Fighting cancer on multiple fronts

for Benjamin IsarBecoming a physician-scientist was a two-step process: “I always wanted to be a physician. It was just an instinct; I never really thought about it,” says Izar, now an assistant professor of medicine at Columbia University's Vagelos College of Medicine.

His decision to go into oncology and conduct cancer research came during his internal medicine residency, when he realized there was a great need for better cancer treatments.

“During my internship, targeted therapies and immunotherapies were emerging to treat solid tumors, but very few patients were being cured,” Izar said. “I knew I wanted to go into this field to work on developing the next generation of treatments.”

After completing his residency at Massachusetts General Hospital and his postdoctoral research at Harvard University and the Broad Institute, where he gained experience in molecular oncology, immunology and computational biology, Isar joined Columbia University and the Herbert Irving Comprehensive Cancer Center in late 2019, just months before the COVID-19 pandemic began.

These days, Izar spends one day a week in the clinic, primarily treating melanoma patients and overseeing early-stage clinical trials, and the rest of his time conducting research that creatively leverages cutting-edge technology to blaze new trails.

Genomics, immunology, metastasis

Initially, he focused on malignant melanoma, but his scope quickly expanded.

“A couple of years ago, we realized that many of the observations we were making in melanoma also applied to other more common diseases, such as lung cancer,” Izar says.

As a result, he has joined a trend in cancer research to focus on the underlying mechanisms of disease, rather than specific forms of cancer. “We focus mainly on lung cancer and melanoma, but we also have projects and collaborations on the most common cancers, so we like to explain our research around biological concepts, rather than individual diseases,” explains Izar. He now divides his lab's research into three pillars: cancer genomics, tumor immunology, and studying the mechanisms underlying cancer cell metastasis.

What is most distinctive about the lab is its ability to fuse single-cell techniques, genome editing, and systems biology to investigate the most pressing problems in the field of cancer. “In my lab, we develop these methods to address challenges in the field of cancer, but they can be applied to a wide range of diseases,” says Izar, who heads Columbia’s Human Immune Monitoring Core Facility, which provides other Columbia researchers with access to these new methods.

These methods have recently New strategies to weaponize the immune system Defense against cancer. “We used base editing to introduce tens of thousands of very specific mutations into regular T cells, and ultimately found some that make the T cells stronger and better able to attack cancer cells,” Izar says. Such an approach could help cancer patients who don't respond well to current immunotherapy.

The new technique developed by the Izar lab Tumors evade detection by the immune system“This method allowed us to, for the first time, investigate how human cancer cells balance their interactions with immune cells,” says Izar. The project has uncovered a promising strategy to illuminate hard-to-detect tumors and could improve the effectiveness of existing immunotherapies.

Metastasis is one of the biggest problems in oncology, and the lab has made groundbreaking discoveries there as well. “We're trying to understand why certain cancers show typical patterns of metastasis, for example why melanoma and lung cancer often metastasize to the brain or liver,” said Izar, adding that “when it spreads to these organs, the patient's condition worsens.” That research led to a major discovery. The mechanisms these cancers use to colonize the liver And we identified ways to disrupt that process.

See the possibilities and limitations of new treatments

Isar strives to translate new research findings across fields directly into his practice: “I'm part of the early drug development group, so there are a lot of clinical trials testing new treatments in cancer patients for the first time, and I see patients who are taking part in these trials,” he says.

He has seen firsthand the promise of new treatments, but also their limitations. In recent years, drug developers have focused on precision oncology, identifying the specific genetic mutations that drive tumor formation and developing drugs that target those gene products. This approach works very well for some patients, but not for the vast majority.

“For many patients, the traditional definition of precision oncology has proven to be an irrelevant concept because they don't have specific mutations that we can target,” says Izar. Instead, he hopes to help move the field forward toward identifying and targeting more general vulnerabilities in cancer cells.

In that respect, new cell-based immunotherapies, in which a patient's own immune cells are genetically engineered to attack cancer, are an attractive option. The cells work for a wide range of patients with certain cancers, but they have another drawback: limited patient access to the treatment. “Currently, only a small percentage of patients can benefit from these groundbreaking developments because these treatments are highly complex and require admission to a large academic medical center,” says Izar, adding that he is working with a team at the university to break down those barriers.

In just a short time, Izar's research has already been recognized with numerous awards, grants and honors. Izar is the recipient of the NextGen Star Award from the American Cancer Society, the Donald Seldin-Holly Smith Award for Pioneering Research from the American Society for Clinical Research, and numerous other awards, including the Schaefer Award, the Gerstner Award, and the V Foundation Award, as well as multiple NIH grants, including an R37 MERIT award.

Izar attributes much of his success to early influences: “In life, it's all about people, especially mentors. My first mentors had a huge impact on the rest of my career. I strive to emulate their philosophy of generosity and lifelong mentorship, and to succeed by creating an environment in which people in the lab can work on important problems.”