Immunotherapy
Unlike drugs that act by chemically killing cancer cells or halting their growth, immunotherapy uses the body’s own immune system to attack cancer tissue from within. City of Hope scientists are working on several immunotherapy approaches:
The Cellular Immunotherapy program, led by Stephen J. Forman, M.D., F.A.C.P., Chair, Hematology & Hematopoietic Cell Transplantation, continues to develop innovative treatments that reduce the need for harsh radiation and chemotherapy. One of the most exciting programs underway at City of Hope, the cellular immunotherapy program is developing technology to take T-cells from a cancer patient and reprogram them through genetic engineering to target and eradicate the patient’s cancer.
Using pioneering technology, we have been able to isolate immune cells from a patient’s blood sample and then engineer those cells to express an artificial receptor that will seek out and attack cancer cells. In the lab, our researchers then grow billions of identical, reprogrammed T-cells and re-infuse them into the patient in the clinic, where they go to work eliminating the cancer. Under Dr. Forman’s leadership, City of Hope has conducted the first-ever FDA-authorized clinical trials using reprogrammed T-cell therapy for lymphoma, neuroblastoma and glioma.
In the glioma study (currently underway), patients are infused with engineered T-cells that respond to an antigen called CD8. An antigen is any foreign substance to which the body reacts by dispatching antibodies such as T-cells. These reprogrammed T-cells act as homing devices to take the body’s T-cells to the cancer. Although only glioma patients were initially targeted for treatment, researchers have plans to expand this therapy to another brain tumor, medulloblastoma, in pediatric patients.
Principal Investigator:
Stephen J. Forman, M.D., F.A.C.P.
One prong of research seeks to formulate a T-cell that is protected from rejection by the patient’s own immune system, thus becoming a potential “universal T-cell” for patients everywhere. Specifically, Generation 2 T-cells are programmed to be accepted without triggering a rejection reaction. By developing such a T-cell, our researchers thus create a means to mass produce T-cells from one patient on behalf of thousands more. The first glioma patient treated with Generation 2 T-cells was in 2007 — the first in the world to be treated with this novel therapy.
Principal Investigator:
Stephen J. Forman, M.D., F.A.C.P.
While City of Hope researchers develop the autoimmune-resistant T-cell, they plan to adapt it to create Generation 3 T-cells. The goal is to develop technology enabling researchers to equip Generation 2 T-cells with additional cancer-fighting therapeutic material to strengthen its impact against cancer. Dr. John Rossi, Chairman and Professor of Molecular Biology at City of Hope, and Dr. Forman are using interfering ribonucleic acid (RNAi) inside T-cells to make them even more effective cancer combatants. A drug using RNAi is set for clinical trials.
Principal Investigators:
Stephen J. Forman, M.D., F.A.C.P. and
John Rossi, Ph.D.
Macrophages are immune cells that act as scavengers feeding upon dead cells, foreign substances, and other debris in the body. Microglia are macrophages specific to the central nervous system. Microglia are normally inactive but become activated in response to inflammation, infection and trauma. Once activated, they proliferate and migrate to the site of injury. Behnam Badie, M.D., is researching ways to improve outcomes in post-surgical brain tumor patients by re-engineering the microglia to deliver therapeutic agents to the tumor site, killing residual tumor cells. He also wishes to extend the life of T-cells using microglia and test their efficacy against cancer. This study will likely garner results within a year, setting the stage for Phase I clinical trials.
Principal Investigators:
Behnam Badie, M.D. and
Leying (Larry) Zhang, Ph.D.
Stem Cell Therapy
Neural stem cells selectively travel to tumor cells. Karen Aboody, M.D., has begun ground-breaking research in discovering and exploiting this finding, allowing her to use neural stem cells to selectively deliver therapeutic agents to target tumor cells in the brain. The neural stem cells are genetically modified to produce therapeutic gene products, which effectively infiltrate and kill brain tumor cells.
Principal Investigator:
Karen Aboody, M.D.
