Fighting Cancer on Multiple Fronts
For Benjamin Izar, becoming a physician-scientist was a two-step process. “I always knew I wanted to be a physician—it was just something intuitive that I had never even thought about,” says Izar, who is now assistant professor of medicine at Columbia University Vagelos College of Physicians and Surgeons.
His decision to enter the field of oncology and perform cancer research came later during his internal medicine residency when he saw the immense need for better cancer therapies.
“When I was an intern, targeted therapies and immunotherapies for the treatment of solid cancers were emerging, but we were curing very few patients,” Izar says. “I wanted to enter the field to work toward the next generation of therapies.”
Izar finished his residency at Mass General, then performed postdoctoral research at Harvard and the Broad Institute, gaining experience in molecular oncology, immunology, and computational biology. He joined Columbia and the Herbert Irving Comprehensive Cancer Center in late 2019, just months before the COVID pandemic began.
Now, Izar spends one day a week in the clinic, primarily treating patients with malignant melanoma and overseeing early phase clinical trials, and the rest of the week conducting research, which has blazed new trails with the creative use of cutting-edge techniques.
Genomics, immunology, and metastasis
Initially, he focused on melanoma, but that soon broadened.
“Two or three years ago, we realized that a lot of the observations we make in melanoma frequently extrapolate to other, more frequent diseases, such as lung cancer,” says Izar.
As a result, he joined a trend in cancer research of focusing more on the underlying mechanisms of the disease than on specific forms of it. “We do focus mostly on lung cancer and melanoma, but we have projects and collaborations on most common cancers, so I like to describe our work around biological concepts rather than individual diseases,” Izar explains. He now classifies the work of his laboratory as having three pillars: studies of cancer genomics, tumor immunology, and the mechanisms underlying cancer cell metastasis.
Where the lab is most distinctive is in its ability to amalgamate the use of single cell techniques, genome editing, and systems biology to explore the cancer field’s most pressing problems. “My lab is developing these methods to address challenges in the cancer field, but they can be applied to a broad range of diseases,” says Izar, who directs Columbia’s Human Immune Monitoring core facility, which gives other Columbia researchers access to these new methods.
These methods have recently helped uncover a new strategy for weaponizing the immune system against cancers. “We leveraged base editing to introduce tens of thousands of very specific mutations into normal T cells and found some that ultimately supercharged the T cells to be more effective in attacking cancer cells,” says Izar. Such an approach could help patients with cancers that don’t respond well to current immunotherapies.
Super-charged cell therapies. Izar's lab recently used novel CRISPR-dependent base editing to increase the ability of T cells to kill cancer cells, which may make such cell therapies more effective for more patients. In the photo, edited T cells killed more cancer cells (left) than unedited T cells (right). Photo courtesy of the Izar lab.
New methods developed by Izar’s lab also have identified a major mechanism that allows tumors to evade detection by the immune system. “The methods allowed us to look for the first time at how human cancer cells balance their interactions with immune cells,” says Izar. That project uncovered a promising strategy for unmasking evasive tumors, which could increase the effectiveness of existing immunotherapies.
Metastasis is one of the biggest problems in oncology, and the lab has also made groundbreaking discoveries there. “We’re trying to understand why certain cancers have stereotypical patterns of metastasis: Why melanoma, for example, and lung cancer frequently metastasize to the brain or to the liver,” says Izar, adding that “patients do poorly when they have metastatic spread to those organs.” That work led him to discover a major mechanism that these cancers use to home to the liver and identified ways to interfere with that process.
Seeing promise and limitations of new treatments
Izar also works to bring new research findings from across the field directly into his practice as a physician. “I’m part of the early drug development group, so there are many clinical trials ongoing, where novel therapies are being tested for the first time in patients with cancer, and I see patients on these trials,” he says.
He sees firsthand the promise of new treatments but also their limitations. For several years, drug developers have focused on precision oncology, identifying specific gene mutations that can drive tumor formation then creating drugs that target the products of those genes. Though that approach works very well for some patients, it fails most.
“It turns out that for many patients, the traditional definition of precision oncology is an irrelevant concept, because they don’t have the specific mutation we can target,” says Izar. Instead, he hopes to help move the field toward identifying and targeting more common vulnerabilities in cancer cells.
In that regard, new cell-based immunotherapies, which genetically engineer a patient’s own immune cells to attack cancer, are an attractive option. The cells work well in a wider variety of patients with certain cancers but suffer from a different drawback: patient access. “These therapies are extremely complex and require admission to a large academic medical center, so only a fraction of patients who could benefit from these exciting developments now get them,” says Izar. He adds that he is collaborating with teams across the university to break down those barriers.
In just a short time, Izar’s research has already been recognized by numerous awards, grants, and honors. Izar has received a NextGen Star Award from the American Association for Cancer Research and the Donald Seldin-Holly Smith Award for Pioneering Research of the American Society for Clinical Investigation. He has received Schaefer, Gerstner, and V Foundation awards, among others, and has secured several NIH grants, including an R37 MERIT award.
Izar credits much of his success to early influences: “Everything in life is about people, especially mentors; my first mentors were really influential when it came to my later career. I try to emulate their philosophy of generosity and lifelong mentorship and succeeding by creating an environment that allows people in my lab to address important questions.”