Glioblastoma is a deadly brain tumor. Vaccines look promising.
Editor's note: Can the immune system be put to work to treat brain malignancies?That’s the hope at Cleveland Clinic where multiple research projects are underway.Manmeet Ahluwalia, MD, Miller Family Endowed Chair in Neuro-Oncology and of Head of Operations with Burkhardt Brain Tumor NeuroOncology Center at Cleveland Clinic spoke to MD Magazine about his work on glioblastoma.
It’s the most common malignant tumor of brain but only 1% of patients have a predisposing condition such as a genetic syndrome. In 98% to 99% there is no known risk factor. The only other identified risk factor is prior radiation treatment. It is most common in people in their fifth and sixth decades but it can happen at any age. We’ve seen 2-year-olds and people in their 90s. The median age is 64 and glioblastoma are more commonly seen in men.
What about cellphone radiation as a cause?
The research is kind of divided, there’s been no real definite association found between increased use of a cell phone and developing glioblastoma. There are concerns about cell phone use in kids because their skull is not completely developed.
In your research, are you actually curing people yet?
Not yet. Everyone knows brain tumors are not good, and glioblastoma is the most common primary brain malignancy, affecting 15,000 US patients a year. Despite advances in surgery, radiation, and chemotherapy the outcomes are dismal—15 to 16 months’ life expectancy.
In recent times there’s been a lot of excitement about immunotherapy including vaccines in cancer and immune checkpoint inhibitors have shown promise for cancers in the lung, melanoma, head and neck, and kidney. Our research has a different focus. People thought the central nervous system was immune-privileged but recent trials in brain metastases have shown that’s not true. We have found a dynamic interaction between the CNS and the immune system.
You’ve written about the protein called “survivin” can you explain what that is?
Survivin is an intracellular protein and we know from prior research that people with high levels of expression in cancer do poorly. In my fellowship I worked in a lab where we were developing a vaccine against survivin. It’s called SurVaxM a synthetic long peptide mimic vaccine that stimulates an immune response to survivin.
Did it work?
We did a phase 1 study and of nine patients who were treated—the intent was to prove safety—we saw a patient response or stable disease in three patients for more than six months.
Overall survival was 20 months so that was promising, compared to six to 10 months seen in the patient population. One patient was on the vaccine for three years.
Why did it stop working?
We recognize that cancers are highly complex. Glioblastoma can take multiple pathways and no matter what the therapy we use some will ultimately develop resistance. We have tried giving the vaccine in combination with chemotherapy and radiation. The belief is we need to treat this tumor (glioblastoma) with a multimodality approach. In a phase 2 study we used SurVaxM with temozolmide in 50 patients newly diagnosed with glioblastoma.
Why only the newly diagnosed?
We feel that immune therapies take time to work, for the patient to mount an immune response. We have seen some promising results in early group of patients treated; a number of them are doing well; they are a year out with no progression. That’s really good.
How large are these tumors and when do they show up?
Tumors vary from less than 1 cm up to 10 cms or greater. The critical part is where they are located. In the frontal lobe they can be fairly large. They can come on suddenly or grow gradually. There are no risk factors other than radiation, no effective screenings. Out of the blue a patient can have a seizure or memory loss, weakness, or even a stroke since these tumors tend to bleed. They often present to an emergency room and an MRI demonstrates lesions. Then they go to a neurosurgeon for a resection.
You also wrote about the ICT-107 vaccine, what is that?
It’s an autologous vaccine targets six antigens associated with glioblastoma. A phase 2 study in a selected group of patients showed a benefit and now that vaccine is in phase 3 trial. Another vaccine is SL-701, a glioma-associated antigen vaccine in phase 2 testing for recurrent glioblastoma. The trial used the vaccine in combination with Avastin for an initial subset of patients and we are awaiting the results.
What about these oncolytic viral therapies that cause tumors to self-destruct?
Basically, the premise is that we can modify a virus to infect tumor cells and weaken them. Tumors are very smart and evade the immune system. We take a virus—there’s been a lot of interest in poliovirus and also retrovirals—and the virus can be implanted directly into the tumor cavity.
Couldn’t that infect the patient?
There was a lot of worry initially so hence putting the virus into the cavity was the safe way. The initial results of some of them have showed safety, we are still awaiting the results from others.
You’re working with an antifungal as well?
Yes, Toca 511 expresses the cytosine deaminase gene and selectively delivers the gene to the tumor. It is being studied in combination with Toca FC, a novel formulation of the antifungal drug flucytosine that gets converted to the anticancer drug 5-fluoroucil within infected cancer cells. We’re part of that study and have enrolled patients at our institution.
In general has there been any change in cancer research funding recently? Former Vice President Joe Biden was going to end cancer, what will happen now?
Yes, the Cancer Moonshot. We didn’t get any funding from that mechanism directly for our work but obviously in the cancer research community we are waiting to see what the current administration’s approach will be. I hope that the support continues because cancer research is so important. In the next few decades, cancer will be the leading cause of death in the US and also the world. We have to continue to do this important work.