Redefining Incurable: New Treatment Options for a Dangerous Tumor

How might the discovery and creation of entirely new treatment routes ignite hope for kids with an incurable form of brain cancer?

More than two decades ago, Sujatha Venkataraman, PhD, met Rajeev Vibhakar, MD. Her son Rishi had been diagnosed with cancer, and Dr. Vibhakar was his bone marrow transplant doctor. When Dr. Venkataraman’s son passed away from his disease, Dr. Vibhakar told her that he wished there was more he could have done to save Rishi. From that day on, the two have worked tirelessly on the same goal: saving young kids from the grips of cancer. With their most recent work, they’ve taken several giant steps toward doing just that.

At the time of Rishi’s passing, Dr. Venkataraman was researching adult cancers. Struck by the incredible impact of childhood cancer, she pivoted to join Dr. Vibhakar in his work. Their research through The Morgan Adams Foundation Pediatric Brain Tumor Research Program and The Morgan Adams Foundation Pediatric Brain Tumor Lab at Children’s Colorado focuses on diffuse midline gliomas (DMGs), a class of tumors that are as rare as they are deadly. Most patients are between the ages of 3 and 8 at diagnosis, and because there is currently no curative treatment, the vast majority die within just one year of diagnosis.  

Because these tumors are located in the pons — the area of the brain responsible for cardiac functioning, respiratory rate and heart rate — surgery is too dangerous. What’s more, chemotherapy is unable to cross the blood-brain barrier, which protects the brain from harmful substances. That leaves radiation, a treatment that buys time, but not much.  

Unlocking new avenues for DMG tumors

Over the years, there have been hundreds of clinical trials that have thrown every tool in a researcher’s arsenal from all angles at DMGs. But those approaches were missing a critical piece of information. In 2016, as biopsies of DMGs became safer and more widely available, researchers found the genetic change responsible: the H3K27M mutation. Upon investigation, they discovered that this mutation was present in 85% to 95% of these tumors, opening up a new area of focus for Drs. Venkataraman and Vibhakar. 

The pair reached out to researchers around the world for tumor specimens and have been focused on DMGs ever since. Their first order of business was to try to better understand how the H3K27M mutation operated and the fundamental biology behind DMGs. 

“Unfortunately, learning all of that was great, but it didn’t really help us understand how we target it or how we attack this tumor,” Dr. Vibhakar says. 

The solution was there all along, but at first, Drs. Venkataraman and Vibhakar didn’t know where to look.

Finding the key to DIPG treatment

“We were doing RNA sequencing to look at the gene expression of what was changing. We were really interested in trying to understand what happens in the nucleus, because that’s where the mutation is,” Dr. Vibhakar recalls. “We started seeing no matter what experiment we did, if we put the mutation into a tumor cell, CD99 went up. If we took the mutation out of a tumor cell, CD99 went down. It was the gene that changed the most of everything that we had done.”

CD99 is a protein that shows up on normal cells but is highly present on the surface of DMG tumor cells. Drs. Venkataraman and Vibhakar found that when they knocked down, or gene edited, CD99, tumor cells stopped growing, indicating that the protein plays an important role in tumor growth. With this new knowledge, the team had found its target.

The first step in developing a treatment was to synthesize a new antibody to target CD99. In preclinical models, they found that the antibody cleared a DMG known as diffuse intrinsic pontine glioma, or DIPG. But there was a catch: Once the animal models stopped receiving the antibody, the tumors came back. 

With this in mind, Dr. Venkataraman got to work on a secondary approach that could provide a much-needed one-two punch. Using the antibody they synthesized as a base, she created a chimeric antigen receptor-T cell (CAR-T cell), which successfully targeted DIPG cells. The team has since iterated on the original CAR-T cell design through gene editing. This next-generation approach takes T cells from a patient’s own body and edits them such that they can target two proteins that are expressed together on the tumor cells. This logic gate allows the CAR-T cells to target tumor cells with precision, while leaving healthy cells untouched.

“We found it very effective in preclinical models, and it completely cleared the tumor,” Dr. Venkataraman says. “There was no relapse, and we did not see off-target toxicities against normal cells.”

Both the antibody and the CAR-T cell are able to cross the blood-brain barrier thanks to an Ommaya reservoir, a plastic bubble implanted under a patient’s skin that offers direct access to the pons. 

Though these two therapies are only in preclinical models, Drs. Venkataraman and Vibhakar already have a treatment plan in mind for the hopeful day these therapies make it through the approval process and into a clinical setting. 

Kids with a suspected DIPG would get a dose of the antibody before getting a biopsy. If the biopsy confirmed the diagnosis, the team would then harvest the patient’s T cells and send them to be edited. While that’s happening, the patient would receive more infusions of the antibody as well as radiation, before finally getting access to the CAR-T cells.

This, Drs. Venkataraman and Vibhakar say, could increase survival by 50%, if not more.

Bringing a promise to life

These therapies promise to revolutionize the treatment of this insidious class of tumors, but the work behind them could reach far beyond this single indication.

“We now have a CAR platform we’re able to use to target multiple different tumors, and Sujatha is well on the way to doing that,” Dr. Vibhakar says. “We’ve created several other CARs for other tumors, and we’re in much earlier phases compared to this, but we’ve actually now developed the expertise and tools to do this, which is a big deal.”

But even though these new treatments could help treat patients of any age and a wide variety of tumors, the pair is laser-focused on ensuring their first application is children. That’s why instead of selling their drug patents, they are holding them close, even if it means lengthening the timeline to treatment. 

“It is very, very difficult to get drugs into kids, because most drugs are developed for adults, and drug companies are very reluctant to provide drugs for trials in kids,” Dr. Vibhakar says. “This is a little bit crazy, but Sujatha and I are doing what a drug company normally would do… We both know that if we were to license this thing to any pharma company, it would never get to kids. So, we will do what it takes to make it all happen.”

It’s worth it to make good on the promise they made to each other all those years ago, and to kids fighting cancer.

“Everything that I have done, everything that I’ve published, every grant that I’ve gotten, every award that I’ve had is all nice. And you could stack all of it together, and it would not even compare close to what this is,” Dr. Vibhakar says. “I mean, honestly, the day the first patient gets this antibody, if I disappear, I will be perfectly happy.