Interfering with cancer’s ability to hide from a person’s immune system, using so-called “immune checkpoint inhibitors,” has proven dramatically successful in some cancer patients. But immune therapy doesn’t work for all patients, and many cancers don’t respond at all, despite early hopes for the treatment.
Now, a radiation oncologist at The University of Texas Southwestern Medical Center, Dr. Todd Aguilera, is trying to develop new therapies that may work in concert with immune therapy to more effectively treat significantly more cancer patients. A physician-scientist, Dr. Aguilera was recruited in 2017 from Stanford University, where he was a resident in radiation oncology, with the help of a First-Time Tenure-Track Award from CPRIT.
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Interfering with cancer’s ability to hide from a person’s immune system, using so-called “immune checkpoint inhibitors,” has proven dramatically successful in some cancer patients. But immune therapy doesn’t work for all patients, and many cancers don’t respond at all, despite early hopes for the treatment.
Now, a radiation oncologist at The University of Texas Southwestern Medical Center, Dr. Todd Aguilera, is trying to develop new therapies that may work in concert with immune therapy to more effectively treat significantly more cancer patients. A physician-scientist, Dr. Aguilera was recruited in 2017 from Stanford University, where he was a resident in radiation oncology, with the help of a First-Time Tenure-Track Award from CPRIT.
Immune checkpoint therapy was pioneered by 2018 Nobel laureate James Allison, an immunologist and CPRIT Scholar at MD Anderson. Using the drug ipilimumab, approved by the FDA in 2011, initial trials found that about 20% of patients with metastatic melanoma could achieve long-term survival, and some effectively cured of their disease. The drug blocks cancer from putting the brakes on the body’s natural immune response. Several different types of immune checkpoint inhibitors have subsequently been developed and proven effective in treating many types of cancers.
Immune-therapy is not cancer-specific; it treats the immune system rather than a particular type of cancer. Nevertheless, not all cancers respond the same way, and it hasn’t made an impact for some cancers, like pancreatic cancer and colorectal cancer. Many researchers are asking why this is so.
Dr. Aguilera’s work centers on cancer cells that have morphed into a more “primitive” type of cell, which enables them to migrate, or metastasize. Cells that have undergone this transition are not only more prone to metastasis, but are also resistant to chemotherapy and radiation, as well as immune therapy.
“We want to better understand how they utilize that mechanism to cloak themselves from the immune system,” he says. “By discovering more about the cloaking response, perhaps we can discover how to make immune therapy more effective for the large majority of patients that are not reached by this class of drugs.” That might mean developing combination therapies to remove the “cloak” and expose the cancer to the immune system again.
Dr. Aguilera’s approach is three-pronged: first, studying mechanisms of immune resistance; second, studying patient tissues to better understand responses to current therapies; and third, engineering new therapies that target the immune system.
While developing new therapies may take years, Dr. Aguilera has been studying an existing immunotherapy drug, which when combined with radiation therapy, has the potential to meaningfully improve the response of some patients. He’s hoping to make the case for beginning a Phase II clinical trial soon.
“One of the things I learned from my graduate research advisor, Nobel laureate Roger Tsien, is to take well thought-out, but calculated risks.” Dr. Aguilera says. “He inspired me to think outside the box and never shy away from a new challenge.” He says that CPRIT has enabled him to be comfortable taking on challenges that a young researcher without flexibility or resources might be more reluctant to do.
He also credits the top-notch radiation oncology department at UT Southwestern, and being part of a great academic center, for helping him recruit excellent researchers to join his team.
Dr. Aguilera studied biology at the University of Portland, and then entered the physician-scientist program at the University of California, San Diego. He earned his Ph.D. in biomedical sciences in 2009, and his M.D. in 2011. He joined the residency program at Stanford in 2012. He has two patents pending for his work at UCSD and at Stanford.
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