Confronting the Challenges of Glioblastoma Treatment
Glioblastoma does not play by the rules of other cancers when it comes to effective therapies. It’s protected by a border of endothelial cells that prevents the necessary drugs from getting to the tumor. Its low mutational load and associated low neoantigen expression reduces its potential to respond to immunotherapy. While glioblastoma presents some of the most daunting challenges in cancer treatment today, the neurosurgeons and their neuro-oncology colleagues at NewYork-Presbyterian Hospital remain confident that they will defeat this deadly disease.
A Novel Drug Delivery Strategy
While there are many drugs that have the potential to kill glioma cells, the problem has always been getting enough of the drug into the brain, but not so much that it causes too much toxicity in the rest of the body. Add to this the additional challenge presented by the blood-brain barrier, which limits the systemic delivery of therapeutics to the tumor. While studies have shown that prolonged infusion in small amounts improves survival, intracerebral convection-enhanced delivery (CED) has been limited to short durations due to a reliance on external catheters and the accompanying risk of infection.
To address this, neurosurgical faculty at Columbia University Irving Medical Center are pioneering a novel drug delivery strategy that utilizes a microinfusion pump to establish a positive pressure gradient in the brain via an implanted catheter. The pump is implanted in the abdomen to facilitate chronic infusion and is controlled by Bluetooth. This CED strategy has been making its way from basic laboratory studies to select appropriate anti-tumor agents, to preclinical testing in animal models, to a phase 1 clinical trial in patients with recurrent malignant gliomas.
When tested in a porcine model, infusion was tolerated without serious adverse events and a large volume of distribution was achieved. Following extensive preclinical studies, a phase 1 dose escalation trial of topotecan by CED was performed in patients with recurrent malignant gliomas with clinical, radiographic, and neuropsychological testing for toxicity and anti-tumor response. Median survival and median time to progression and at six months compared favorably with the best standard treatment available for this tumor group.
The pilot study, the first of its kind, showed that the delivery system was successful in all patients and in analyzing the tumor, the approach was killing the tumor cells but safe for the normal cells.
Learn more about the delivery system at https://thejns.org/view/journals/j-neurosurg/aop/article-10.3171-2019.3.JNS1963/article-10.3171-2019.3.JNS1963/article-10.3171-2019.3.JNS1963/article-10.3171-2019.3.JNS1963.xml
Making Immunotherapy Work
Glioblastoma, unlike lung cancer and some other solid tumors, does not typically respond to immunotherapy. With lung cancer, proteins are expressed, such as PDL1, that correlate with a response to immunotherapy. Not so for glioblastoma, which has a relatively low mutational load and associated low neoantigen expression. With the immune system, recognizing and eliminating the tumor is believed to be more plausible in tumors with high mutational burdens with a significantly elevated number of neoantigens. Studies bear this out, indicating that GBM does not appear to be intrinsically responsive to immunotherapy via checkpoint inhibition – at least in trials conducted so far.
Despite this, neurosurgeons and neuro-oncologists at Weill Cornell Medicine are not deterred in their pursuit of immunotherapy approaches and have been investigating the effect of neoadjuvant immunotherapy on GBM, as well as the immunosuppressive microenvironment as a potential target for treatment. Their interest is based on recent studies that have shown that immunotherapy via checkpoint inhibition alters the tumor microenvironment and causes genetic changes in the tumor itself. Weill Cornell faculty recently reported their own study findings, which were published, in the July 2020 issue of Cancer Discovery, showed that the tumor microenvironment is critical for the maintenance of cellular states found in primary glioblastomas. Learn more at: https://cancerdiscovery.aacrjournals.org/content/10/7/964
Weill Cornell Medicine is now a principal study site of the CAPTIVE trial, an innovative phase 2 clinical trial for recurrent glioblastoma that is evaluating the combination of a genetically modified common cold virus, followed by pembrolizumab, an immunotherapy given every three weeks for up to two years or until disease progression. When the virus is injected into the tumor, it triggers an immune response against the tumor. The dying tumor cell releases signals and generates neoantigens that stimulate the immune system to kill additional tumor cells. By selectively replicating within cancer cells, but not normal cells, the virus sets off a chain reaction of tumor cell killing and further spreads the oncolytic virus to adjacent tumor cells. A week after the virus injection the patient starts treatment with pembrolizumab, which activates an immune response against tumor cells. Preliminary results demonstrated that the combination of the two agents is well tolerated and associated with promising survival. Results of the trial are now being processed.
More recently, Weill Cornell Medicine faculty have begun exploring the possibility of combining immune checkpoint blockade with radiation for the treatment of brain and other metastases. While still in the early stages of investigation, success with this combination strategy has the potential to result in enhanced rates of brain control, less brain exposure to radiation, and improved cognitive outcomes. Learn more about the mechanisms behind this synergy and ways to move the field forward at https://www.sciencedirect.com/science/article/abs/pii/S1878875019310241?via%3Dihub