Researchers at The University of Texas MD Anderson Cancer Center have discovered a novel immunotherapy combination, targeting checkpoints in both T cells and myeloid suppressor cells, that successfully reprogrammed the tumor immune microenvironment and significantly improved antitumor responses in preclinical models of pancreatic cancer. In the study, published by Gulhati et al in Nature Cancer, researchers used comprehensive immune profiling in mouse and human pancreatic cancers to systematically identify mechanisms of immunotherapy resistance and investigate potential therapeutic targets. They found that neutralizing several distinct immunosuppressive mechanisms of the tumor immune microenvironment improved survival rates in laboratory models, pointing to a potential novel treatment option.
Ronald DePinho, MD
“This triple combination therapy led to an unprecedented curative response in our models,” said corresponding study author Ronald DePinho, MD, Professor of Cancer Biology at MD Anderson. “The prevailing view has been that pancreatic cancer is impervious to immunotherapy, but this preclinical study shows that it can be vulnerable to the right combination therapy. Moreover, the presence of these targets in human pancreatic cancer specimens raises the exciting possibility that such therapeutic combinations could one day help our patients.”
Pancreatic cancer is considered to be “nonimmunogenic,” meaning it is unresponsive to commonly used anti–PD-1 and anti–CTLA-4 immune checkpoint inhibitors. This is due in part to the immunosuppressive conditions in the tumor immune microenvironment, but the mechanisms behind this resistance are not fully understood.
Current Study Details
The researchers used high-dimensional immune profiling and single-cell RNA sequencing to study how the tumor immune microenvironment is affected by a variety of immunotherapies. They identified specific immune checkpoint proteins—41BB and LAG—that were highly expressed in exhausted T cells.
In testing antibodies targeting these checkpoints, the researchers observed that models treated with a 41BB agonist and LAG3 antagonist in combination had slower tumor progression, higher levels of antitumor immunity indicators, and significantly improved survival rates compared to treatment with either antibody alone or with other checkpoint inhibitors. Notably, these preclinical studies mirrored the human data in their lack of efficacy of anti–PD-1 or anti–CTLA-4 therapy.
The researchers also confirmed these two therapeutic targets are present in human pancreatic cancer samples, with 81% and 93% of patients analyzed having T cells with 41BB and LAG3 expression, respectively.
Because this dual-therapy combination did not completely eliminate established tumors, the investigators also examined efforts to reprogram the tumor immune microenvironment to further sensitize tumors to immunotherapy. At baseline, the tumor immune microenvironment contained an abundance of myeloid-derived suppressor cells (MDSCs) expressing CXCR2, a protein associated with recruiting immunosuppressive cells. Inhibiting CXCR2 alone decreased MDSC migration and blocked tumor growth, but it was not curative. This prompted the investigators 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 lab model that develops multiple spontaneously arising tumors with higher treatment resistance, the combination achieved complete tumor regression in over 20% of cases.
“These are encouraging results, especially considering the lack of effective immunotherapy options in pancreatic cancer,” Dr. 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 still need to see how this combination translates into a safe and effective regimen in the clinic, and we invite other researchers to build upon these results. We are optimistic that pancreatic cancers, and hopefully other nonimmunogenic cancers, can ultimately be rendered vulnerable to combination immunotherapy.”
The authors pointed out that these particular immunotherapy agents currently are undergoing clinical trials as monotherapies, suggesting potential opportunities to rapidly translate this triple combination into clinical studies.
Disclosure: This work was supported by the National Institutes of Health/National Cancer Institute, the Elsa U. Pardee Foundation, MD Anderson’s Advanced Scholar Program, the Eleanor Russo Fund for Pancreatic Research, Ralph A. Loveys Family Charitable Foundation, the Cultural & Charitable Club of Somerset Run, the New Jersey Health Foundation, the Sheikh Ahmed Bin Zayed Al Nahyan Center for Pancreatic Cancer Research, and MD Anderson’s Pancreatic Cancer Moon Shot. For full disclosures of the study authors, visit nature.com.
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