Cancers that originate inthe brain are termed primary brain tumors and are among the most difficult tumors to treat. The effectiveness of chemotherapy is often hindered by the presence of the blood brain barrier, which prevents most drugs from getting into the brain. Traditional chemotherapy tends
to kill both cancer cells and normal cells, often resulting in undesired side effects.
City of Hope researchers are studying ways to target only the brain tumor while limiting damage to normal brain tissue using neural stem cells (NSCs) to deliver anti-cancer treatment directly to tumor cells in the brain. NSCs hold the promise of improved treatment for brain cancers because they have a natural ability to seek out and distribute themselves within a tumor, as well as track to other sites of tumor in the brain. Because they can find tumor cells, NSCs may offer a new way to bring more chemotherapy directly to brain tumors. After modifying the NSCs by transferring a therapeutic gene into them, NSCs can serve as vehicles to deliver anti-cancer treatment directly to the primary tumor, as well as potentially to target malignant cells that have spread away from the original tumor site.
Principal investigator:
Jana Portnow, M.D.
Caption: Neural Stem Cells (NSCs) have a natural tendency to migrate to tumor cells. The orally given inactive drug (prodrug) crosses the blood brain barrier and is converted into a chemotherapeutic agent within the NSC. The agent is then released from the NSC to selectively destroy dividing tumor cells. This strategy has a large ‘bystander effect’ thereby resulting in destroying many surrounding tumor cells with just one NSC.
Carbon nanotubes are a fraction of the size of a cell. In collaboration with NASA, Behnam Badie, M.D. has begun using nanotubes to deliver cancer-killing chemicals inside macrophages. These macrophages rush to areas of inflammation, like tumor cells, where the nanotube’s deadly payload is deposited. Current research centers on developing the best nanotube prototype.
Principal Investigators:
Behnam Badie, M.D. and
Leying (Larry) Zhang, Ph.D.
Gene Therapy
Despite advances in surgical techniques and the use of radiotherapy and chemotherapy, metastatic brain tumor still remains a disease of high mortality; therefore alternative treatments warrant further investigation. Gene therapy is one such alternative treatment, and is based upon understanding the disease at a molecular level.
Gene therapy is an experimental treatment that involves introducing genetic material (DNA or RNA) into a person’s cells to fight disease. The purpose of cancer gene therapy is to eliminate tumor cells while sparing non-tumor cells from the cytotoxic (cell-killing) effects of the cancer treatment. In general, a gene cannot be directly inserted into a person’s cell. It must be delivered to the cell using a carrier, or “vector.” The vectors most commonly used in gene therapy are viruses.
Researchers are exploring adeno-associate virus (AAV) as a gene therapy vector because of a number of positive attributes:
- AAV appears to be non-pathogenic (the virus doesn’t cause disease).
- It can easily infect most cells.
- It stably integrates into the host cell DNA at a specific site without causing harmful mutations.
- It causes very little immune response.
Given the above, we propose to use a suicide gene, which is only expressed in metastatic brain tumor but not in normal cells, and insert that gene into the AAV virus vector. The virus, bearing the suicide gene, then infects cells, but only metastatic brain tumor cells are affected by the cancer-killing suicide gene protein. This elegant approach should provide the selectivity necessary to treat this challenging disease.
Principal Investigator: Michael Y. Chen, M.D., Ph.D., and Rahul Jandial, M.D., Ph.D.
Michael Y. Chen, M.D., is studying a gene therapy approach that makes use of the basic biological difference between normal brain tissue and cancer tissue (melanoma). Tyrosinase promoter is a cellular switch that is highly functional in cancer tissue while inactive in normal brain tissue. The saporin protein is a compound that acts on the ‘switch’ activity, such as the tyrosinase promoter, and converts itself into a therapeutic agent. Dr. Chen’s research team intends to use the tyrosinase promoter as a switch to control the expression of the therapeutic agent saporin that will limit destruction to only cancer cells. The saporin gene will be introduced into a viral gene therapy vector and implanted into the tumor via Convection-Enhanced Delivery (CED). CED is the process of continued injection under increased pressure of a fluid containing a therapeutic agent.
Principal Investigator: Michael Y. Chen, M.D.,Ph.D.
