Revolution, Not Revolt: The New Era of Stem Cell Cancer Research

Irving L. Weissman, MD’s stem cell research using PET and optical imaging has revealed how a novel antibody-based biomarker highlights areas of residual cancer with broad potential for therapeutic use. In other research, the reintroduction of cancer patients’ own stem cells could replace bone marrow transplantation and its inherent risk of complication after high-dose chemotherapy.

Weissman is hailed as the first scientist to identify stem cells in any species. His specialized stem cell research spans decades and has culminated in a well-respected professorship at California’s Stanford University and multiple companies specializing in stem cell applications. Recently he was featured as the Horizon Lecturer at the 2013 Radiological Society of North America (RSNA) annual meeting in Chicago, where he outlined findings representing several years of related stem cell studies.

The antibody for every cancer

Prior to the turn of the millennium, Weissman, professor of pathology and developmental biology and director of the Stanford Institute of Stem Cell Biology and Regenerative Medicine, and his team of researchers were studying acute myeloid leukemia and found that the blood and bone marrow cancer retained secreted-away hematopoietic stem cells that were able to avoid programmed immuno-removal. In subsequent years, the researchers implicated a protein called CD47 (cluster of differentiation 47), or integrin associated protein, and observed as it functioned along the tumor cell surface to cloak them from being recognized, swept up and eliminated by macrophages in the process of phagocytosis. Later still, the team developed an anti-CD47 monoclonal antibody and was able to eradicate leukemia in preclinical studies. Further research has shown that the protein is overexpressed in not just leukemia, but also non-Hodgkin’s lymphoma, neuroblastoma and bladder cancer and could be found to be involved in many more as the research evolves. While the protein appears to be ubiquitous among both cancerous and healthy cells, there is a clear distinction between the two.

“We have found that every cancer overexpresses this signal called CD47, and they have it at very high levels,” Weissman says.

Cancer cells express it at far higher levels, as it turns out, than normal cells. This was encouraging for the researchers and led to the preliminary development of molecular imaging biomarkers that could one day be used either semi-invasively using fluorescence microscopy in a perioperative context or non-invasively with PET or some other advanced molecular imaging technique. A preliminary paper showed the results of fluorescence microscopy in the context of bladder cancer and brought to light the opposite of CD47—calreticulin, which activates phagocytosis (Sci Transl Med 2(63): 63ra94). As a therapy, an anti-CD47 compound would smoke out diffused clusters of 10 to millions of tumor cells with monoclonal antibodies that seek to turn off the CD47 protein signal. Once these tumor cells have been unmasked and revealed to the immuno surveillance system, the natural process of phagocytosis would take over. In the past three years, Weissman and his colleagues have started moving toward the validation of a viable formula for what could one day be a groundbreaking antibody therapy to go hand in hand with radiotherapy. Researchers are working to perfect a compound of small molecules for imaging that could be used for therapy planning. Pinpointed areas of clustered primary or metastatic tumor cells could be mapped and used to direct external beam radiation therapy.

“It works best if most of the tumor is gone and the rest of the cancer is spread throughout the body, but every site is tiny,” adds Weissman. “Then the antibody works like a charm as a therapy. It will go hand in hand with radiation therapy.”

In its therapeutic incarnation, antibodies such as rituximab could potentially be compounded with chemotherapy for a stronger kill (Cell. 2010 Sep 3;142(5):699-713). Radioimmunotherapy, on the other hand, does not appear to be an ideal candidate in this instance, says Weissman. Many normal cells express CD47 and investigators run the risk of substantial collateral damage if they adapted this technique using therapeutic radioisotopes.

Weissman’s team has published well over a dozen papers on hematopoietic stem cell research and the role of CD47 in cancer development and resistance. The amount of preclinical research undertaken suggests that human trials for escalated antibody therapy could be in the not-too-distant future.

The problem of rejection

Weissman’s exploration of stem cells has not only led to the promise of new imaging biomarkers and cancer therapy, but a powerful new bone marrow transplantation technique using patients’ own stem cells. The cells are harvested from patients’ skin and preserved in a frozen state for replanting after high-dose chemotherapy, which often requires a bone marrow transplant. There is a high risk of failure in conventional transplantation due to a residual immune response from donated blood harboring foreign T cells that are apt to mount an attack on patients’ lymphoid system, the tissues that form lymphocytes and disease fighting antibodies. The potential of personal stem cell lines for transplantation is staggering, because, if successful, years of anti-rejection drug regiments and all of the risks and complications of such treatments would then be unnecessary.

This technique would not be possible without high-tech microfluidics and cell sorters that can now remove cancerous cells from harvested samples for purified reintroduction without the risk of recurrent cancer. Not only do these samples stand to improve the success rate of bone marrow transplant, but they could also be used for genetic blood disorders.

Clinical trials on the horizon

As of Jan. 6, the Stanford University School of Medicine announced that the institution would be receiving a generous gift of $90 million from Ludwig Cancer Research and its founder, Daniel K. Ludwig. Stanford is one of six institutions sharing a total of $540 million for stem cell related projects. It is being called one of the largest gifts from a single donor in the history. Other funding for U.S. clinical trials comes from the California Institute of Regenerative Medicine, a state agency established in 2004 as a result of California’s proposition 71 (The California Stem Cell Research and Cures Act) to develop stem cell and cancer related therapies.

For Weissman and his team, some form of the antibody therapy was scheduled for regulatory investigation by both the FDA and the European Medicines and Healthcare products Regulatory Agency (MHRA) at the end of January or the beginning of February.

“We’ve presented our results to the FDA and they have encouraged us to file for initial new drug application and we are now bringing together all the data required,” Weissman explains.

If the FDA does not put the drug on clinical hold within 30 days, clinical trials will begin at Stanford as well as Oxford University in the United Kingdom, where a “deep collaboration” has been formed between the institutions’ cancer centers.

The future of stem cell research looks bright. There is vast potential for new treatments and possibly even a cure for a range of cancers, but stem cell research also is applicable to treat a gamut of diseases including Parkinson’s and diabetes. A new era for regenerative medicine appears to have given Weissman and his team no shortage of job security.