Patient-Derived Antibody Appears to Selectively Target Tumor Cells, Spur Immune Attack
June 6, 2016, by NCI Staff
Researchers have developed an antibody derived from patients with early-stage lung cancer that enlists the immune system to destroy cancer cells.
The antibody killed tumor cells in cell lines of several different cancer types and slowed tumor growth in mouse models of brain and lung cancer without obvious evidence of side effects, the researchers reported May 5 in Cell Reports.
“This is one of the first studies showing that scientists can isolate an inhibitory antibody from cancer patients as a potential new class of therapeutics,” said Mitchell Ho, Ph.D., of NCI’s Center for Cancer Research.
The antibody targets a regulatory protein known as complement factor H (CFH), which normally protects healthy cells in the body from attack and destruction by the immune system. The antibody, the researchers found, recognizes a unique conformation, or shape, of CFH that occurs only in tumors, suggesting that it has the potential to selectively target tumors in people without harming healthy cells.
Clues from Early-Stage Cancer Patients
The new study, led by Edward Patz, Jr., Ph.D., and Hua-Xin Liao, M.D., Ph.D., of Duke University Medical Center, stems from a 2010 study by Dr. Patz and his colleagues, which identified a group of patients who had early-stage non-small cell lung cancer (NSCLC) that had not metastasized. Dr. Patz’s team has been studying the immune response in these patients in hopes of discovering new approaches for treating cancer. In the 2010 study they found that NSCLC patients whose cancer had not spread were much more likely to have antibodies that react against CFH.
CFH normally protects healthy cells by binding to the cell surface and preventing an immune system protein known as complement C3b from being deposited there. Complement C3b initiates the breakdown of the cell membrane, which causes the cell to die. Tumor cells have been found to produce CFH and take advantage of the protection it confers to evade destruction by the complement system, which is a component of the body’s immune response.
Dr. Patz and his colleagues reasoned that antibodies to CFH might counteract this protective effect, promoting tumor cell destruction and preventing tumors from metastasizing. A 2015 follow-up study supported this hypothesis; it also provided evidence that CFH antibodies from cancer patients recognize a distinct form of CFH.
Autoantibodies as Potential Therapy
Scientists have known since the 1970s that some cancer patients develop autoantibodies—antibodies that react against substances made by the person’s own body—Dr. Ho noted. “Normally, these autoantibodies are used as markers for early detection and diagnosis,” he added. “But so far it has not been shown that they can be used for therapy.”
To explore the potential of CFH antibodies as a targeted therapy for cancer, the Duke team needed to produce antibodies that recognize the same portion of the CFH protein as the autoantibodies produced by patients with early-stage NSCLC. To do so, they used an approach that had been developed previously to isolate potent HIV-neutralizing antibodies produced by certain HIV-infected individuals.
In this case, the researchers pooled the white blood cells from patients who made CFH antibodies and used a small piece of the CFH protein as “bait” to fish out individual CFH antibody-producing B cells. They then purified seven different CFH antibodies from these B cells.
The Duke researchers tested five of the CFH antibodies in a human lung cancer cell line and selected one for further testing. This antibody promoted tumor-cell killing in four different lung cancer cell lines as well as in human gastric cancer, breast cancer, and three other human cancer cell lines.
A mouse version of the CFH antibody delayed growth of human brain tumors implanted in mice and of tumors in a mouse model of lung cancer and did not cause any obvious damage to normal tissues. Antibody treatment also led to infiltration of the tumors by inflammation-causing white blood cells, suggesting that the CFH antibody activates a longer-term immune response against the cancer cells. Such a response could be triggered by molecules that are produced when tumor cells are damaged and that help spur immune system cells into action.
“We believe it might be this additional cellular response that could potentially have the most profound impact on cancer outcomes long-term,” Dr. Patz said in a news release. Further animal studies of the immune response to the antibody will be needed to understand the full potential of this approach, the study authors noted.
Precision Medicine Potential
The Duke team also studied the interactions between the CFH antibodies and their target site on the CFH protein. The findings confirmed that the antibodies they had produced recognize a unique conformation of CFH that occurs only in tumors.
Indeed, Dr. Ho said, the approach developed by Drs. Patz and Liao and their colleagues “aligns very well with what we think of as the future of precision medicine,” which involves finding tumor-specific targets that differ in subtle ways from the corresponding molecule on normal cells. Finding such targets for antibody-based cancer therapies is challenging, he continued, especially for solid tumors like lung, liver, and pancreatic cancers.
“This [approach to developing a possible therapeutic antibody] is an exciting and interesting concept,” Dr. Ho said. “Further comprehensive preclinical studies will be needed to fully evaluate the antibody’s antitumor activity and ability to prevent metastasis, possible side effects and drug resistance, and the role of the immune program in its mechanism of action.”