HOUSTON – Researchers at the University of Texas MD Anderson Cancer Center have discovered a new immunotherapy combination, targeting checkpoints on both T cells and myeloid suppressor cells, that successfully reprogrammed the tumor immune microenvironment (TIME). and significantly improved antitumor responses in preclinical models of pancreatic cancer.
In this study, published today in nature cancer, the investigators used comprehensive immune profiling in human and mouse pancreatic cancers to systematically identify mechanisms of resistance to immunotherapy and investigate potential therapeutic targets. They found that neutralizing several immunosuppressive mechanisms other than TIME dramatically improved survival rates in laboratory models, pointing to a potential treatment option for this notoriously lethal and insensitive cancer.
“This triple combination therapy led to an unprecedented curative response in our models,” said corresponding author Ronald DePinho, MD, professor of Cancer Biology. “The prevailing opinion has been that pancreatic cancer is impervious to immunotherapy, but this preclinical study shows that it may be vulnerable to appropriate combination therapy. Furthermore, the presence of these targets in human pancreatic cancer samples raises the exciting possibility that such therapeutic combinations may one day help our patients.”
Pancreatic cancer is one of the leading causes of cancer death in the United States, in part because 80% of cases are diagnosed at an advanced stage. Pancreatic cancer is also considered “nonimmunogenic,” meaning it does not respond to the commonly used anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors. This is partly due to the immunosuppressive conditions at TIME, but the mechanisms behind this resistance are not fully understood.
The researchers used high-dimensional immunological profiling and single-cell RNA sequencing to study how TIME is affected by a variety of immunotherapies. They identified specific immune checkpoint proteins, 41BB and LAG, that were highly expressed in depleted T cells.
By testing antibodies targeting these checkpoints, the researchers found that models treated with a 41BB agonist and LAG3 antagonist in combination had slower tumor progression, higher levels of antitumor immunity indicators, and significantly better survival rates compared with treatment with antibodies alone or with other checkpoint inhibitors. In particular, these preclinical studies closely reflected human data in their lack of efficacy of anti-PD1 or anti-CTLA-4 therapy.
The investigators also confirmed that these two therapeutic targets are present in human pancreatic cancer samples, with 81% and 93% of patients tested having 41BB and LAG3-expressing T cells, respectively.
Because this dual therapy combination did not completely kill established tumors, the researchers also examined efforts to reprogram TIME to further sensitize tumors to immunotherapy. Initially, TIME contained a large number of myeloid-derived suppressor cells (MDSCs) expressing CXCR2, a protein associated with the recruitment of immunosuppressive cells. CXCR2 inhibition alone decreased MDSC migration and blocked tumor growth, but was not curative. This led the researchers to consider a combination targeting 41BB, LAG3, and CXCR2.
It was this triple combination that resulted in complete tumor regression and improved overall survival in 90% of preclinical models. In a more stringent laboratory model developing multiple spontaneously occurring tumors with increased resistance to treatment, the combination achieved complete tumor regression in more than 20% of cases.
“These are encouraging results, especially considering the lack of effective immunotherapy options in pancreatic cancer,” DePinho said. “By targeting multiple synergistic mechanisms that get in the way of the immune response, we can give T cells a fighting chance to attack these tumors. Of course, we have yet to see how this combination translates into a safe and effective regimen in the clinic, and we invite other investigators to build on these results. We are optimistic that pancreatic cancers, and hopefully other non-immunogenic cancers, may ultimately become vulnerable to combination immunotherapy.”
The authors note that these particular immunotherapy agents are currently in clinical trials as monotherapies, suggesting potential opportunities to rapidly translate this triple combination into clinical studies.
This work was supported by the National Institutes of Health/National Cancer Institute (P01 CA117969, RO1CA240526, RO1CA236864, R01CA231349, R01CA220236, P50CA221707), the Elsa U. Pardee Foundation, the MD Anderson Advanced Scholar Program, the Eleanor Russo Fund for Pancreatic Research, Ralph A. Loveys Family Charitable Foundation, Cultural & Charitable Club of Somerset Run, New Jersey Health Foundation, Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, and MD Anderson’s Pancreatic Cancer Moon Shot®. A full list of contributing authors and their disclosures with the full paper can be found here.
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