Below is Part II of our two-part Q&A with Dr. John Sampson of Duke University on the topic of immunotherapy. In Part I of this Q&A last week, Dr. Sampson discussed what immunotherapy means and how it works, what the different types of immunotherapy are, how they differ from other treatment types, and where they have shown success in other cancers. Today we turn the focus onto the use of immunotherapy specifically in the brain and central nervous system (CNS) setting:
Q: What are the challenges, especially when it comes to using immunotherapies in the brain tumor settings?
JS: Three critical challenges facing immunotherapy are:
- The tumor-specificity of therapy
- Efficiently eliminating heterogeneous tumor cells
- Overcoming the immunosuppressive tumor microenvironment
First, it can be difficult to find a tumor-specific immunotherapeutic target that is present on tumor cells but completely absent from normal cells. If the target of immunotherapy is also present on a small number of normal cells, it can cause toxicity to normal tissue. Second, all tumor cells from the same tumor are not identical, because of this tumor cells are heterogeneous (different from each other). Therefore, a successful immunotherapy against a heterogeneous target still may only kill a portion of the total tumor cells. Third, the immediate location around a tumor (the microenvironment) can be filled with molecules that turn immune responses off (immunosuppression). This is one of the ways that tumors are able to continue growing.
For the central nervous system (CNS) there are additional barriers to successful immunotherapy. The brain is surrounded by the blood brain barrier (BBB) which can impede the ability of both standard therapies and immunotherapies to access the tumor behind the BBB. Tumors within the brain are also generally not very immunogenic, which means the immune system has a harder time recognizing them than immunogenic tumors like melanoma. Also, the brain is very sensitive to any damage to normal tissue or inflammation induced swelling as these can harm a person’s ability to function normally. Therefore, treatment of CNS tumors can be more sensitive to nonspecific toxicity in comparison to tumors in other parts of the body.
Q: After years of doubt that immune-based treatments could work in the brain, what is the rationale that emerged that encouraged the increased interest in this field?
JS: Because of the lack of immune cells present in the brain and the restrictive BBB, it was believed that cells of the immune system could not effectively access the brain. However, it is now known that activated T cells from an ongoing immune response can enter the CNS. Also, patients with melanoma possessing brain metastases treated with adoptively transferred tumor-targeted T cells showed shrinkage of these CNS metastases. This demonstrates that activated T cells can not only travel to the CNS, but effectively and safely destroy tumor cells within the brain.
Q: What are some immunotherapy approaches Duke’s BTIP is examining currently?
A: One major area of research at the Duke BTIP (Brain Tumor Immunotherapy Program) targets the epidermal growth factor receptor variant type III (EGFRvIII), which is a tumor-specific mutation present in a type of primary brain tumor called glioblastoma (GBM). Patients with GBM usually survive for less than 15 months. However, patients with EGFRvIII positive GBM receiving a vaccine containing a portion of the EGFRvIII protein (Rindopepimut) have shown a significantly longer overall survival (~26 months), based on some still preliminary trial results. This EGFRvIII-targeted vaccine is now in an international Phase III trial.
(Editor’s Note: Results from a Phase II trial of Rindopepimut were just published last week. A summary can be viewed here.)
We are also targeting the EGFRvIII mutation using both adoptive transfer of genetically modified T cells and recombinant antibody-based molecule approaches. Trials with intracerebral administration of the EGFRvIII-CAR and EGFRvIII-BiTE for patients with GBM are currently being planned.
Another area of interest for the Duke BTIP is targeting viral Cytomegalovirus (CMV) proteins in GBM. Although it is unclear why, our laboratory as well as other groups have shown that GBM cells have viral CMV proteins while normal brain tissue does not. This means CMV proteins can serve as tumor-specific proteins in the immunotherapy of GBM. We have two consecutive clinical trials from our laboratory using CMV pp65 loaded DCs (DC vaccination) in patients with GBM. Both trials have demonstrated overall survival of greater than 36.6 months thus far. (Editor’s note: National Brain Tumor Society provided some early funding into CMV treatment approaches.)
National Brain Tumor Society thanks Dr. Sampson for his time in explaining the challenges and opportunities that an immunotherapy approach to treating brain tumors presents. If you would like to learn more about what Duke’s BTIP is working on, you can visit their website here. Also note that many of the large cancer centers around the country are also pursuing research into immune-based treatments for brain tumors. National Brain Tumor Society always recommends asking your medical team about all possible treatment options, as well as possible clinical trial options.
And, as always, we’ll keep the community updated on any major news coming from the field.