Targeting T cells and myeloid cells together improved anti-tumor response and survival in preclinical models – ScienceDaily

Researchers at the University of Texas MD Anderson Cancer Center have discovered a new combination of immunotherapy that targets checkpoints on both T cells and myeloid suppressor cells, successfully reprograms the tumor immune microenvironment (TIME), and significantly improves anti-tumor responses in preclinical pancreatic models. cancer.

In this study published today, Nature Cancer, researchers used comprehensive immune profiling in mouse and human pancreatic cancers to systematically identify mechanisms of immunotherapy resistance and explore potential therapeutic targets. They found that neutralizing several different immunosuppressive mechanisms of TIME significantly improved survival rates in laboratory models, pointing to a potential treatment option for this notoriously deadly and unresponsive cancer.

“This triple combination therapy led to an unprecedented curative response in our models,” said Ronald DePinho, professor of Cancer Biology and corresponding author. “The prevailing view was that pancreatic cancer is resistant to immunotherapy, but this preclinical study shows that it may be vulnerable to the right combination therapy. Furthermore, the presence of these targets in human pancreatic cancer samples raises the exciting possibility that such therapeutic combinations could one day help our patients.” we can be.”

Pancreatic cancer is one of the leading causes of cancer-related death in the United States, partly because 80% of cases are diagnosed at an advanced stage. Pancreatic cancer is also considered “non-immunogenic,” meaning it does not respond to the commonly used anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors. This is due in part to the immunosuppressive conditions in TIME, but the mechanisms behind this resistance are not fully understood.

The researchers used high-dimensional immune profiling and single-cell RNA sequencing to examine how TIME is affected by various immunotherapies. They identified specific immune checkpoint proteins, 41BB and LAG, which are highly expressed in depleted T cells.

When 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 anti-tumor immunity markers, and significantly improved survival rates compared to treatment alone or with other antibodies. observed that they had checkpoint inhibitors. Notably, these preclinical studies faithfully mirrored human data in terms of the lack of efficacy of anti-PD1 or anti-CTLA-4 therapy.

The researchers also confirmed that these two therapeutic targets were found in human pancreatic cancer samples; 81% and 93% of analyzed patients had T cells with 41BB and LAG3 expression, respectively.

Because this dual therapy combination did not completely eliminate established tumors, the researchers also examined efforts to reprogram TIME to make tumors more susceptible to immunotherapy. Initially, TIME contained abundant myeloid-derived suppressor cells (MDSCs) expressing CXCR2, a protein associated with recruitment of immunosuppressive cells. Inhibiting CXCR2 alone reduced MDSC migration and blocked tumor growth, but was not therapeutic. This prompted 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 the preclinical models. In a tighter laboratory model that developed multiple spontaneously arising tumors with higher treatment resistance, the combination resulted in 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. Said. “By targeting multiple synergistic mechanisms that get in the way of the immune response, we can give T cells a chance to fight back to attack these tumors. Of course, we need to see how this combination translates into a safe and effective regimen in the clinic. And we invite other researchers to build on these results. Pancreatic cancers.” and we are hopeful that other non-immunogenic cancers may eventually be made vulnerable to combination immunotherapy.”

The authors point out that these specific immunotherapy agents are currently undergoing clinical trials as monotherapies, suggesting potential opportunities to quickly translate this trio combination into clinical trials.

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’s Advanced Scholar Program, the Eleanor Russo Fund for Pancreatic Research. Ralph A. Loveys Family Charity Foundation, Somerset Run Culture and Charity Club, New Jersey Health Foundation, Sheikh Ahmed Bin Zayed Al Nahyan Pancreatic Cancer Research Center and MD Anderson’s Pancreatic Cancer Month Vaccine®.

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