A novel combination of triple immunotherapy improves antitumor responses in preclinical models of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a poor prognosis and limited treatment options. Researchers at Rutgers Cancer Institute of New Jersey, the state’s leading cancer program and the only National Cancer Institute-designated Comprehensive Cancer Center, along with RWJBarnabas Health, in collaboration with researchers at MD Anderson Cancer Center, have discovered a new combination of triple of immunotherapies targeting checkpoints to both T-cells and myeloid suppressor cells, which dramatically improved antitumor responses by reprogramming the tumor microenvironment in preclinical models of PDAC. Prateek Gulhati, MD, PhD, physician-scientist in the Gastrointestinal Oncology Program at Rutgers Cancer Institute and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School, is lead author of the paper and shares more about the findings published in Nature Cancer (https://doi.org/10.1038/s43018-022-00500-z).

Why is this topic important?

PDAC is one of the leading causes of cancer death in the United States and is considered “nonimmunogenic,” meaning it does not respond to commonly used anti-PD-1 and anti-CTLA-4 immune checkpoint therapy. This is partly due to immunosuppressive conditions in the tumor microenvironment, but the mechanisms behind this resistance are not well understood.

How was the study structured and what did you and your colleagues discover?

We used comprehensive immune profiling in murine and human pancreatic cancers to systematically identify mechanisms of resistance to immunotherapy and explore potential new therapeutic targets. We found that neutralizing several different immunosuppressive mechanisms in the tumor microenvironment dramatically improves antitumor responses. We identified a novel combination immunotherapy regimen that resulted in tumor regression and improved survival in preclinical models of pancreatic cancer.

What are the implications of these findings?

The prevailing opinion is that pancreatic cancer is resistant to immunotherapy, however this study shows that it may be sensitive to the right combination of immunotherapy. These results are encouraging and we remain optimistic that pancreatic cancer and other “non-immunogenic” cancers will ultimately be susceptible to combination immunotherapy.

What are the future steps related to this work?

Prospective clinical trials will be needed to support the hypothesis derived from this work and evaluate this combination immunotherapy regimen for the treatment of PDAC patients. The targets identified in this study are present in a significant proportion of pancreatic cancer patient samples, raising the possibility that such a regimen could be worth investigating in a clinical trial. We continue our research to identify new mechanisms of resistance to immunotherapy and discover new vulnerabilities to target pancreatic cancer.

Source:

Rutgers Cancer Institute of New Jersey

Journal reference:

https://doi.org/10.1038/s43018-022-00500-z

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