Our immune systems are on constant alert for signs of disharmony. In situations of threat—such as when tumors develop—immune cells launch an attack. This action sometimes wipes out the enemies—other times not. Tumors always search for ways to hide from the immune system and can often persuade immune cells to change their allegiance.
The macrophage is one such example. Whether this type of immune cell fights for or against a tumor largely depends on the mix of cells in the tumor microenvironment and the tone of the conversations between the tumors and immune cells.
macrophage
Tumor-associated macrophages—or TAMs—are immune cells that typically advocate for the tumors, preventing helpful immune cells, such as T cells, from engaging an attack.
Such immunologically “cold” or immunosuppressive tumors are often untouchable—even by immunotherapy—the revolutionary cancer treatment introduced over a decade ago.
Immunotherapy has wondrous effects when it works, but currently, only 20-40% of patients respond to it. Clearly, there is more to do. We need ways to convert cold tumors into hot ones by reawakening the immune system to kill the cancer.
Fiachra Humphries, PhD, came up with an intriguing idea.
Manipulating the immune system
Dr. Humphries and his team noticed that some TAMs carry a macrophage membrane receptor (MMR) that is controlled by the innate immune system—our first defense against foreign invaders.
“When we conducted RNA sequencing on [these macrophages], we found that the immune system controls the levels of this receptor like an innate checkpoint. So, we worked out a way to switch it on and off,” says Dr. Humphries.
By pharmacologically turning this receptor off, immune cells can infiltrate the tumor and destroy it. In preliminary work, the team found high expression of this receptor in melanoma, pancreatic tumors, and glioblastoma, confirming the importance of finding a way to target this receptor with drugs.
Turning an idea into a concrete reality
MMR provides a perfect landing spot for drugs to attach, making them ideal drug targets. With the help of a UMass Chan BRIDGE Fund from the BRIDGE Innovation and Business Development Office, Dr. Humphries is moving forward with plans to develop a nanobody that can attach to MMR and block its function. Nanobodies are small single domain antibodies produced after immunizing llamas with a protein to trigger an immune response. After the immune response has time to mount, the nanobodies will be extracted from the blood and used in drug development. The compact size of nanobodies relative to antibodies gives them several advantages, including ease of production, greater stability, and enhanced potency.
Cartoon of a nanobody
The team will screen candidate molecules, searching for ones that bind well and neutralize MMR, ultimately choosing one or two lead candidates to test in vivo. The study will focus on designing a nanobody that works effectively in a mouse model of melanoma with the longer-term goal of applying the treatment to other cancers that express high levels of MMR.
“It would be very exciting if we could develop a therapy that can be used in combination with checkpoint inhibitors or on its own as a monotherapy,” says Dr. Humphries.
Patient selection and treatment monitoring
The discovery that MMR is an innate checkpoint target for therapy not only opens new treatment possibilities but can also help refine cancer screening to identify patients most likely to respond. Eventually, assessing MMR expression status can be utilized as a valuable biomarker for evaluating therapeutic response.
The BRIDGE funds will be instrumental in helping Dr. Humphries develop a nanobody and subject it to preclinical tests both as a monotherapy or a combination therapy with traditional checkpoint inhibitors. The final goal, of course, is to bring the drug to patients.
