Brain Tumor Vaccines

In the recent weeks, there has been a lot of media attention given to brain tumor vaccines. In this post, the two of the more publicized vaccines will be reviewed. First, though, a bit about the immune system and the effects of cancer.

1. Cancer and the Immune System. Our immune system recognizes cells by their surface proteins, and can distinguish between cells that are supposed to be in our body and cells that are foreign (for example, transplanted organs) or cells that are infected with a virus. When our immune system recognizes a cell as foreign or infected, it has ways to eliminate those cells. Even though cancer cells have unusual surface proteins (due to mutation, for example), the cancer cell has developed complicated methods to avoid elimination by our immune system.
2. Immunology 101. For our purposes, there are three main types of cells in the immune system: T cells, B cells, and dendritic cells. T cells can recognize foreign cells or infected cells and can actually seek them out and destroy them. B cells produce antibodies that help guard against infectious diseases. Dendritic cells are also known as antigen presenting cells and are critically important in immune recognition of foreign cells and proteins. Dendritic cells actually take up bits and pieces of proteins, shuttle them to their cell surface and present them to T and B cells. When dendritic cells present foreign proteins from either transplanted cells or virus, for example, to T or B cells, the immune response is triggered. For many reasons, this does not happen properly in people with cancer.
3. The brain tumor vaccine concept. The thinking is that the immune system can be triggered to attack a cancer cell if the dendritic cell is primed with abundant cancer cell proteins. The dendritic cell is primed by injecting various forms of cancer proteins into the patient. The patient's own dendritic cells ingest this cancer protein, present it to T and B cells which then jump into action to find the cells bearing those cancer proteins on their surface.
4. Oncophage vaccine. This vaccine is manufactured from the patient's own glioblastoma (GBM) tissue. At surgery, a portion of the tumor tissue removed is specially packaged and sent to a company called Antigenics in Massachusetts. Antigenics purifies a protein cocktail from the tumor tissue, especially containing the key protein called heat shock protein gp96. The vaccine, called Oncophage, is prepared and sent back to the treating physician. The patient receives the vaccine through an injection every week or two. Right now, the vaccine is not for general release, it still has to go through additional clinical trial evaluation. There are currently two Phase II clinical trials, both led by Neurosurgeon Andrew Parsa at the University of California in San Francisco. One trial is for patients with newly diagnosed GBM, the second is for patients with recurrent GBM.
5. EGFRvIII vaccine. EGFR stands for epidermal growth factor receptor and it is a normal cell surface protein. In about one third of patients with GBM, their tumors have a mutated form of EGFR, called variant III or vIII. EGFRvIII is turned on all the time as opposed to normal EGFR that is turned on only when a particular chemical binds to it. In patients with GBM positive for the EGFRvIII mutation, a vaccine containing a portion of the EGFRvIII protein is given through an injection. The bits of EGFRvIII protein are ingested by dendritic cells, which in turn, activate T cells so that they will seek out and destroy tumor cells with EGFRvIII on the surface. Results from a Phase II clinical trial was recently reported. The main study sites were MD Anderson in Texas and Duke University in North Carolina. The study looked at 18 patients treated with vaccine and 17 patients treated in current standard fashion. The vaccinated patients had an average overall survival of 26.0 months compared to 15.0 months for the matched control group. That is statistically significant. The vaccine is called CDX-110 (Celldex) or Rindopepimut (Pfizer). A Phase III clinical trial will be needed prior to FDA approval.
6. Conclusions. The Oncophage vaccine is made from a patient's own tumor. The EGFRvIII vaccine is "off the shelf" and will only work in those patients with an EGFRvIII positive tumor. Though the results of clinical trial for both vaccine strategies are exciting, please remember, only very small numbers of patients have been treated, and Phase III clinical trials involving many hundreds of patients at a variety of centers will be required to determine if there is, in fact, significant benefit. These types of trials can take a long time to organize and complete.
   

New Clinical Research Project Now Enrolling Patients

The UMBTC is beginning another clinical research study at MGH.

The study is entitled, "Is the presences of cytomegalovirus (CMV) in tumor tissue a prognostic factor for patients with newly diagnosed glioblastoma multiforme (GBM)?"

Background: CMV is a member of the herpesvirus family. Other members of this family include the viruses that cause chicken pox and mononucleosis. Between 50% and 80% of adults in the United States are infected with CMV by age 40. Most CMV infections are silent, causing no symptoms.  CMV infection can be serious, especially when transmitted to an infant at birth or in a patient immunosuppressed because of medication (i.e. transplant patients) or HIV. Once CMV is in our body, it stays there, dormant, for life.  Currently, there is no treatment for CMV.

Is there a link between CMV and GBM?  In 2002, Charles Cobbs, a Neurosurgeon, first reported finding CMV DNA in GBM tumor samples.  This result was confirmed by other investigators, including Duane Mitchell at Duke University.

It is unlikely that CMV causes GBM. But because CMV related proteins have an effect on cell growth and survival, CMV may contribute to the aggressive behavior of GBM. For example, CMV might make tumor cells more resistant to chemotherapy and radiation therapy or it might help tumor cells evade the immune system.

Study objectives: 

1. Quantify the amount of CMV DNA that is present in tumor tissue. We plan to develop a test that will tell us how much, if any, CMV DNA is present in a specimen of tumor tissue. We will use a technique called real time polymerase chain reaction (PCR). For this test, DNA will be extracted from a  small amount of tumor tissue removed at the time of surgery.  

