Strategies to Improve Treatment of Advanced Brain Cancers
by Dr. C.H. Weaver M.D. updated 1/2021
Malignant brain tumors can be slow or fast-growing and are usually life threatening due to their ability to invade and destroy normal brain tissue. The most common primary malignant brain cancer is glioblastoma multiforme (grade IV astrocytoma), which makes up approximately 20% of all primary brain cancers. Malignant brain cancers are difficult to remove without causing some damage to normal brain tissue. They are also difficult to treat because surgery rarely removes the entire cancer and systemic chemotherapy medications aren’t very good at treating the cancer and don't effectively penetrate the central nervous system to reach the cancer cells.
Little progress has been made in improving the treatment of cancer involving the brain and new treatment strategies are desperately needed. The following treatment approaches are being developed and evaluated at cancer centers with a major focus on treating brain cancer and patients with a primary brain cancer should strongly consider being evaluated at a major research center.
CAR T-Cell Therapy
CAR T cell therapy is a type of gene therapy that modifies a patient’s own T cells (a type of immune cell) to detect and kill the patient’s cancer cells. It is unique in comparison to other types of available immune therapies for cancer, in that the patient’s own T cells are the actual treatment; no other medications are used as an active component of therapy. The process involves removal of T cells from the patient’s blood to undergo genetic engineering outside of the body. The genetically modified T cells, now referred to as CAR T cells, are multiplied in the laboratory into the hundreds of millions and infused back into the patient’s body where they attach to cancer cells and stimulate an immune attack and destruction of the cancer cells.
The process spanning from the initial collection of a patient’s T cells to the infusion of the modified CAR T cells back into the patient takes approximately one week. CAR T is already approved for the treatment of leukemia and lymphoma and undergoing active evaluation as a primary treatment for brain tumors.
Some treatments being developed involve the use of genetically engineered viruses that are no longer disease-causing. The viruses are used to deliver specific genes to certain cells, causing them to make those proteins that can treat the cancer.
- Ad-RTS-hIL-12 is an engineered virus that delivers the IL-12 protein and increases its production in specific cells. This is considered an immunotherapy treatment because IL-12 is a protein that may enhance the ability of the immune system to kill tumor cells.
- DNX-2401, a replication competent adenovirus plus gamma interferon.
Immunotherapy is a type of treatment that helps a patient’s immune system fight cancer. Normally, the immune system recognizes and eliminates foreign or abnormal cells, like bacteria, viruses, and cancer cells. However, the immune system cannot always recognize cancer cells for various reasons; some tumor cells may not look different enough from normal cells, while other cancer cells have specific features that allow it to “hide” from the immune system.
- Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer by releasing checkpoints that cancer uses to shut down the immune system. PD-1 and PD-L1 are proteins that inhibit certain types of immune responses, allowing cancer cells to evade detection and attack by certain immune cells in the body. A checkpoint inhibitor can block the PD-1 and PD-L1 pathway and enhance the ability of the immune system to fight cancer. By blocking the binding of the PD-L1 ligand these drugs restore an immune cells’ ability to recognize and fight the cancer cells.
- PD-1: PD-1 is a protein that inhibits certain types of immune responses, allowing cancer cells to evade an attack by certain immune cells. Opdivo (Nivolumab) and Keytruda (pembrolizumab) are both antibody-based treatments designed to block the PD-1 pathway enhance the ability of the immune system to fight cancer and are referred to as checkpoint inhibitors for their ability to help the immune system recognize and attack cancer. Blocking PD-1 allows the immune system to activate the T-cells and recognize these cancers as cells to be attacked.
- WP1066 represents a new class of drugs called ‘Immune/Transduction Modulators’ because it has demonstrated the ability to both stimulate a natural immune response to tumors and directly attack tumor cells. It is being developed at MDACC.
Treatment vaccines are designed to help T cells recognize and target tumor cells, specifically those carrying certain mutations. This strategy takes advantage of known mutations that exist in brain tumor cells, but not normal cells. To create a treatment vaccine, synthetic molecules are created in the lab to correspond to the mutated DNA sequence in a patient’s tumor. Often, these need to be personalized, since each patient has a unique profile of tumor antigens. Once injected, the treatment vaccine will initiate an immune response that activates T-cells and antibodies. The T-cells and antibodies will then recognize, attack, and continually “remember” how to identify tumor cells based on the tumor-specific antigens in the vaccine.
- SurVaxM targets a cell-survival protein called survivin that is present in 95% of patients with glioblastomas. The vaccine has dual mechanisms of action to stimulate a patient’s T-cell immunity and also employs antibody-directed inhibition of the survivin pathway to control tumor growth and prevent or delay tumor recurrence.
- DCVax is a personalized vaccine designed to target not just one but the full set of biomarkers on a patients cancer.
GBM AGILE (Glioblastoma Adaptive Global Innovative Learning Environment)
An international trial testing several therapies for patients with newly diagnosed and recurrent GBM by using a master protocol so several therapies or combinations of therapies from pharma companies can be tested simultaneously. AGILE is sponsored by the non-profit charitable organization the Global Coalition for Adaptive Research (GCAR), by the end of the year GBM AGILE will open in over 40 academic medical centers and community-based institutions across the US.
A similar approach has already been used in breast cancer, where the I-SPY trials have used a platform design to test several different breast cancer drugs against the same control group. The first drug being evaluated is Regorafenib which showed promise compared to standard of care in the REGOMA clinical, published in The Lancet Oncology in December, 2018.
Regorafenib is is an oral multi-kinase inhibitor that potently blocks multiple protein kinases involved in tumor angiogenesis (VEGFR1, -2, -3, TIE2), oncogenesis (KIT, RET, RAF-1, BRAF), metastasis (VEGFR3, PDGFR, FGFR) and tumour immunity (CSF1R).