Two antibodies synergize in a triple whammy for childhood cancers, study finds | Information Center

“In the localized tumor model, healing was maintained,” Theruvath said. “We imagined the mice: their tumors shrank and did not come back.”

Although the antibody combination was somewhat less potent in osteosarcoma, it prevented the cancer from spreading to the mice’s lungs. This finding was encouraging because lung metastases are a common cause of death in people with this disease. “Currently, survival is extremely low for osteosarcoma patients with metastases,” Theruvath said. “We believe that survival rates for children with metastatic disease can really be improved.”

Two antibodies, three beneficial effects

The researchers conducted a series of experiments to understand how the two antibodies worked together. They found that GD2, whose mechanism of action was unknown, also functions as a “don’t eat me” signal. When GD2 and CD47 “don’t eat me” signals were blocked by their respective antibodies, cells were much less able to hide from scavenging macrophages, the researchers found.

Additionally, cells can signal to macrophages when they are ready to be consumed. They attract macrophages by placing an “eat me” signal, called calreticulin, on their surface. When anti-GD2 antibodies are administered, the cells produce more calreticulin and are therefore more attractive targets for the immune system.

In short, the combination of anti-GD2 and anti-CD47 antibodies deals a triple whammy to cancer cells: the antibodies block two types of “don’t eat me” signals, while allowing an “eat me” signal to become more abundant. . Macrophages – which assess the balance of cellular signals – get a clear message to gobble up cancer cells.

“It opened up whole new avenues in my lab to understand how cancer cells are killed and cleared by macrophages,” Majzner said.

The results also gave the research team new criteria for determining which combinations of antibodies might lead to the most potent cancer immunotherapies.

“We’ve learned that there really is a reason why antibodies work well together,” Theruvath said.

The study’s other co-authors at Stanford are MD student Benjamin Smith; graduate students Miles Linde, John Silberstein and Allison Banuelos; Garry Coles, PhD, Pediatric Hematology-Oncology Affiliate; postdoctoral fellows Guillermo Dalton, PhD, and Wei Wu, PhD; Louise Kiru, PhD, lecturer in radiology; principal investigator Elena Sotillo, PhD; Anna Geraghty, PhD, Lecturer in Neurology and Neurological Sciences; Sabine Heitzeneder, MD, fellow at the Stanford Cancer Institute; life science researchers Molly Thomas Radosevich, Aidan Tousley, John Lattin, Peng Xu, Jing Huang, Andy He, Shaurya Dhingra and Rachel Brewer; medical students Amira Barkal and Payton Marshall; Kristopher Marjon, PhD, instructor; Jose Vilches-Moure, DVM, PhD, assistant professor of comparative medicine; Michelle Monje, MD, PhD, associate professor of neurology and neurological sciences; Jennifer Cochran, PhD, professor of bioengineering; Heike Daldrup-Link, MD, professor of radiology; Irving Weissman, MD, professor of developmental biology; Julien Sage, PhD, professor of pediatrics and genetics; Ravindra Majeti, MD, PhD, professor of medicine; Carolyn Bertozzi, PhD, professor of chemistry; William Weiss, PhD, Professor of Structural Biology, Molecular and Cellular Physiology, and Photon Science Branch; and Crystal Mackall, MD, professor of pediatrics and medicine.

Majzner, Kiru, Monje, Cochran, Daldrup-Link, Weissman, Sage, Majeti, Bertozzi, and Mackall are members of the Stanford Maternal and Child Health Research Institute. Vilches-Moure, Monje, Cochran, Daldrup-Link, Weissman, Sage, Majeti, Bertozzi, Weiss, Mackall and Majzner are members of Stanford Bio-X. Vilches-Moure, Cochran and Weissman are members of the Stanford Cardiovascular Institute. Vilches-Moure, Monje, Cochran, Daldrup-Link, Weissman, Sage, Majeti, Bertozzi, Weiss, Mackall and Majzner are members of the Stanford Cancer Institute. Monje, Weissman and Majeti are fellows of the Stanford Institute for Stem Cell Biology and Regenerative Medicine. Monje, Cochran, Daldrup-Link, Weissman and Bertozzi are members of the Wu Tsai Neurosciences Institute at Stanford. Bertozzi is the director, and Cochran, Sage, and Weiss are faculty members at Stanford ChEM-H.

Scientists from the University of California, San Francisco; ALX Oncology; the British Columbia Cancer Agency; and the University of Oxford also contributed to the research.

The research was funded by Alex’s Lemonade Stand, the National Institutes of Health (grant P01 CA217959), German Cancer Aid, the National Cancer Institute (grants R01-CA227942, F30-CA231997, U01-CA217864, U01-CA213273 and R35-CA231997 ), the American Cancer Society, the Virginia and DK Ludwig Fund for Cancer Research, the Stanford School of Medicine Medical Scientist Training Program (grant T32-GM007365), the Blavatnik Family Fellowship, the Stanford Bio-X Bowes Fellowship, and the Waxman Family ResearchFund.


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