2. We will next determine if the presence of CMV DNA in GBM samples is an independent prognostic factor. That is, does a person whose tumor contains CMV DNA respond better or worse to treatment? We will also use statistical tests to determine if a particular level of CMV DNA can predict response to treatment.

3. If the results look promising, we hope to expand the study to include other brain tumor centers and pediatric patients.

4. If it turns out that CMV DNA has a negative impact on patients, new and specific treatments can be developed to target CMV.

This study has been approved by the Institutional Review Board at MGH and the HIPAA compliance officer at MGH. That means that this study meets federal guidelines to protect a patient from harm and to protect confidential medical information.

If you or your family have questions about this clinical research, please contact the UMBTC at 906-225-7739 or email us at info@hopestartshere.org.

UMBTC brings clinical trials to Marquette General Hospital

The Upper Michigan Brain Tumor Center has brought three clinical trials to Marquette General Hospital. Clinical trials give patients an opportunity to receive novel or experimental therapies or to contribute to the scientific knowledge regarding their tumor.

There are four types of clinical trials.

Treatment trials: test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
Prevention trials : look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes.
Diagnostic trials : conducted to find better tests or procedures for diagnosing a particular disease or condition.
Screening trials : test the best way to detect certain diseases or health conditions.
Quality of Life trials (or Supportive Care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness

The trials now available at MGH include one treatment trial, a diagnostic trial and a screening trial.

The treatment trial is entitled, “KARE 004: A PHASE II STUDY OF GLIADEL, CONCOMITANT TEMOZOLOMIDE AND RADIATION, FOLLOWED BY DOSE DENSE THERAPY WITH TEMOZOLOMIDE PLUS BEVACIZUMAB FOR NEWLY DIAGNOSED MALIGNANT HIGH GRADE GLIOMA.” This study is sponsored by the Kentuckiana Cancer Institute in Louisville, Kentucy. Renato V. LaRocca, M.D is the principle investigator for this national study while Richard A. Rovin, MD FACS and Suresh Nukala, MD are the principle investigators at MGH.

Briefly, this study is for patients with malignant gliomas at the time of the initial diagnosis. The current standard treatment at MGH is to undergo maximal, safe surgical resection (when possible). At the time of surgery, Gliadel wafers are placed into the cavity after resection. The Gliadel wafer is a biodegradable polymer disc that slowly releases chemotherapy called BCNU directly to the brain tissue surrounding the tumor cavity. About 2 weeks after surgery, the patients begin radiation therapy in combination with oral chemotherapy called temozolomide (Temodar). After radiation is completed, the patients continue to receive the temozolomide orally for five days of a 28 day cycle.

For patients participating in the KARE 004 study, there are some differences compared to the current standard therapy. Following completion of radiation treatments, instead of receiving the temozolomide for 5 days, patients will receive two 7-day courses of the temozolomide within each 28 day cycle. Every 14 days, they will also receive an intravenous infusion of a medication named bevacizumab. This will continue for up to 12 cycles.

Bevacizumab (or Avastin) is a monoclonal antibody that binds to and inactivates a protein called VEGF. VEGF stands for vascular endothelial growth factor. VEGF is a normal protein that is needed for blood vessel formation. As it turns out, in order to grow, tumors need to develop extra blood supply. Some tumors produce high levels of VEGF and so trick the body into building them new blood vessels. Bevacizumab is designed to prevent VEGF from bringing new blood vessels to the tumor. Without an adequate blood supply, the tumor can’t grow. Bevacizumab is already used in combination with other chemotherapy to treat colon cancers and is FDA approved for the treatment of recurrent malignant glioma.

This study will help determine if patients receiving more doses of temozolomide and bevacizumab have a better outcome than patients receiving the current standard therapy.

The second clinical trial is entitled, “TOTAL CANCER CARE” and it is sponsored by the Moffit Cancer Center in Tampa, Florida. This is not a treatment trial, rather it is a diagnostic trial. This is a study to evaluate genetic changes that occur in tumor tissue. In this study, a small sample of excess tumor tissue removed at the time of surgery or biopsy is frozen and shipped to Moffit Cancer Center. The scientists at Moffit can look at tens of thousands of different genes within the tumor at the same time. Once they have looked at tumors from many thousands of patients, they will be able to see patterns of gene expression. Once this information is known, it may be possible to design treatments that target the specific genetic changes identified. This is the first step towards personalized tumor therapy.

The third clinical trial is entitled, “IS VEGF A USEFUL SERUM BIOMARKER FOR PATIENTS DIAGNOSED WITH MENINGIOMA OR GLIOMA?” This study is sponsored by the UMBTC. Drs. Rovin and Nukala along with Dr. Robert Winn from Northern Michigan University are the lead investigators.  This is a screening trial.

As described above, tumors need to recruit extra blood supply in order to grow. To get these extra blood vessels, tumors send out a signal—a protein called VEGF. This study looks at the level of VEGF in the bloodstream in patients diagnosed with a glioma or meningioma. The idea is that the level of VEGF in the bloodstream might be an indicator of tumor growth, or how a tumor is responding to treatment. Right now, an MRI is used to determine if a tumor is growing or responding to treatment.  This study will correlate VEGF levels with tumor behavior as assessed by MRI.  Someday it might be possible to use VEGF levels to monitor tumor behavior--certainly an easier and less expensive alternative to MRI.

If you or a family member is interested in learning more about the clinical trials or perhaps participating in a trial, call the UMBTC at 906-225-7739 to arrange for a consultation.