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Glioblastoma Immunotherapy Guru Capitalizes on Collaboration

Dr. Timothy F. Cloughesy of NBTS’ Defeat GBM Research Collaborative doesn’t have hobbies. He can’t offer recommendations from a list of books he’s currently reading. “Work is my hobby,” he explains. “It’s exciting, it’s fun, it’s challenging. I get to work with really smart people.”

Dr. Cloughesy and his Defeat GBM colleagues Drs. Ingo Mellinghoff (Memorial Sloan Kettering Cancer Center) and John de Groot (MD Anderson Cancer Center), as well as NBTS advisor Patrick Wen (Dana Farber Cancer Institute), recently published a report in Nature Medicine providing evidence that the immune checkpoint inhibitor, pembrolizumab (Keytruda), when given prior to surgical resection in recurrent glioblastoma (GBM) patients promotes a survival benefit. In essence, immune checkpoint inhibitors are drugs that allow T-cells — the body’s primary immune response — to go after cancer cells. This is a major finding that reveals the potential for using drugs that were previously thought ineffective in treating this deadly type of brain tumor.

Dr. Cloughesy recalls modest beginnings — entering into the field of neuro-oncology “somewhat by accident” as a neurology resident overseeing epilepsy surgeries who wanted to do more to help patients. He has now dedicated an entire career to brain tumor research and serves as Director of the Neuro-Oncology Program at the University of California Los Angeles (UCLA).

Dr. Cloughesy (center) with other members of the Defeat GBM Research Collaborative (L-R: Drs. John de Groot, Frank Furnari, Cloughesy, Paul Mischel, and Ingo Mellinghoff)

In 1999, after five years better learning the field, Dr. Cloughesy had an opportunity to develop programs at UCLA, one of which focused on collecting patient information through brain tumor imaging. To date, the program has collected close to 10,000 patients-worth of data. Program building, he explains, offered him the chance to “dream a little bit about what we would like to see ourselves become in the future.”

Roughly two decades later, “with Defeat GBM,” he says, “it was the dream of getting a group of smart people together…to explore with limited barriers around us.” Those dreams are now coming to fruition in the form of multiple potential new treatment strategies, including his latest discovery regarding the timing at which drugs given to stimulate the body’s natural defenses ought to be administered.

“We found that patients who had the drug before surgery lived twice as long as those who had it after,” he says. By giving the PD-1 antibody blockade in a “neoadjuvant” setting (before surgery), Dr. Cloughesy is confident that immunotherapy is going to make an impact on treatment options in the near future. “We just need to learn how to do it right and to better capitalize on it. I feel that, hopefully, we could set some examples for how to better study drugs. Show that people can make drugs specifically for brain cancer.”

It’s extremely expensive to develop drugs for brain tumors — hundreds of millions of dollars for late-stage development to get a drug FDA approved. “That bet turns a lot of people away,” Dr. Cloughesy explains. “Trying to raise that much capital becomes a problem.” Often, this leads to researchers trying to make guesses through less expensive evaluations that don’t always yield useful results. Partnering with NBTS programs, then, is a unique and valuable opportunity for Dr. Cloughesy and teams of researchers because NBTS’ multi-institutional initiatives allow them to push the boundaries. It’s also a big win for the brain tumor community.

Dr. Cloughesy at the 2016 NBTS Scientific Summit

“That’s [also] why a large group of people got together to develop GBM AGILE,” he says. By engaging top scientists in multiple countries at the same time, a significant amount of financial risk is mitigated, and the science is better, too. Not only does this collaborative approach get projects down to a fraction of the cost, “we get more shots on goal,” he says. “If we have more experimental trials for patients, in five to 10 years we will have had tens of clinical trials completed…by doing this, we will create an efficient environment to rapidly and cheaply identify clinical benefits and create new standards of care.”

Dr. Cloughesy credits early collaborations with Drs. Paul Mischel, Mellinghoff, Charles Sawyers, David Nathanson, Robert Prins, and Linda Liau, and others from UCLA and Memorial Sloan Kettering with helping him think about the best approaches to problem-solving. “You have to answer a question with your clinical trial, and the question you’re trying to answer should be tissue-based.”

Currently, that question is: what are the immune-suppressive factors inside brain tumors that can be molecularly inhibited or eliminated? Given the higher patient survival rates in the initial randomized study of 35 patients conducted with funding from NBTS, Dr. Cloughesy says they are getting ready to start enrolling more patients by May of 2019 for further clinical trials using neoadjuvant combinations of immunotherapeutics.

Dr. Cloughesy says his greatest personal motivator is, “for sure, realizing how much suffering occurs with this disease. And how wonderful these patients and their families are.” When Dr. Cloughesy isn’t in the lab, the rest of his time is devoted to his own family. And while he doesn’t necessarily foresee any of his three children pursuing careers as bench scientists, he hopes his work “provides an example for them for things they love going after. If you can align helping people and doing something you really enjoy and having passion for it, there’s a lot of value in doing that.”

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