DUARTE, Calif., October 28, 2009 — City of Hope received two grants totaling a $32.5 million from the California Institute for Regenerative Medicine (CIRM) for research into tumor targeting stem cells to deliver cancer killing agents specifically to brain tumors and research into an AIDS-related lymphoma therapy that may provide patients with permanent immunity to HIV.
Karen Aboody, M.D., associate professor in the departments of neurosciences and neurosurgery, will lead a four-year study supported by an $18 million grant to research a novel treatment for high-grade glioma. Aboody was one of the first researchers to demonstrate that neural stem cells migrate to invasive brain tumors. The team uses tumor targeting stem cells to deliver cancer killing agents specifically to brain tumors. The study is aimed at further refining the therapeutic potential of this technology, which has already been submitted as an investigational new drug, in order to deliver far more potent and effective cancer killing agents. City of Hope will collaborate with Childrens Hospital Los Angeles on this study.
The co-principal investigators on the grant are Larry Couture, Ph.D., senior vice president, Sylvia R. and Isador A. Deutch Center for Applied Technology Development, and Jana Portnow, M.D., assistant professor of medical oncology.
A $14.5 million grant supports AIDS research. The therapy introduces mutations into the CCR5 gene, which have been shown to provide certain people with innate resistance against HIV infection. John Zaia, M.D., the Aaron D. and Edith Miller Chair in Gene Therapy, and chair of virology, City of Hope, will lead a multidisciplinary team of investigators in the four-year study. His grant submission received the highest evaluation score among all of the submissions CIRM received for this round of funding.
City of Hope pioneered research, beginning in the 1990s, using hematopoietic cell transplantation (HCT), more commonly known as bone marrow transplantation, to treat patients with HIV and AIDS-related lymphoma. The initial research was conducted to determine if HCT, which is a standard therapy option for lymphoma patients, would also impart the potential benefit of providing new blood stem cells to reboot the immune system with uninfected cells.
“One of the most difficult obstacles to achieving success with HCT treatment is the resilience of HIV, which can resurge and once again destroy the immune system through any virus that hides away in the lymph nodes,” said Zaia. “We need to provide patients with new immune cells that are resistant to HIV infection so that we can potentially limit the reservoir of infected cells that allows progression of the disease despite long-term therapy and the continuous attack on the immune system that can lead to numerous opportunistic diseases, such as AIDS-related lymphoma.”
In late 2008, German physicians reported a case in which a patient with AIDS underwent HCT to treat his leukemia, which was unrelated to the HIV infection. The bone marrow donor had the CCR5 mutation, and the patient experienced an increase in T-cell count, a drop in viral load to undetectable levels and has stopped all HIV drug treatments. Only a relatively small portion of people have the CCR5 mutation, so researchers set out to develop an equivalent immunity that could be imparted to patients.
“We are collaborating with investigators from the University of Southern California (USC) and from Sangamo BioSciences Inc. who have developed application of zinc finger nucleases, which are enzymes that were built in the lab to target and break the CCR5 gene in a manner similar to the natural CCR5 mutation in the population,” said John Rossi, Ph.D., the Lidow Family Research Chair, in molecular and cellular biology, City of Hope, and member of the research team. “The nucleases create a permanent change in the DNA of hematopoietic stem cells, which can give rise to every different type of blood cell that are now all resistant to HIV infection in the lab.”
The CIRM grant will support the research team’s efforts to further refine the therapy to improve its effectiveness in creating hematopoietic stem cells that can produce HIV-resistant blood cells, as well as to develop an efficient manufacturing method that can produce the volume necessary for clinical use. Additionally, the team’s goal by the end of the four-year grant is to submit an investigational new drug application with the U.S. Food and Drug Administration, the first step in getting a new drug or treatment approved for wide use.
David DiGiusto, Ph.D., professor in City of Hope’s Department of Cancer Immunotherapeutics and Tumor Immunology, will lead efforts to develop a process of manufacturing the therapy. Other City of Hope investigators involved in the research include Amrita Krishnan, M.D., director of the Multiple Myeloma Program in the Department of Hematology & Hematopoietic Cell Transplantation, and Couture. Other participating members of the research team include: Paula Cannon, Ph.D., associate professor of molecular microbiology and immunology, pediatrics, and biochemistry and molecular biology, Keck School of Medicine of USC; Philip Gregory, D.Phil., chief scientific officer and vice president of research, Sangamo BioSciences Inc.; and Michael Holmes, Ph.D., senior director of therapeutic gene modification, Sangamo BioSciences Inc.
Couture is participating in three additional studies receiving CIRM grants. He will be manufacturing two therapies for a different HIV study focusing on RNA interference as well as a sickle cell disease study, both led by the Broad Stem Cell Research Center at the University of California, Los Angeles, in addition to a therapy for an age-related macular degeneration study led by the Keck School of Medicine of USC.