Claudin May Be the Next Big Target in Pancreatic Cancer Treatment

Pancreatic adenocarcinoma is one of the hide-and-seek champions of the cancer world, great at evading attempts by the immune system to find it and stealthily sending its carcinoma cells to invade other parts of the body, often before the main tumor is even discovered.

While immunotherapy and other targeted treatments involving monoclonal antibodies have been successful in other cancers, pancreatic cancer has been notoriously tough to target because of a lack of suitable cell surface targets to which the antibodies can bind.

But a new target has been identified, and researchers are hopeful that an investigational drug that homes in on it may be an effective treatment for metastatic pancreatic cancer.

Taking Advantage of a New Target

Claudin proteins regulate paracellular barriers to control the flow of molecules between cells, acting like a glue between cells that holds them together. They are found in healthy intestinal systems, but a certain isoform—CLDN18.2—is highly expressed in cancers of the gastrointestinal tract, especially in esophagogastric and pancreatic cancers.

In this form, the glue is weaker, which may contribute to metastasis, since it becomes easier for cancerous cells to detach from the primary tumor and disperse. But it could also help expose antibodies for monoclonal antibodies to bind to.

One such monoclonal antibody, zolbetuximab (IMAB362), has been developed to seek out CLDN18.2 on the surface of tumor cells and bind to it, identifying the cells for immune-mediated destruction.

Adding This New Immunotherapy to Standard Treatment

Early trials in advanced/recurrent gastric and gastroesophageal junction cancers have shown promise, and researchers are now testing the drug in metastatic pancreatic cancer patients in a large international trial.

In hopes that zolbetuximab may work synergistically with other chemotherapy drugs to further strengthen the immune response by enhancing T-cell infiltration and inducing pro-inflammatory cytokines, participants in the experimental arm of the phase ll, open-label, randomized study will receive the drug in combination with nab-paclitaxel and gemcitabine. They must first undergo a screening test, which takes about two weeks. Those with expression of CLDN18.2 in over 75 percent of their cancer cells can get randomized into the trial at a 2:1 ratio. About 28 percent of pancreatic cancer patients fall into this category.

Participants will receive the drugs by IV infusion every two weeks. The researchers will track their ability to tolerate the drug regimen, as well as its efficacy. The patients can be treated on continuous cycles until they no longer derive clinical benefit, have unacceptable toxicity, or meet one of the other discontinuation criteria.

Those in the control arm will receive the standard nab-paclitaxel and gemcitabine treatment.

In the Trial

In order to participate in the trial, patients must have metastatic pancreatic cancer that has not yet been treated with gemcitabine and nab-paclitaxel; they may have received prior chemotherapy for pancreatic cancer, but no chemotherapy after the cancer spread. Participants must be in relatively good health—fully ambulatory, capable of all self-care, and capable of all but physically strenuous activities.

Patients who have had surgery and a recurrence after six months of completed adjuvant chemotherapy are highly recommended for screening.

Medical oncologist Wungki Park, M.D., of Memorial Sloan Kettering Cancer Center in New York, a principal investigator on the trial along with Eileen M. O’Reilly, M.D., is excited by the potential of the strategy.

“I believe biomarker-driven strategies and biology-driven treatments are the future of cancer care,” he says.