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Novel Therapies Set to Revolutionize Glioma Treatment

Greg Kennelty
Published Online:11:19 PM, Mon February 8, 2016

"The biggest question is 'why hasn't anything worked.' It's a difficult question to answer and it poses a problem with the outcomes of all our different diseases."

- Andrew S. Chi, MD, PhD

Novel Therapies Set to Revolutionize Glioma Treatment

Andrew S. Chi, MD, PhD

The heterogenic nature of brain cancers has made the malignancy a difficult one to treat, with very few therapies panning out in large clinical trials. However, despite the letdown of prior research, the future looks bright for immunotherapeutics and novel targeted therapy approaches for patients with gliomas.
Recently, the PD-1 inhibitor nivolumab demonstrated early signs of activity as a monotherapy for patients with recurrent glioblastoma in the CheckMate-143 trial. Furthermore, other immune-based therapies targeted against EGFRvIII have shown exceptional signs of activity and tolerability. Adding to the immunotherapy excitement, targeted therapies directed against IDH also represent a potential new treatment paradigm.
To put these advancements into perspective, Targeted Oncology spoke with Andrew S. Chi, MD, PhD, head of Neuro-Oncology at NYU Langone's Laura and Isaac Perlmutter Cancer Center, on recent developments in the treatment paradigm for patients with brain cancer, including his recent study into mutant IDH1 gliomas and the role of the NAD metabolite.
TARGETED ONCOLOGY: What are some of the biggest unanswered questions in brain cancer currently?
CHI: The biggest question is “why hasn’t anything worked.” It’s a difficult question to answer and it poses a problem with the outcomes of all our different diseases. There has been an enormous amount of research into the biology of these tumors and there has been a significant amount of understanding that we have developed, yet that has not translated into clinical benefit or patient outcomes.
The real question is how we are going to get things that we understand to translate into better outcomes for patients. Whether that is discovering new therapies, or maybe we have to take a fresh look at the things we are researching in the laboratory. Maybe the drugs that we have will be effective and we just need to find the right way to test these drugs.
We have so much knowledge about the biology of these tumors and a proliferation of different drugs and therapies that have been developed over the past few years are working in other cancers. We have to figure out how to get these drugs to work in brain cancers. We have a paradigm and a framework to be able to think through this and be able to solve that problem.
TARGETED ONCOLOGY: Do you see any possibilities with immunotherapies in brain cancer?
CHI: Immunotherapies are really riding a big wave in research and therapeutic development and they are generating a lot of excitement in a lot of cancer types, as well as brain cancer. When these immunotherapies work in other cancers, they have worked phenomenally well.
The excitement for brain cancers has been high because, when you look at the biology of these tumors, there is significant rationale that these immunotherapies should work. Whether it be vaccines or immune checkpoint inhibitors, there has been a tremendous amount of research into the immunobiology, gliomas in particular, that suggests that some of these immune therapies should work.
Right now in the field of brain cancers, many of these immunotherapies are currently being tested in clinical trials or are just starting to be tested. These trials are looking at glioblastoma and other gliomas.
TARGETED ONCOLOGY: Would chimeric antigen receptor (CAR) T-Cell therapy possibly impact the treatment paradigm of brain cancer?
CHI: That paradigm is creating excitement as well in gliomas. CAR involves designer T-cells that hone in one specific mutation or abnormal proteins on the surface of glioma cells, and ones that are only on glioma cells and not normal brain cells. This would be a very specific attack and one without much toxicity.
Some of the problems we need to overcome in brain cancer therapy are if the T-cells are actually getting into the brain and actually getting into the tumor. Another problem we deal with is that maybe the T-cells that are designed to hit an abnormal molecule aren’t because those specifically abnormalities might not be on every single glioma cell.
What we are beginning to understand about glioblastoma, and gliomas in general, is that they are very heterogeneous. So some parts of the tumor are very different than other parts on a molecular and biological level. If you design a T-cell to attack one specific protein, then you may not get the effectiveness of essentially killing the entire tumor.
CAR T-cell therapy has incredible promise and we hope that it leads to better patient outcomes down the line, but it also highlights some of the difficulties that we have in brain tumor development and therapeutic development. How do we get drugs into the brain? Or to the tumor where we want it?
How do we deal with the issue of tumor heterogeneity, especially considering that heterogeneity is not specific to any patient’s tumor. We understand that not all gliomas are one specific disease – they are all very different diseases defined by very specific molecular subtypes.

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