that the recruitment of myeloid derived suppressor cells was curtailed. “At the same time, there was an increase in recruitment of killer T cells and in the ability of dendritic cells to activate T lymphocytes,” says Dr. Brodt. “This had the effect of inhibiting metastatic expansion.”
The team then combined the IGF-Trap with an antibody to mimic immunotherapy drugs currently in use in treating cancer patients. They found that the two treatments combined were much more effective than either is alone. In effect, the IGF-Trap potentiated the tumour cell-killing potential of T lymphocytes to help eradicate liver metastases in the murine model.
“These exciting discoveries advance our understanding of how pancreatic cancer cells evade the immune system,” says co-author Andrew Lowy, MD, of the Moores Cancer Center in La Jolla, California. “The IGF-Trap can sensitize pancreatic cancer cells to current immunotherapies, findings that will hopefully be tested in patients.”
“Our results show that a combinatorial immunotherapy could provide a significant therapeutic benefit in the management of PDAC metastases,” concludes Dr. Brodt. “We are thrilled that this effect could be demonstrated with our IGF-Trap. Having established the benefit of this approach in a preclinical model, we hope it will open the way for additional treatments based on this prototype and eventually lead to clinical trials and new treatments for PDAC and other immunotherapy-resistant cancers.”
About the study:
Read the publication in the Molecular Cancer Therapeutics
The authors gratefully acknowledge support from the MUHC Foundation, the Canadian Institutes for Health Research, and MITACS.