Thursday, October 7, 2010

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.

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