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by Dr. C.H. Weaver M.D. updated 5/2022

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.

Brain CancerConnect 490

Precision Cancer Medicines

Not all brain cancer cells are alike. They may differ from one another based on their unique genetic mutations. Molecular testing can be performed to test for certain genetic mutations or the proteins they produce and the results can help select treatment including newer precision cancer medicines designed to attack specific cancer cells with specific genetic mutations.

Two precision cancer medicines; the BRAF and MEK inhibitors Tafinlar (dabrafenib) and Mekinist (trametinib) are widely used to treat melanoma, colon and other cancers and now appear to be effective for some glioblastomas (GBM). BRAF V600E is an actionable cancer causing mutation targeted by these medicines.  Both drugs target proteins in the MAPK pathway, a signaling chain of proteins that acts as a switch for cell growth and can become stuck in the “on” position, causing uncontrolled growth leading to tumors. The drug combination has been reported to shrink GBM tumors by 50% or more in one-third of 45 patients with hard-to-treat high-grade gliomas, including glioblastomas. 

The use of precision cancer medicines to treat identifiable cancer causing mutations has revolutionized the treatment of many types of cancer. Few patients with Glioblastoma have benefited from these treatment advances but research now suggests routine NGS testing should be performed for BRAFV600 and other cancer causing mutations in all GBM patients. 

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 in multiple research centers.5

Selinexor

Selinexor (KPT-330) is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. Selinexor functions by binding with and inhibiting the nuclear export protein XPO1 leading to the accumulation of tumor suppressor proteins in the cell nucleus. This reinitiates and amplifies their tumor suppressor function and is believed to lead to the selective induction of apoptosis in cancer cells, while largely sparing normal cells.  Selinexor induced antitumor activity with durable responses and disease stabilization among patients with recurrent glioblastoma (GBM), according to the results of a phase 2 study presented at the American Society of Clinical Oncology Annual Meeting. Learn more...

Cellular Therapy

IGV-001 is an autologous cell therapy that combines glioblastoma cells from an individual patient’s tumor with an antisense oligodeoxynucleotide against IGF type 1 receptor mRNA (IMV-001). Doctors at Thomas Jefferson treated 33 patients with GBM cells from surgical resection specimens, treated the cells with IMV-001 and then implanted back into patients with newly diagnosed GBM at an abdominal acceptor site.

Overall patients survived on average 9.8 months without cancer progression which compares favorably with the 6.5 month achieved for patients who receive standard of care therapy. A sub-analysis of 10 patients with methylated O6-methylguanine–DNA methyltransferase promoter (a known favorable marker) demonstrated an average survival duration without progression of 38 months. Further development and testing of IGV-001 will be driven by collaborations between investigators at Jefferson Health and at Imvax Inc.1

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Engineered Viruses

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.

  • AV-GBM-1 AIVITA Biomedical announced findings from a phase 2 clinical trial of the personalized cancer vaccine AV-GBM-1 in patients with newly diagnosed glioblastoma. AV-GBM-1 consists of autologous dendritic cells loaded with autologous tumor neoantigens derived from self-renewing tumor-initiating cells isolated from tumors after routine surgical debulking. In the study, 57 patients received 8 doses of AV-GBM-1 over 6 months and early results showed that the median progression-free survival  was 10.4 months which is an improvement over historical controls. Median survival has not been reached and will be assessed after the final patient has a minimum follow-up of 15 months.2
  • VBI-1901 In June 2021, the FDA granted Fast Track Designation to VBI-1901, a novel anti-CMV vaccine for the treatment of patients with recurrent GBM with first tumor recurrence. In a small phase 2a trial investigators randomized 20 patients to VBI-1901 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) or AS01B.  In the GM-CSF arm, the 6-month OS rate was 80% with a 12-month OS of 60%. In the AS01B arm, the 6-month OS rate was 89%, and the 12-month OS rate was not reached.3
  • 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

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

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.
  • AV-GBM-1 is an immunotherapy consisting of autologous dendritic cells loaded with autologous tumor neoantigens derived from self-renewing tumor-initiating cells isolated from the cancer after routine surgical debulking. The median survival duration with GBM progression of the first treated patients was 10.4 months which represents a 42% reduction in the risk of progression or death at 6.9 months. A phase III trial is ongoing.

Brain Cancer Newsletter 490

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 trial.

Clinical Trials at Cancer Centers Doing Significant Research in Advanced Brain Cancer

References

  1. https://clincancerres.aacrjournals.org/content/clincanres/early/2021/02/09/1078-0432.CCR-20-3805.full.pdf
  2. AIVITA Biomedical's. AIVITA Biomedical's phase 2 glioblastoma trial shows improved progression free survival. News release. June 8, 2021. Accessed June 18, 2021. https://prn.to/3q9REr7

  3. Wen PY, Reardon DA, Forst DA, et al. Evaluation of GM-CSF and AS01B adjuvants in a phase I/IIa trial of a therapeutic CMV vaccine (VBI-1901) against recurrent glioblastoma (GBM). J Clin Oncol. 2021:39(suppl 15);abstr 2047. doi:10.1200/JCO.2021.39.15_suppl.2047

  4. https://www.nature.com/articles/s41586-022-04489-4