Attacking pancreatic cancer with a novel immuno-oncology drug conjugate

Pancreatic cancer
An antibody-drug conjugate being developed by Boston Children's Hospital to target pancreatic cancer includes DM1, one component of Roche’s Kadcyla. (CC BY-SA 4.0 via Wikimedia Commons)(By Manu5 (http://www.scientificanimations.com/wiki-images/) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], via Wikimedia Commons)

One of the reasons pancreatic cancer is so hard to treat is that the tumors are difficult to penetrate, making it challenging to deliver drugs to them. Researchers at Boston Children’s Hospital have engineered a combination treatment that’s designed to home in on and penetrate pancreatic cancer cells—and they have promising evidence in mice that the approach may work.

The Boston Children’s team developed an antibody-drug conjugate (ADC) that binds to ICAM1, a molecule on pancreatic tumor cells, and delivers a cancer-killing compound. In mouse models of pancreatic cancer, two doses of the drug shrank tumors and prevented metastasis, the researchers reported in the journal Advanced Science.

The researchers started by screening the surface of pancreatic tumor cells for proteins that were abundant enough to serve as good binding targets. When they found ICAM1, they didn’t hesitate to choose it as their target. ICAM1 facilitates some immune responses, and they knew from their previous research that the protein is abundant in other cancers, including melanoma and triple-negative breast cancer. In fact, they reported last year that an ICAM1-targeted treatment developed at Boston Children’s was effective in mouse models of triple-negative breast cancer.

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They went on to select the best drug to include in their ADC by screening compounds that are already used in the treatment of cancer. They tested four different combinations before landing on DM1, the cancer-killing drug used in Roche’s ADC Kadcyla for HER2-positive breast cancer.

For the mouse study, they compared their DM1-ICAM1 combo with two other treatments and a placebo over a 14-week treatment period. One of the ADCs they tested combined DM1 with Gemzar, a chemotherapy drug that’s typically given as a first-line treatment for pancreatic cancer. The DM1-ICAM1 ADC outperformed all of them.

Several biotech companies are working on ADCs to treat pancreatic cancer, with mixed success. One, developed by MedImmune several years ago, failed in early human testing due to severe side effects. The Boston Children’s researchers believe that ICAM1 is expressed at higher levels in pancreatic cancer than the target of MedImmune’s drug, which “may render enhanced therapeutic effect and reduced side effects,” they wrote in the study.

The Boston Children’s team developed an MRI-based imaging technique that they used to confirm the presence of ICAM1 on pancreatic tumor cells during the study. They believe the same technique would be able to be used with their ADC to track its efficacy over time in patients.

"The precision of our approach comes from both the specific targeting and the ability to monitor that targeting with MRI," said co-author Marsha Moses, Ph.D., director of the vascular biology program at Boston Children’s, in a statement.

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