Trial May Fight First Common Target in All Human Cancers
With $20 million in funding from the California Institute of Regenerative Medicine (CIRM), researchers at Stanford University and Oxford University are preparing for the first clinical trial of a monoclonal antibody designed against a common target that is overexpressed in a wide variety of cancers.
The trials are scheduled to begin in the first quarter of next year, and will be led by Stanford University stem cell pioneer Irving Weissman, the director of Stanford University’s Institute for Stem Cell Biology and Regenerative Medicine. His co-principal investigators on the clinical trials are Ravindra Majeti and Beverly Mitchell at Stanford University, and Paresh Vyas at Oxford University. "We plan to carry out trials at Oxford and Stanford simultaneously," says Weissman.
The monoclonal antibody, called Hu5F9, targets the protein CD47, which has been known to be overexpressed on the surface of cancer cells. Weissman and his team first discovered that the protein was overexpressed in cancer in 1998 and since then have discovered that a minimum of 20 cancers express the protein, reporting new findings in a dozen papers in the last three years alone.
CD47 is usually expressed on the surface of healthy young cells, and healthy stem cells. The protein issues a kind of “don’t eat me” signal to the body’s cancer-eating macrophage immune cells, protecting them while they are growing and forming. “Young cells overexpress CD47 to avoid phagocytosis,” Weissman explained during his keynote address at the New York Stem Cell Foundation annual conference earlier this month.
Cancer cells, however, co-opt that mechanism to protect themselves. In their funding application to the CIRM, Weissmann and colleagues wrote “to our knowledge, CD47 is the first common target in all human cancers, one which has a known function that enables cancers to grow and spread.”
Through preclinical studies in mice, Weissman’s team has shown that Hu5F9 can wipe out cancer cells that express CD47 while leaving younger healthy cells that also express the protein untouched. A further study revealed the reason behind this selective targeting: cancer cells, unlike healthy cells, also express on their surface an “eat me” protein, calreticulin, a second signal that is necessary to activate macrophages to dine on them.
In a paper published this summer in the Proceedings of the National Academy of Sciences, Weissman and colleagues reported that the anti-CD47 antibody rouses not only macrophages to eat cancer cells but T cells as well. Blocking the signal also appears to stop metastasis.
In addition, preliminary research indicates that Hu5F9, which co-opts the immune system in a couple of ways, also works well in conjunction with other therapies that manipulate the immune system. For example, it works with the monoclonal antibody rituximab, normally known for blocking a protein on B cells, against non-Hodgkin lymphoma. Rituximab, alone, does not work well against non-Hodgkin.
The first trial of the antibody will enroll solid cancer patients in one location, and acute myeloid leukemia (AML) patients in the other. A key reason to choose AML, Weissman said: his group found that “CD47 overexpression is a crucial step in the progression from (benign) myelodysplastic syndrome to AML.”
CD47 is particularly overexpressed on AML cancer stem cells. Cancer stem cells are often the most resistant to traditional chemotherapy and radiation. The hope is that anti-CD47 therapy will wipe out those highly resistant cells either on their own, or in conjunction with other therapies. “Cocktails are often the right way to go,” Weissman said after the NYSCF conference. So the first trials will feature "Hu5F9 solo," he said, but later trials will add antibodies.
In their CIRM grant application, the group wrote: “Our studies show that Hu5F9 is a first-in-class therapeutic candidate that offers cancer treatment a totally new mechanism of enabling the patient’s immune system to remove cancer stem cells and their metastases.” With that funding for the first clinical trials of their antibody, Weissman and colleagues now have the opportunity to prove that bold claim.