Defusing Leukemia Killer Cells: From Basic Stem Cell Research to Therapeutic Human Drug Development

Ravi Majeti, MD, PhD

Physician-scientists at Stanford are nurturing the equivalent of a biotech start-up, right in the halls of the university, to develop a new therapy for acute myeloid leukemia (AML), a rapidly fatal cancer of the blood and bone marrow. It is “unprecedented,” explains Ravi Majeti, MD, PhD (associate professor, Hematology), who is part of a team of researchers that used advanced techniques to identify and test an antibody that could lead the immune system to “eat” the cancer-forming cells in leukemia and solid tumors. Starting with discoveries in the lab, the researchers found that one particular protein marker on the surface of leukemia stem cells - CD47 - is a culprit in AML. That has led to a new experimental approach to treat AML without chemotherapy or bone marrow transplantation, with an antibody therapy that interferes with the actions of CD47 and defuses the killer cancer cells. Now the CD47 Disease Team has developed and manufactured a clinical grade therapeutic targeting CD47 on cancer stem cells, which could eliminate those cancer-forming cells in AML while preserving normal, healthy stem cells.

“AML is the cancer with the strongest evidence for the critical involvement of cancer stem cells", says Majeti, “and it is the most common acute leukemia affecting adults. Targeted antibody treatment offers the possibility of improved clinical outcomes for AML.” Currently, most patients with AML will die within the first year of diagnosis, even with aggressive chemotherapy and bone marrow transplantation; and five-year overall AML survival rates are as low as 30 percent.

“We are really hoping to make a difference in this disease,” Majeti continues. “We have embarked on a massive undertaking inside the university to make an impact on the outcomes of patients with AML. We have manufactured a drug that targets the CD47 molecule, and we have an open, active clinical trial at Stanford. We did basically what a start-up biotech company would do, but we got some unique grant funding to allow us to do it all inside the university. It’s been a new experience both for the university and for us as researchers.” Clinical trials at Stanford have begun in patients with solid tumors, to measure tumor response and safety, and trials with AML patients will begin towards the end of 2015.

Their work is part of a collaborative effort in hematology that crosses the campus and also includes researchers at the pioneering AML Working Group in the UK. “We established the CD47 Disease Team as an integrated program, with a highly collaborative group of scientists and clinicians working to bring CD47-targeted therapies to patients,” says Majeti. The team includes important clinical and research partners in the US and the UK – from investigators who see patients in clinical trials, to leading drug development experts. The CD47 Disease Team was awarded funding for this groundbreaking translational research from the California Institute for Regenerative Medicine

The targeted antibody treatment for AML is an outgrowth of research by Majeti with Irving Weissman, MD (professor, Pathology), a leading investigator in the biology and translational applications of normal blood stem cells and cancer stem cells. In the 1990s, Weissman helped develop the then-controversial theory that there are specific cancer stem cells within the whole tumor or cancer mass, and that those cells drive the growth of the cancer. He hypothesized that molecules only found on the cancer stem cells could be targeted by antibody therapeutics to eliminate cancer and cure patients. In parallel, Weissman identified a method to remove and purify the patient’s own blood-forming stem cells and return them to the body, purged of cancer, so patients could rebuild their blood supply from scratch.

Further research by Majeti, along with Weissman and a team of researchers in 2012, set the stage for a new understanding of how AML develops. Their research proved that leukemia develops from mutations that occur in blood stem cells and also determined the order in which such mutations occur. Weissman directs Stanford’s Institute for Stem Cell Biology and Regenerative Medicine and the Ludwig Center for Cancer Stem Cell Research and Medicine. Majeti, who is also a member of the Stanford Cancer Institute and the Institute for Stem Cell Biology and Regenerative Medicine, pointed out that having the correct model of how leukemias arise is important because it may eventually help determine what kind of therapy might be most effective.

This has led to the establishment of the Translational Program in Hematologic Malignancies that brings together interested researchers from across the campus to better understand these malignancies and make progress towards treatment. The team incorporates clinical investigators enrolling patients in clinical trials, along with laboratory scientists in other areas of cancer research. “We established this program as an integrated effort with a highly collaborative group of scientists to focus on problems related to hematologic malignancies and to accelerate improved treatment for cancers of the blood,” says Majeti.

Other research at the Majeti lab is also aimed at understanding AML and moving towards new treatments. One project is looking at recurrent genetic mutations in AML to determine their role in the development of the disease and to create new therapies based on that understanding. Another project isolates residual blood-forming stem cells in bone marrow samples from patients at the time of AML diagnosis to demonstrate that not all leukemic mutations are contained in the residual cells. That investigation could support the hypothesis that mutations must be serially acquired in clones of blood-forming stem cells, and it could help identify the source of relapse that causes significant mortality in AML.

One of the unique things about academic medicine is that physician scientists can be actively involved in clinical care as well as research and drug development. “It is incredibly motivating to interface with patients and their families and to move towards a therapy that we hope will eventually improve their lives,” says Majeti.

“My long-term goal is to make an impact on outcomes of patients with AML. That’s my personal mission and vision,” Majeti says. In 2015, he was awarded the prestigious Leukemia & Lymphoma Society Scholar Award, with five years of support for his original investigations that could be translated into improved treatments and cures for patients with hematological cancers. Majeti concludes: “We are treating patients with the same crappy chemotherapy drugs that were being used in the 1980s, and patients don’t do well. We need to bring new approaches to our patients.”

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