Research at the Mission Bay Campus of the University of Calfiornia, San Francisco.. Photo: Elena Zhukova
Immunotherapies that fight cancer have been a life-saving advancement for many patients, but the approach only works on a few types of malignancies, leaving few treatment options for most cancer patients with solid tumors. Now, in two related papers published April 28, 2021, in Science Translational Medicine, researchers at UCSF have demonstrated how to engineer smart immune cells that are effective against solid tumors, opening the door to treating a variety of cancers that have long been untouchable with immunotherapies.
By “programming” basic computational abilities into immune cells that are designed to attack cancer, the researchers have overcome a number of major hurdles that have kept these strategies out of the clinic up to now. The two new papers show that the resulting “smart” therapies are more precise, flexible and thorough than previous approaches, and the researchers say that their approach may be ready for clinical trials in the near future.
In one paper, research teams led by Wendell Lim, PhD, chair and Byers Distinguished Professor of cellular and molecular pharmacology, and Hideho Okada, MD, PhD, the Kathleen M. Plant Distinguished Professor of neurological surgery, tested the system in glioblastoma, the most aggressive form of brain cancer that affects adults and children, and which physicians have yet to successfully treat with immunotherapies due to the complexity of the tumors. The team showed the new system, which uses a two-step process to hunt down cancer cells, could completely clear human patient-derived tumors from the brains of mice without the dangerous side effects or high risk of recurrence currently associated with immunotherapy treatment in solid tumors.
In the second paper, Kole Roybal, PhD, assistant professor of microbiology and immunology, and Bin Liu, PhD, professor of anesthesia at UCSF, led a study showing how components of this system can be switched out like the heads of an interchangeable screwdriver to target other difficult-to-treat cancers in other parts of the body. The team also identified a particularly important set of “screwdriver heads'' that could make powerful tools against cancers of the ovaries, lungs and other organs, which together kill tens of thousands every year.
In addition, both papers address the issue of so-called “T-cell exhaustion,” a long-standing challenge in which traditional CAR-T cells — the re-programmed intruder-hunting immune cells behind some of the most promising cancer immunotherapies — tire out when engaged in prolonged battles against the cancer. The new smart cells stay consistently strong through the entire fight, conserving their energy by switching to a standby mode when not directly engaged with the cancer.
“These findings address all critical challenges that have been in the way of developing immunotherapies for patients who suffer from these cancers,” said Okada, who also serves as director of the Brain Tumor Immunotherapy Center at UCSF. “This science is ready to move towards clinical trials.”
Expanding Immunotherapies to Deadly Brain Cancers
Glioblastomas are a particularly tragic case in which patients so far haven’t been able to benefit from CAR-T cells. Every year, over 20,000 adults in the United States are diagnosed with glioblastoma or other types of malignant brain cancer, and with current treatments, the prognosis is grim.