Experimental drug enhances immunotherapy against pancreatic cancer in mice

By Leah Sherwood, The Science Advisory Board assistant editor

November 5, 2021 -- A combination treatment that included an experimental small molecule drug not only led to a reduction in tumor growth in mouse models of pancreatic cancer, but it also eliminated the cancer in some mice. The findings were published in the Journal for ImmunoTherapy of Cancer on November 4.

"This combination treatment not only cured some mice but also demonstrated having instilled an immune-cell memory so that, when the cured mice were injected with cancer cells months later, the immune systems in 10 of 13 mice recognized and killed the cancer cells, leaving the mice cancer-free again," said co-first author Allison Fitzgerald, PhD, in a statement. "If this result holds true in humans, it means the therapy may have the potential to offer long-lasting remissions for patients with pancreatic cancer."

The combination of anti-programmed cell death protein 1 (anti-PD1) with BXCL701, a dipeptidyl peptidase (DPP) inhibitor developed by BioXcel Therapeutics, was used to explore the small molecule's ability to promote immunotherapy. BioXcel researchers teamed up with Fitzgerald and other scientists at the Georgetown Lombardi Comprehensive Cancer Center at Georgetown University to conduct the study.

Previous preclinical work had shown that BXCL701 slowed the growth of syngeneic tumors derived from fibrosarcoma, lymphoma, melanoma, mastocytoma, rhabdomyosarcoma, and bladder cancer cell lines in mice. Yet subsequent clinical trials failed to replicate BXCL701's success as a monotherapy.

In the current research, the scientists explored whether BXCL701 may be more effective clinically used in combination with immunotherapy against pancreatic cancer rather than as a monotherapy.

The scientists studied mice injected with cells that closely mimic human pancreatic cancer (Pan02 and mT3-2D tumors). The mice were randomized into treatment groups so that each group would have an approximately equivalent starting tumor volume.

The mice were then given anti-PD1 by intraperitoneal injection. Anti-PD1 is an immunotherapy that works by blocking a pathway that shields tumor cells from immune system components that fight the cancer.

Depending on the treatment group, some of the mice were then administered 20 µg of BXCL701 daily by oral gavage to see if the drug would boost the effectiveness of the anti-PD1 treatment through DPP inhibition.

The effects of DPP inhibition on the tumors were then explored using RNA sequencing, immunohistochemistry, cytokine evaluation, and flow cytometry. The analyses showed that the combination of anti-PD1 and BXCL701 enhanced the immunotherapy's effectiveness, reduced tumor growth, and improved overall survival.

An analysis revealed two distinct mechanisms by which DPP inhibition was able to enhance the immune response: first, by boosting two key immune system components, T cells and natural killer cells; and second, by activating the nucleotide-binding leucine-rich (NLR) family pyrin domain containing 1 (NLRP1) inflammasome, resulting in proinflammatory cytokine release and T-helper cell (Th1) response.

The reduction in tumor volume was maintained even after treatment ended. In fact, 10 of the 13 mice treated with the combination therapy developed an anti-tumor immune memory that cleared tumors even after re-exposure to cancer cells months later, leaving the mice cancer-free again.

"While our success in mice is promising, we hold out additional hope due to the benefits of this DPP inhibitor seen in other types of cancer," said co-author Dr. Louis Weiner, director of the Lombardi Comprehensive Cancer Center. "What we found to be unique in our study was how this drug candidate seems to enhance the effectiveness of immune response in pancreatic cancer, which is remarkable as standard immunotherapies have been unsuccessful to date."

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest types of cancer; it is the most common cancer found in the pancreas and accounts for 90% of all cases. There will be 60,430 new cases of pancreatic cancer diagnosed in 2021 with an estimated 48,220 deaths, according to the National Cancer Institute.

PDAC is a poor immunogenic tumor, meaning it is resistant to current immunotherapies. The researchers hope that BXCL701 may offer a breakthrough in PDAC immunotherapy and that further studies can help researchers understand how the treatment works.

"We would like to conduct additional studies in mice to better understand the biology of why this treatment is working so well and how we can make it work even better," Fitzgerald said. "We are also hoping to develop a clinical trial based on the results of this study to see if this combination treatment works as well in humans as it does in mice."

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