Researchers at The University of Texas MD Anderson Cancer Center have discovered a novel immunotherapy combination that targets checkpoints in T cells and myeloid suppressor cells, successfully reprograms the tumor immune microenvironment (TIME) and significantly improves Antitumor responses in a preclinical model of pancreatic cancer.
In the study, published today in natural cancer, researchers used comprehensive immunoassays in mouse and human pancreatic cancer to systematically identify immunotherapy resistance mechanisms and investigate potential therapeutic targets. They found that neutralizing several different immunosuppressive mechanisms of TIME significantly improved survival in laboratory models, pointing to a potential therapeutic option for this notoriously deadly and unresponsive cancer.
“This triple therapy produced an unprecedented curative response in our model,” said corresponding author Ronald DePinho, MD, professor of cancer biology. “The prevailing view is that pancreatic cancer is immune to immunotherapy, but this preclinical study suggests that it may be susceptible to the right combination of therapies. Furthermore, the presence of these targets in human pancreatic cancer specimens adds to the potential of this therapeutic combination.” The exciting possibility of this could one day help our patients.”
Pancreatic cancer is one of the leading causes of cancer death in the United States, in part because 80 percent of cases are diagnosed at an advanced stage. Pancreatic cancer is also considered “non-immunogenic,” meaning it does not respond to commonly used anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors. This is partly due to an immunosuppressive condition in TIME, but the mechanisms behind this resistance are not fully understood.
The researchers used high-dimensional immunoassays and single-cell RNA-sequencing to study how TIME is affected by various immunotherapies. They identified specific immune checkpoint proteins 41BB and LAG, which are highly expressed in exhausted T cells.
When testing antibodies against these checkpoints, the researchers observed slower tumor progression and higher levels of markers of antitumor immunity in models treated with a combination of 41BB agonists and LAG3 antagonists compared with antibodies alone or with other antibody treatments , survival was significantly improved with checkpoint inhibitors. Notably, these preclinical studies faithfully reflect human data on the lack of efficacy of anti-PD1 or anti-CTLA-4 therapies.
The researchers also demonstrated that these two therapeutic targets were present in human pancreatic cancer samples, with 81% and 93% of T cells from the patients analyzed expressing 41BB and LAG3, respectively.
Because this dual treatment combination did not completely eliminate established tumors, the researchers also examined efforts to reprogram TIME to further sensitize tumors to immunotherapy. At baseline, TIME contained high numbers of myeloid-derived suppressor cells (MDSCs) expressing CXCR2, a protein associated with the recruitment of immunosuppressive cells. Inhibition of CXCR2 alone reduces MDSC migration and prevents tumor growth, but not cure. This prompted the researchers to consider combinations 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 that developed multiple spontaneous tumors with greater treatment resistance, the combination achieved complete tumor regression in more than 20% of cases.
“These are encouraging results, especially given the lack of effective immunotherapy options for pancreatic cancer,” DePinho said. “By targeting multiple synergistic mechanisms that thwart the immune response, we can give T cells a fighting chance to attack these tumors. Of course, we still need to understand how this combination translates into a safe and effective treatment option in the clinic, and we invite additional research We build on these results. We are optimistic that pancreatic cancer, as well as other non-immunogenic cancers, can eventually become susceptible to combination immunotherapies.”
The authors note that these specific immunotherapy drugs are currently in clinical trials as monotherapies, suggesting that it is possible to quickly translate this triple combination into clinical research.
This work was supported by the National Institutes of Health/National Cancer Institute (P01 CA117969, RO1CA240526, RO1CA236864, R01CA231349, R01CA220236, P50CA221707), Elsa U. Pardee Foundation, MD Anderson Senior Scholars Program, Eleanor Russo Pancreas Research Fund , Ralph A. Loveys Family Charitable Foundation, Somerset Run Cultural and Philanthropic Club, New Jersey Health Foundation, Sheikh Ahmed Bin Zayed Al Nahyan Pancreatic Cancer Research Center and MD Anderson’s Pancreatic Cancer Moon Shot®.