City of Hope Launches Alpha Clinics – A New Stem Cell Clinic


Cancer patients usually have three different options: surgery, chemotherapy and radiation therapy. None of these options elicits a great deal of confidence. A new study at City of Hope will officially open the Alpha Clinic for Cell Therapy and Innovation. At this center, patients battling cancer and other life-threatening diseases will have another option: stem cell-based therapy.

The Alpha Clinic, which officially opened March 19, is funded by an $8 million, five-year grant from the California Institute for Regenerative Medicine. This grant will also be supplemented by matching funds from City of Hope. The Alpha clinic will combine the uniquely patient-centered care for which City of Hope is well-known with the most innovative, stem cell-based therapies being studied to date. This approach will hopefully revolutionize the treatment of not only cancer, but also AIDS and other life-threatening diseases.

“We are in a new era of cellular therapy,” said John Zaia, M.D., the Aaron D. Miller and Edith Miller Chair in Gene Therapy, chair of the Department of Virology and principal investigator for the stem cell clinic. “The California Institute for Regenerative Medicine recognizes this, and they have been leading the field. Alpha Clinics like ours aim not only to provide research to benefit patients in the future, but also to get these innovative treatments running in real-life clinics to benefit patients now.”

The christening of City of Hope’s Alpha Clinic is the culmination of a decade of planning and visionary thinking. When the state of Californian voted to found the California Institute for Regenerative Medicine, the funds now became available to start the institute. New stem cell therapies are ready for clinical trials, and City of Hope is home to one of three Alpha Clinics in the state. The other two clinics are at the University of California San Diego and a joint clinic by University of California Los Angeles and University of California Irvine.

City of Hope’s first trials will study stem cell-based therapies for leukemia, and the use of neural stem cells to deliver treatments to brain tumors. The first such study will modify a patient’s own immune cells so that they can recognize and fight cancer cells. Cancer researchers hope the modified cells will be able to attack existing cancer cells, and also be able to attack the cancer again should it recur.

Brain cancer patients will also be able to enroll in a study that uses neural stem cells, which have an innate ability to home to tumor cells, as a delivery mechanisms for cancer drugs. Genetically engineered neural stem cells can bring targeted therapies across the blood-brain barrier, and can potentially deliver drugs directly to tumor sites, which eliminates systemic toxicity.

The US Food and Drug Administration (USFDA) has already approved a new HIV trial that will be conducted at the City of Hope Alpha Clinic. This trial will use “molecular scissors” known as zinc finger nucleases to edit the blood cells of HIV patients and remove a specific gene. Without this particular gene, the cells are unable to produce a protein that HIV requires in order to invade cells and replicate. The approach has the potential to eliminate HIV from the body.

“As we move forward with our Alpha Clinic, we will also be defining a new discipline in nursing of cellular therapy,” said Shirley Johnson, R.N., senior vice president, chief nursing and patient services officer at City of Hope. “This clinic is a unique opportunity to provide patients with the most leading-edge treatments while still giving them the compassionate comprehensive care City of Hope patients expect.”

The Alpha Clinic launched officially on March 19. Future trials will include T cell immunotherapy for blood cancer, new brain cancer therapies, treatments for breast cancer metastases and ovarian cancer treatments. Zaia said the clinic also plans to work with City of Hope’s diabetes researchers to introduce treatments for diabetes, exploring both the potential of pancreatic stem cells and preventing the immune system from attacking insulin-producing cells.

Engineered Neural Stem Cells Deliver Anti-Cancer Drug to the Brain


Irinotecan is an anticancer drug that was approved for use in 1996. It is a modified version of the plant alkaloid camptothecin, and even though it shows significant activity against brain tumors in culture, but in a living body, this drug poorly penetrates the blood-brain barrier. Therefore irinotecan usually does not accumulate to appreciable levels in the brain and is typically not used to treat brain tumors.

That could change, however, if a new strategy published in paper by Marianne Metz and her colleagues from the laboratory of Karen Aboody at the Beckman Research Institute at the City of Hope in Duarte, California, in collaboration with colleagues from several other laboratories.

In this paper, Metz and her co-workers genetically engineered neural stem cells to express enzymes called “carboxylesterases.” These carboxyesterase enzymes convert irinotecan, which is an inactive metabolite, to the active form, which is known as “SN-38.” The efficient conversion of irinotecan to SN-38 in the brain greatly accelerates the therapeutic activity of this drug in the brain. Also, the constant conversion of irinotecan to another molecule accelerates the transport of irinotecan past the blood brain barrier.

To test this strategy. Metz and others grew the engineered neural stem cells in culture and measured their ability to make carboxylesterases in culture, and their ability to convert irinotecan into SN-38 in culture.  In both cases, the engineered neural stem cells made a boat-load of carboxylesterase and converted irinotecan into SN-38 in spades.  More importantly, the genetically engineered neural stem cells behaved exactly as they did before, which shows that the genetic manipulation of these cells did not change their properties.

Next, Metz others tested the ability of the engineered neural stem cells to kill human brain tumor cells in culture in the presence of irinotecan.  Once again, the genetically engineered neural stem cells effectively killed human brain tumor cells in culture in a irinotecan-concentration-dependent manner.  When these genetically engineered neural stem cells were injected into the brains of mice with brain tumors, intravenous administration of irinotecan produced high levels of SN-38 in the brain.  This shows that these cells have the capacity to increase the production of SN-38 in the brain.

This strategy is similar to other strategies that been used in various clinical trials, but because neural stem cells have a tendency to move into brain tumor tissue and surround it, they represent an efficient and effective way to deliver anticancer drugs to brain tumors.  Also, since the particular neural stem cell line used in this experiment (HB1.F3.CD) does not cause tumors and is also not recognized as foreign by the immune system, it is a particularly attractive stem cell line for such an anti-tumor strategy.