Washington University School of Medicine, St. Louis and Rush University Medical Center, Chicago investigators have found that a type of white blood cell called tumor-associated macrophages that been deceived by pancreatic cancer cells into not attacking them can be “reprogrammed” by a specially designed molecule that activates a protein found on their surfaces.
Known as ADH-503, the midwestern investigators hope that this immune system boosting molecule can eventually make the checkpoint inhibitor immunotherapies that revolutionized the treatment of many cancers available to pancreatic cancer patients.
The third deadliest cancer in the United States and unfortunately has not been responsive to most advanced current immunotherapies reports Onclive.
Research Work Product
The team has produced a paper titled “Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies” was authored by Vineet Gupta, Ph.D. (Rush) and David DeNardo, Ph.D. (Washington University) and colleagues.
ADH-503 interferes with the migration and polarization of myeloid cells—a type of immune system cell that circulates through the body identifying and attacking pathogens such as cancer reports Onclive. Macrophages (a myeloid cell) are present in the tumors were a particular focus, as cancer cells are especially adept at disrupting the processes in which macrophages (“big eaters” in Greek) can control tumor growth.
A protein called CD11b seems to play a vital role in recruiting the “big eaters” to tumors and in addition, to detecting threats and signaling whether the immune system should respond. For some reason when it comes to pancreatic cancer the number of macrophages that aid tumor growth considerably outnumbers those that suppress them.
Enter ADH-503 that moves in, binds and activates the CD11b receptor proteins on the myeloid cell surface. When conducting research on mice, the research team found the number of myeloid cells in and near the tumors in the mice declined and interestingly—the remaining myeloid cells turned out to be ones that promoted immune responses—not suppress the responses. What is the net result of this designed environment: a greater number of cancer-killing T cells in the tumor which means slower tumor growth and longer survival. The team is planning Phase I clinical trials this fall!
Vineet Gupta, Ph.D., Rush Vice Chair for Research & Innovation, Department of Internal Medicine
David DeNardo, Ph.D., Associate Professor of Medicine & Pathology & Immunology, Washington University