Brain Tumor Research

 
At City of Hope, our team of researchers and physicians is dedicated to developing more effective treatments without the burden of toxic side effects. This mission is being carried out with the greatest urgency. It is here where we are conducting translational research — bringing together the most promising science, technologies, clinical studies and patient care in a research continuum that accelerates the development of more effective treatments in our fight against brain tumors and spine tumors. Methods range from mechanical devices to immune-and-gene-based therapies.
 
IMMUNOTHERAPY

Unlike drugs that act by chemically killing cancer cells or halting their growth, immunotherapy uses the body’s own immune system to trigger its ability to seek out and kill cancer. City of Hope scientists are working on several immunotherapy approaches designed to exploit the body’s natural defenses against the disease:

Nanotubes: Small and Lethal Envelopes Used to Kill Cancer

Nanotubes are microscopic technology shaped into tiny tubes about 1/10,000th the width of a human hair.  Behnam Badie, M.D., is working closely with Jacob Berlin, Ph.D., to use nanotubes to deliver a drug called CpG, which activates immune cells called macrophages to recognize and attack tumor cells. Because nanotubes can carry the drug directly to macrophages around the tumor, patients can receive stronger dosages, tolerate their therapy better and recover more quickly.
Principal investigators: Behnam Badie, M.D. ; Jacob Berline, Ph.D. and Leying (Larry) Zhang, Ph.D.
 
Nanoparticles: Guiding Cancer Treatment to the Tumor with Magnets

Behnam Badie, M.D., is collaborating with scientists at Caltech to design a dynamically programmable, low-intensity magnetic field to route and traffic macrophages that have been treated with CpG to tumor sites. In this method, patients would receive CpG-loaded nanoparticles engineered with an iron oxide, so that the macrophages become magnetic.  The magnetic field is generated by a grid, which allows for control over the spatial and temporal profile. Dr. Badie believes that directing CpG-treated macrophages to the areas where they are needed will make this treatment approach even more effective and durable.
Principal investigator: Behnam Badie, M.D.
 
Macrophages and Microglia: Harnessing the Immune System's Clean-up Crew

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 aims 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.
 
T cells: Maximizing a Patient's Immune System

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. In the clinic, the T cells are re-infused into the patient, where they go to work eliminating the cancer. Under 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.
 
Generation 2 T cells: Universal T cells

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.
 
Generation 3 T-cells: Stacking the Deck Against Cancer

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 that enables researchers to equip Generation 2 T cells with additional cancer-fighting therapeutic material to strengthen their impact against cancer. John Rossi, Ph.D., chairman and professor of Molecular Biology at City of Hope, and 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.
 
 
STEM CELL THERAPY
 
Neural Stem Cells: One-Way Tickets to Tumors

Neural stem cells selectively travel to tumor cells. Karen Aboody, M.D., has begun groundbreaking 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.
 
Finding Better Treatments for Brain Tumors

Cancers that originate in the brain, termed primary brain tumors, are among the most difficult 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. 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.
 
 
GENE THERAPY
 
Creating an Innovative Approach to Therapy

Macrophages are plentiful around tumor sites; however, they aid tumor growth instead of mounting an immune attack.  Behnam Badie, M.D., has found that these tumor-associated macrophages express high levels of an enzyme that inhibits the attack of T cells, the next line of immune response, and he has devised a pioneering concept to use tumor-associated macrophages to deliver genetic material to tumors.
 
The first step is a bone marrow transplant to remove the patient’s existing immune system and replace it with white blood cells that give rise to new modified macrophages. These macrophages are engineered with an inactive gene, which needs a promoter to become active. The modified macrophage will still respond to the tumor’s manipulation by traveling to the tumor site and secreting proteins that stimulate tumor growth. These proteins are the “promoters” that activate the genetic material.
 
At the same time, the patient is administered a prodrug, which is inactive. The activated gene makes material that converts the prodrug into active chemotherapy — which kills tumor cells. Meanwhile, that same active genetic material induces suicide in macrophages, so that they can no longer be employed for tumor growth. And because these modified macrophages are born from the new white blood cells, if the tumor reappears, the new macrophages will halt new tumor growth.
Principal Investigator: Behnam Badie, M.D.
 
 
Gene Therapy for Metastatic Brain Tumors

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 inserting a suicide gene, which is only expressed in metastatic brain tumors but not in normal cells, into the AAV virus vector. The virus, bearing the suicide gene, then infects cells; however, only metastatic brain tumor cells are affected by the cancer-killing suicide gene protein. This extraordinary approach should provide the selectivity necessary to treat this challenging disease.
Principal investigators: Michael Y. Chen, M.D., Ph.D. , and Rahul Jandial, M.D., Ph.D.
 
 
Convection-enhanced Delivery

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. 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.
 
 
MINIMALLY INVASIVE APPROACHES
 
Designing Leading-Edge Technology for Delivering Targeted Treatment

Behnam Badie, M.D., has designed a minimally invasive technique to debulk and treat brain tumors without open surgery – making treatment more effective while reducing trauma, the amount of drug used and time involved. The technique involves Badie inserting into the tumor a narrow cylinder, through which a small instrument reaches in and debulks it. The result is a reservoir in the center of the tumor into which a small tube is inserted and left just under the scalp to inject large amounts of targeted therapy.
Principal investigator: Behnam Badie, M.D.
 
 
CHEMOTHERAPY

Uncovering New Targets for Treatment

Macrophages are a first line of immune defense. They detect foreign debris, like bacteria and viruses, and present the proteins from these invaders to T cells, another type of immune cell that then mounts a coordinated attack. Brain tumor cells evade this response and more – they manipulate macrophages to work for them by supplying the tumor with oxygen and nutrients. Macrophages found around tumor cells also secrete proteins that encourage tumor cell growth.
 
Behnam Badie, M.D., and his team are researching new therapies to fight or reverse this manipulated response. They have found a protein secreted by tumor cells called S100B, which they believe plays a feature role in cancer’s ability to attract and subvert macrophages, and they are now working with City of Hope’s High Throughput Screening Core to identify lead compounds that inhibit S100B.
Principal investigator: Behnam Badie, M.D.

Microdialysis Catheter

Delivering substances to the brain has long been a barrier to effective treatment of brain tumors. New targeted therapies that can cross the blood-brain barrier offer promising treatment options. However, difficulties in determining whether these agents can attain therapeutic levels within the brain hinder their screening and evaluation.
 
To determine how chemotherapy drugs perform within the brain, City of Hope researchers are implanting eligible brain tumor patients who volunteer for the study with a microdialysis catheter, which is a temporary small tube that has a semi-permeable membrane at the tip. Through this tube, they can sample the fluid in the brain to measure concentrations of chemotherapy. The results will help reveal how drugs work to fight cancer cells in real time, leading to more effective treatments in the future.