Once-failed cancer drug from BioXcel ramps up immunotherapy in mouse models of pancreatic cancer

Pancreatic cancer
Combining DPP inhibition with anti-PD-1 therapy in mice created “immune memory” in some that had been cured of pancreatic cancer, allowing them to clear tumors after they were re-exposed months later. (By Manu5 (http://www.scientificanimations.com/wiki-images/) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons)

When BioXcel Therapeutics raised $60 million in an initial public offering a few years back, it said it would pour part of the proceeds into developing talabostat, a drug that failed a phase 3 trial in pancreatic cancer in 2007. Now, BioXcel, along with collaborators at Georgetown University, has preclinical data suggesting the drug may boost the benefits of immunotherapy in this tough-to-treat cancer.

Georgetown researchers tested talabostat (also known as BXCL701) alone and alongside a treatment that inhibits the immune checkpoint PD-1 in mouse models of pancreatic cancer. Both treatments slowed tumor growth, and the combination significantly increased the recruitment of cancer-fighting immune cells, the researchers reported in the Journal for ImmunoTherapy of Cancer.

Talabostat works by inhibiting the protein dipeptidyl peptidase (DPP). Knowing that earlier studies had suggested the drug might improve immunotherapy, the Georgetown researchers wanted to see what would happen if they combined it with PD-1 inhibition. Checkpoint blockade has worked in many cancer types but has so far not panned out in pancreatic cancer.

They discovered that talabostat ramped up the infiltration of T cells and natural killer (NK) cells into the pancreatic tumor environment. Combining the drug with anti-PD-1 therapy not only slowed tumor growth and boosted immune activity, it also created “immune memory” in 10 out of 13 mice that had been cured by the initial therapy, allowing them to clear some tumors after they were re-exposed to pancreatic cancer months later.

The researchers believe the key to the combination’s effectiveness rested in the recruitment of NK cells, which combat cancer in two ways: They kill cancer cells directly, and they release “signaling molecules” that regulate other aspects of the immune system in ways that control tumor growth, they explained in a statement.

To back up their hunch, they studied real-world data in the National Institutes of Health’s Cancer Genome Atlas and found that increased levels of NK cells in human pancreatic tumors correlated with longer survival, the team reported.

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NK cells are of great interest to several research groups and biotechs that are searching for new approaches to treating solid tumors. Fate Therapeutics, for example, is developing an NK cell therapy that in preclinical studies killed cancer cells—including pancreatic tumor cells—when combined with anti-PD-1 therapy. The investigational product, FT500, is now in phase 1 testing in advanced solid tumors.

Other combinations designed to boost the immune response are under investigation in pancreatic cancer. Last year at the American Association for Cancer Research conference, a University of Minnesota team reported that combining a PD-L1 inhibitor with a CD40 blocker in mouse models of pancreatic cancer eliminated tumors in 60% of the animals. Apexigen is testing its CD40-targeted drug in combination with Bristol Myers Squibb’s PD-1 blocker Opdivo and other therapies in pancreatic cancer and reported survival benefits over the standard of care earlier this year.

As for BioXcel, it is currently testing talabostat in combination with Merck’s blockbuster PD-1 inhibitor Keytruda in metastatic castration-resistant prostate cancer and some tumors that are resistant to immune checkpoint inhibitors.

The Georgetown researchers said they're planning to conduct additional animal trials to better understand the mechanism of action of the talabostat-anti-PD-1 combination in pancreatic tumors. From there, they hope to design a clinical trial, they said.