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Should immunotherapy be the standard of care for patients with glioblastoma?
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Immunotherapy could become one of the most powerful cancer treatments of our time.
Glioblastoma continues to be one of the most aggressive malignancies, with no profound breakthroughs despite incremental improvements. Patients and physicians are desperate for new treatments, and immunotherapy rapidly should become a standard of care if any positive data develop.
The immune system is highly complex, which likely leads to a highly variable response rate. We cannot predict which patients or tumors will respond to immunotherapy, so it would be appropriate to start treating all patients during continued research into the mechanism of action.
There are countless examples in medicine of positive results that were achieved without knowing the exact mechanism. For example, sildenafil originally was tested as an antihypertensive but was found to be beneficial as an erectile dysfunction medication. That serendipity may be essential in the development of immunotherapy for glioblastoma. Learning experiences — such as the identification of HLA-A2 responders with ICT-107 — can direct our therapy. There has yet to be a definitive immunotherapy trial showing efficacy against glioblastoma. However, the response of immunotherapy in other cancer sites points to the potential in glioblastoma.
These therapies should be available to patients both on and off study in a compassionate use mechanism, as there are few alternatives once standard treatments have failed. Many patients are not healthy enough for clinical trials but may benefit from immunotherapy, which they would not receive off protocol. A registry could be established to monitor these patients who receive immunotherapies off trial protocol.
Immunotherapy also could be seen as a natural/holistic treatment, as it uses the body’s own immune system to fight cancer without toxic chemicals entering the body. Still, there are many things that we do not understand about the complexities of the immune system and glioblastoma that would argue against immunotherapy being the current standard of treatment.
James D. Battiste, MD, PhD, is assistant professor in the department of neurology at The University of Oklahoma. He can be reached at james-battiste@ouhsc.edu. Disclosure: Battiste reports no relevant financial disclosures.
It is too early to tell.
It is a very promising area, but even if the data were more mature, I do not think immunotherapy will ever completely replace standard of care. Immunotherapy might be more complementary.
Glioblastoma is a highly infiltrative tumor that grows invasively in the brain. It has a lot of features that have made focal therapy, such as surgery, quite challenging. This is one of the reasons why people in our field are interested in immunotherapy.
There is a lot of excitement with immunotherapy in cancer and in brain tumors. There is one particular target for many studies, EGFR, and there is a particular mutation that many have seen — variant III (vIII) — that is highly expressed in glioblastoma. EGFR vIII has been targeted by peptide vaccine approaches. Data from one study in recurrent glioblastoma was positive and indicative of an effect of the vaccine. However, a large phase 3 study did not meet the endpoint above the control group, so the vaccine was not approved. The data are conflicting, but perhaps this is a basis to build upon.
There are no specific immunotherapies approved by the FDA for glioblastoma, but I think we are moving in this direction. At University of Pennsylvania, we completed a small phase 1 study that assessed chimeric antigen receptor (CAR) T cells against EGFR vIII. We found some interesting translational data that suggest what happens when you administer CAR T cells in patients with glioblastoma. We do not think this single study — in such a limited number of patients — will be enough to gain approval, but I think we will have the basis of a template on which to build.
T-cell adoptive transfer studies targeting CD19 in hematologic malignancies are very much ahead of solid tumor treatment; however, we have pushed this similar strategy with different targets, and we are hopeful that we have a solid tumor CAR T-cell therapy that will eventually benefit patients.
There also are a lot of data on immune checkpoint inhibitors. University of Pennsylvania is participating in studies that are assessing PD-1 blockade and other strategies. The goal is to unleash the immune system and have much more of an antitumor effect. It may be that the CAR T-cell approach in combination with checkpoint inhibition is the way that we will see efficacy in patients with glioblastoma. It is important to have a good target. In glioblastoma, EGFR vIII is only seen in about 30% of cases, so there are 70% of patients with glioblastoma for whom there is no explicit target with this approach. We, along with many other groups, are working to try to identify additional targeted treatments for these patients.
There are a number of different arms to the immunotherapy effort in glioblastoma, but right now, it still requires further testing. That testing will consist of identifying the best combination of all of these agents, the best timing and the most appropriate patient population. I hope we soon will have data showing benefit with both immunotherapy and targeted therapy so standard chemoradiation approaches are not applied in the same way with every patient, but rather that we use genetic information to inform how we can treat patients in a more individualized manner.
Donald O’Rourke, MD, is associate professor in the department of neurosurgery at Abramson Cancer Center at University of Pennsylvania Perelman School of Medicine. He can be reached at donald.orourke@uphs.upenn.edu. Disclosure: O’Rourke reports no relevant financial disclosures.