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Jan 15, 2011 (Vol. 31, No. 2)

Stem Cells Grapple with High Expectations

Hopes Are High, Yet Potential Pitfalls Abound as Research Wends Its Way through the Clinic

  • Immune Targeting of Glioblastoma

    Glioblastoma multiforme presents a myriad of challenges, notes John S. Yu, M.D., professor and vice-chair, department of neurosurgery, Cedars-Sinai Medical Center, and chairman and CSO at Immunocellular Therapeutics. “Despite years of advances with glioblastoma, survival remains less than 15 months. One problem is that of cancer stem cells that infiltrate the brain as microsatellites of tumors.”

    Dr. Yu was fascinated by the possibility of affecting disease at its root, at the cancer stem cell level. “We have historically targeted the less important daughter cell with radiation and chemotherapy. Cancer stem cells are resistant to these forms of therapy, so targeting cancer stem cells may get at the root of these tumors.”

    Dr. Yu’s group utilized a dendritic cell vaccine strategy to target tumor-specific antigens that are overexpressed on glioblastoma cancer stem cells. In a trial with ICT-107, Dr. Yu’s group is targeting six specific proteins in this cell population. Early results, Dr. Yu notes, are promising. “Of 17 glioblastoma patients treated in this Phase I trial, 41 percent of patients developed an antigen-specific interferon gamma response after vaccination,” he says. “The median progression-free survival was over 17 months, and the median survival was not reached to date. The planned Phase II trial will enroll 102 patients.”

  • hESC-Derived Cardiomyocytes

    Click Image To Enlarge +
    Geron’s GRNCM1 shows expression of cardiac markers alpha-actin and Nkx-2.5.

    Companies expanding into the frontier include Geron, which recently launched a clinical trial using hESC-derived oligodendrocyte progenitor cells called GRNOPC1, which is a population of living cells containing precursors to oligodendrocytes. Oligodendrocytes are lost in spinal cord injury, resulting in myelin and neuronal loss that causes paralysis in many patients.

    Katharine Spink, Ph.D., vp operations and regenerative medicine programs, will be presenting preclinical results from Geron’s study on GRNCM1, an hESC-derived cardiomyocyte for the treatment of heart failure. This includes methods for high efficiency differentiation of cardiomyocytes from hESCs, characterization of the resulting cell population, preclinical data on cellular function, and steps for the development of this product toward the clinic.

    Researchers have demonstrated proof-of-concept in mice, Dr. Spink explains. Mouse embryonic stem cells have been used to derive mouse cardiomyocytes. When injected into the hearts of recipient adult mice, the cardiomyocytes repopulated the heart tissue and stably integrated into the muscle tissue of the adult mouse heart, she says. She believes that in human medicine, it is possible that hESC-derived cardiomyocytes could be developed for cellular transplantation therapy in humans suffering from congestive heart failure and the damage caused by heart attacks.

  • Myocardial and Critical Limb Ischemia

    Autologous stem cell therapy can be defined as an attempt to regenerate and replenish tissue by increasing the supply of naturally occurring reparative cells at sites of damage. This approach relies on the phenomenon of plasticity—autologous stem cells from one tissue generating specialized cells of another tissue.

    Douglas Losordo, M.D., director, Feinberg Cardiovascular Research Institute, and professor, heart research, Feinberg School of Medicine, Northwestern University, will be presenting his group’s work in patients with advanced cardiac and vascular disease. “We have results from two randomized, controlled clinical trials of CD34 stem cell therapy for cardiovascular disease,” says Dr. Losordo.

    “One shows significant improvements in chest pain and exercise capacity in treated versus controls. The other is a Phase IIa study in patients with critical limb ischemia that shows a significant reduction in amputation rates in patients treated with their own CD34 cells.”

    The goal is to spur the growth of small blood vessels that make up the microcirculation of the heart muscle, he says. Researchers believe that the loss of these blood vessels contributes to the pain of chronic, severe angina. “Autologous cells have been used for a long time in transplants, providing some history of safety, albeit in different indications,” says Dr. Losordo. “The challenges are similar, I think, to the development of any novel therapy: establishing proof of principal, evidence for safety, and so on.”

    The results seem promising; Dr. Losordo adds, “Phase III studies for cell therapies for cardiovascular disease will be performed in the next 12–18 months.”

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