Immune Checkpoint Inhibitors Advance Treatment of Glioblastomas.

A few articles ago immunotherapy was mentioned and introduced via the usage and progression in the research of CAR-T therapy and its use with ALL (B-cell) and lymphomas. Another branch of immunotherapy is quietly emerging, called immune checkpoint inhibitors. Specifically for the treatment of Glioblastoma, which is an aggressive form of brain cancer.

Glioblastomas (GBM) arise from the astrocytes that make up the supportive tissue in the brain. Usually found in the cerebral hemispheres of the brain, but it isn’t unusual to find them elsewhere like the spinal cord. They are highly malignant due to the access of a large network of blood vessels. There are two forms of GBM; de novo and secondary. De novo or primary GBM are very aggressive and the most common form. Secondary GBM is slower growing, but still fairly aggressive. Secondary GBM represents about 10% of all GBM diagnoses. There is no known cause for glioblastomas, but they represent about 15.4% of all primary brain tumors and 60-75% of all astrocytomas. Typically affect men more than women are seen in people of older age rather than youth or adolescents although it isn’t unheard of.

Standard treatment for GBM is surgery to remove as much of the tumor as possible in combination with chemotherapy and radiation. Surgery is difficult because of the extensive network that glioblastomas have that reach to multiple areas of the brain, thus the wide array of symptoms that lead to the diagnosis of GBM. Standard chemotherapy agent is temozolamide, trade name Temodar®. Temozolamide is an alkylating agent meaning that it is most active during the resting phase of the cell. It is also cell-cycle non-dependent.

Prognosis of GBM reported in years of medium survival in the context of an equal number of patients do better and an equal number of patients do worse is about 14 months after diagnosis is made. The two year survival rate is 30%. Diagnosis is made by both identifying and characterizing physical appearance and growth rate along with molecular techniques which leads to greater diagnostic accuracy as well as improved patient management and treatment response. Tumors with methylated O-6-Methylguanine-DNA Methyltransferase (MGMT) have been found to respond better to chemotherapy and radiation and allow longer patient survival. The IDH1 gene mutation is present in 12% of all GBM and is used as a predictor of survival and for the efficacy of treatment. IDH1, also called isocitrate dehydrogenase 1, catalyzes the conversion of isocitrate to alpha-ketoglutarate as part of normal brain physiology and metabolism. From these examples, it is important to consider the fundamental biological base of these tumors and to consider each tumor as a separate entity. With the addition of molecular techniques to expand the diagnosis of GBM has opened up researchers to begin journeys of novel treatments.

In GBM there are several growth factor receptors that are over expressed in the tumor cells. EGFR, VEGF, PDGFR to name a few. This over expression allows unchecked proliferation of tumor cells and increased vascular supply to the tumor. Also called tumor-induced immunosuppressive mechanisms. Because of the recent breakthroughs in the mechanisms of leading to complete T-cell activation and immune recognition there has been a push to uncover effective anti-tumor responses.

One such group of new therapies being developed is called immune checkpoint inhibitors. Checkpoint proteins are proteins that signal the immune system that a cell is healthy. Because of the tumor cells ability to manipulate the cells machinery and biology although there may be molecular signals that signify the cell is cancerous the checkpoint proteins on the cells surface signal the immune system to overlook those cancerous markers from the cell. One of the most common checkpoint proteins is called the PD-L1 (Programmed Death Ligand 1) protein and its receptor PD-1. PD-L1 is used to keep the cytotoxic CD8 T-cells from attacking the hosts own healthy cells. Cancer cells can upregulate the expression of PD-L1 that when bound to its receptor; PD-1 not the surface of the T-cell, induces apoptosis of the T-Cell. The immune checkpoint inhibitors are drug-antibodies that bind to the checkpoint proteins, inhibiting them so the signal doesn’t get to the T-cell that the cell is healthy causing the host immune system to target the cancerous cells.

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There have been multiple FDA approved checkpoint inhibitors; Optivo®, Keytruda®, and Tecentriq®. All for the treatment of metastatic melanoma, lung cancer, Hodgkins lymphoma, renal cancer, and bladder cancer.

The advancement of understanding the complete host immune system response coupled with the understanding of the molecular biology of each individual tumors gives rise to a new generation of immune therapies. There are multiple clinical trials happening now evaluating the response of tumors, not just GBM to the immune checkpoint inhibitors; those established and those in development. There are researchers working constantly to refine and come up with the most effective way to treat these tumors and different cancers. This is one step closer to a cure.

-Caleb

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