Researchers have assessed the efficacy of targeting the CD47 protein combined with traditional immunotherapy drugs in patients with colorectal cancer, with a recent study published by Arai et al in the Journal for ImmunoTherapy of Cancer. The findings indicated that the combination approach could be more effective in treating colorectal cancer.
Background
Traditional immunotherapy drugs, known as immune checkpoint inhibitors, work on the adaptive immune system. These agents have transformed cancer care by helping the body’s immune system fight cancer as it does other diseases. Immune checkpoint inhibitors are designed to block immune checkpoints—proteins that hinder the immune system from attacking healthy cells. Cancer cells often exploit these proteins to evade detection by immune cells.
Until recently, immunotherapy drugs could only target the body’s learned immune response, once cancer cells had already avoided the innate immune system. The CD47 protein is part of the innate immune system.
“Up until now, immune checkpoint inhibitors targeting the adaptive immune system have been the mainstream in immunotherapy,” explained lead study author Hiroyuki Arai, MD, PhD, Assistant Professor of Clinical Oncology at the St. Marianna University School of Medicine in Kawasaki, Japan. “But in our current study, we focused on CD47, a checkpoint molecule in the innate immune system,” he added.
Previous studies have shown that colorectal cancer cells use the immune checkpoint CD47 to escape macrophages, innate immune cells that would otherwise target and destroy them. However, little has been known about how cancer cells manipulate CD47 and whether the protein could be used to treat colorectal cancer.
Study Methods and Results
In the recent study, the researchers sequenced the DNA and RNA from 14,287 colorectal cancer tumor samples stored within the Caris Life Sciences database. They then compared the tumors with levels of CD47 expression above the median level with those that levels of expression below the median level, seeking to better understand immune signaling and other biological processes.
The researchers found that higher levels of CD47 expression were linked to higher oncogenic signaling, more aggressive tumors, more activated cancer pathways, and more immune cells within the tumors—suggesting that the tumors may be growing and spreading. Higher CD47 expression was also associated with changes in several key immune pathways such as the suppression of the signal used to activate macrophages—which would otherwise eliminate the cancer cells—as well as the formation of new blood vessels.
The researchers hypothesized that the development of an immune checkpoint inhibitor capable of blocking the activity of CD47 could improve outcomes among patients with colorectal cancer.
Conclusions
The findings revealed that CD47 may be a critical target for novel colorectal cancer drugs, which could be administered alongside one or more of the currently available therapies—including chemotherapy, angiogenesis inhibitors, and adaptive immune checkpoint inhibitors.
“The most important takeaway is this data suggests that CD47 is a very attractive target for drug development,” commented senior study author Heinz-Josef Lenz, MD, Professor of Medicine and Preventive Medicine at the Keck School of Medicine as well as Deputy Director for Research Programs and Co-Director for the Rosalie and Harold Rae Brown Center for Cancer Drug Development at the Norris Comprehensive Cancer Center at the University of Southern California. “The key is to develop an antibody or an engineered immune cell that can inhibit CD47 signaling, but it has to be used in combination with other drugs. The right combination is not clear yet, so more research is needed,” he underscored.
The researchers are currently exploring other methods of shrinking colorectal cancer tumors, including with compounds that stimulate macrophages to attack cancer cells.
Disclosure: The research in this study was supported by the National Cancer Institute of the National Institutes of Health, the Gloria Borges WunderGlo Foundation, the Dhont Family Foundation, the Victoria and Philip Wilson Research Fund, the San Pedro Peninsula Cancer Guild, Ming Hsieh Research, and the Daniel Butler Research Fund. For full disclosures of the study authors, visit jitc.bmj.com.
