Anti-CTLA-4 immune checkpoint inhibitor may hold promise for glioblastoma treatment
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Researchers at Salk Institute for Biological Studies have achieved promising results in early studies using an anti-CTLA-4 antibody for treatment of glioblastoma, the most common and deadliest form of brain cancer.
The findings — published in the journal Immunity — suggest use of the immune checkpoint inhibitor may stimulate specialized immune cells to attack cancer cells within the brain.
“There is no cure for glioblastoma — there is not even a good therapy for glioblastoma,” study author Susan Kaech, PhD, director of NOMIS Center for Immunobiology and Microbial Pathogenesis at Salk Institute for Biological Studies, told Healio. “Even with today’s standard therapies, almost every patient’s tumor will recur with no other forms of treatment available.”
In preclinical work, Kaech and colleagues compared outcomes among mice with glioblastoma treated with anti-CTLA-4 vs. anti-PD-1 therapy. Results showed blocking CTLA-4 substantially improved survival, whereas PD-1 blockade did not.
Kaech spoke with Healio about the findings, the next steps for this research and the potential implications for treatment of this aggressive malignancy.
Healio: Why is glioblastoma such a difficult cancer to treat?
Kaech: It’s a very rapidly growing tumor, and there’s no preventive type of clinical care for brain cancer. Also, a large part of how we treat cancer is, initially, through surgical removal of the tumor. In brain cancer, that is very difficult, because surgical removal of the tissue will cause considerable damage. It takes an extremely devastating toll on the patient. Chemotherapy and radiation are the most common forms of treatment, but there is a 100% recurrence rate for glioblastoma, because they can never get into the edges of the tumor.
When we think about a particular type of cancer where our very selective “immunological scalpel” would be potentially the most beneficial, brain cancer is going to be high on that list. If we can direct our immune cells into all those little crevasses and get rid of all of the tumor cells without harming the healthy neurons and other brain cells, then that would be ideal.
Healio: What prompted you to study anti-CTLA-4 therapy in this setting?
Kaech: We worked with animal models of brain cancer. Generally, many are not very good. One of the reasons for that — and the reason we were attracted to the model that we ended up using — is that human glioblastoma is very heterogenous. There are four major subtypes of glioblastoma that we could genetically identify. No person’s brain tumor is 100% uniform — it’s always a mix of tumor cells in different states. Some of these we can classify into one of these four types, but some we can’t. If you developed a pie chart of the four different types, every patient will have a different-looking pie chart.
The model that we worked with is helpful in better representing these different subtypes of human glioblastoma. We implanted the brain tumor into the animals’ brains and treated it with immunotherapy. We used a few different forms of immunotherapy and found one that worked and one that did not. The one that did not work in this model — an anti-PD-L1 antibody — is precisely the type of immunotherapy that has failed to work in all the human trials thus far. Most of the trials over the last decade or so in glioblastoma have been focused on anti-PD-L1 therapy and combinations of anti-PD-L1 with radiation, chemotherapy or some other agent. They have all failed.
The other immunotherapy that we used was one that blocks the CTLA-4 molecule, and that was the first to actually be put into clinical testing. Excitingly, we found that inhibition of CTLA-4 did work in this brain cancer model.
Healio: Did you discover anything unique?
A lot of work has been done in studying immune checkpoint blockade in glioblastoma. However, there were some unique aspects of our study. In particular, we found that anti-CTLA-4 therapy elicited a protective CD4 T-cell response, but surprisingly the “killer” CD8 T cells were not involved. The CD4 cells were critical to the therapeutic effect of this immunotherapy, and we found that it was working in cooperation with the brain’s resident macrophages, the microglia. These macrophages were stimulated by the CD4 T cells being activated by this drug. In short, the drug turns on the CD4 T cells, and the CD4 T cells turn on the microglia to change their state to become more effective at killing cancer cells.
Healio: What are the potential long-term implications of these findings for glioblastoma treatment?
Kaech: Trials are now being done in humans with glioblastoma that combine this drug class with anti-PD-1 antibodies, and this is being done on a larger scale. We’re excited to see if we can identify any of these pathways and biomarkers of response. No one has looked extensively at the microglia and the receptor system that we found to be involved in the phagocytosis. We are very excited to look more closely at the microglia and see if we can help to find any evidence that these pathways are being engaged.
We’re also looking at other models. As I mentioned, there are four main subtypes of glioblastoma. We’ve been studying a model that replicates one type, and we’ve found some collaborators who have been working to generate models for all four subtypes. We’re now getting their models, and we’re going to start comparing and see if the subtypes of tumors have different responses to these different immunotherapies.
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For more information:
Susan Kaech, PhD, can be reached at Salk Institute for Biological Studies, 10010 N. Torrey Pines Road, La Jolla, CA 92037-1002; email: skaech.@salk.edu.
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