MRI of glioblastomas.
Immunotherapies that fight cancer have been a life-saving advance for many patients, but the approach only works for a few types of malignancies, leaving few treatment options for most cancer patients with solid tumors. Now, in two related articles published April 28, 2021, in Science Translational Medicine, UCSF researchers have shown how to develop smart immune cells that are effective against solid tumors, opening the door to the treatment of a variety of cancers that have long been untouchable. immunotherapies.
By ‘programming’ basic math skills into immune cells designed to attack cancer, the researchers have overcome some of the major hurdles that have kept these strategies out of the clinic so far. The two new papers show that the resulting “smart” therapies are more accurate, flexible and thorough than previous approaches, and the researchers say their approach could 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 most often. aggressive form of brain cancer that affects adults and children and which doctors have not yet successfully treated with immunotherapies due to the complexity of the tumors. The team showed that the new system, which uses a two-step process to detect cancer cells, could completely remove tumors from human patients from the brains of mice without the dangerous side effects or high risk of recurrence currently associated with solid immunotherapy treatment. fabrics. 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 that showed how components of this system can be interchanged such as the heads of an interchangeable screwdriver align. to other difficult-to-treat cancers in other parts of the body. The team also identified a particularly important set of screwdriver heads that could be powerful tools against cancers of the ovaries, lungs and other organs, which together kill tens of thousands each year.
In addition, both papers address the issue of so-called “T cell depletion,” a long-term challenge in which traditional CAR-T cells – the reprogrammed immune cells that prey on invaders behind some of the most promising cancer immunotherapies – fatigue over long periods of time. fights against the cancer. The new smart cells remain consistently strong throughout the fight, conserving their energy by switching to a standby mode when they are not directly involved in the cancer.
“These findings address all of the critical challenges that have hindered the development of immunotherapy for patients suffering from these cancers,” said Okada, who also serves as director of UCSF’s Brain Tumor Immunotherapy Center. “This science is poised to evolve into clinical trials.”
Extending immunotherapy to deadly brain cancers
Glioblastomas are a particularly tragic case where patients have not been able to take advantage of CAR-T cells until now. More than 20,000 adults in the United States are diagnosed with glioblastoma or other types of malignant brain cancer each year, and with current treatments, the prognosis is bleak.
“It’s like a death sentence,” Okada says, noting that brain tumors are also the leading cause of cancer-related mortality and morbidity in children. “The outcome for malignant brain tumors in children remains bleak.”
Okada, an expert in brain cancers, worked with Lim, who was developing new cell technologies, hoping to change this.
Previous work had identified a molecule commonly found on glioblastoma cells, leading researchers to hope that CAR-T cells could target this molecule and eliminate the deadly cancer. While this strategy was effective in killing some glioblastoma cells, not all glioblastoma cells display this molecule. This allowed some cancer cells to evade CAR-T therapy, ultimately resulting in the cancer’s recurrence.
Targeting other molecules posed the opposite, but equally dangerous problem. While some molecules are found on glioblastoma cells, they are also found in healthy, non-brain tissues such as the liver, kidneys, esophagus, and genitals. Targeting cells displaying these molecules with CAR-T can damage healthy tissue and put patients at risk. This catch-22 leaves clinicians without an ideal molecular target, a pervasive problem that has thwarted the use of CAR-T in most solid tumors.
The scientists came up with a solution to this problem by using a system called synNotch, an adaptable molecular detector that Lim’s lab has been perfecting for several years. The synNotch system allows scientists to program CAR-T cells to detect specific molecules on the surface of cancer cells so that CAR-Ts only attack when they encounter the molecules they are programmed to.
Wendell Lim, PhD.
To kill glioblastomas, the team took a new two-step approach. The first step uses synNotch to give CAR-Ts the ability to carefully assess whether they are in a tumor relative to other parts of the body, while a second set of synNotch sensors provides a strong and comprehensive response to killing tumors. Once the CAR-T cells confirm that they are in the tumor, the second set of sensors is activated, allowing the CAR-Ts to detect and kill glioblastoma cells based on multiple brain tumor molecules. This two-step process leads to more complete tumor killing and prevents tumor cells from accumulating simple mutations that would allow them to evade CAR-Ts.
Experiments described in the paper show that this strategy is effective. In mice with glioblastomas from human patients, synNotch destroyed CAR-Ts tumors that were not cleared by normal T cells or traditional CAR-Ts, with no signs of dangerous side effects.
“We’ve been saying for a while now to think of these cells as computers – smart enough to integrate multiple data points and make complex choices,” said Lim, who also heads UCSF’s Cell Design Institute. “Now we see this working in a realistic model of a very deadly cancer for both adults and children.”
SynNotch is a flexible, powerful system for building smarter immunotherapies
The second paper further demonstrated the effectiveness of this approach by identifying additional molecular targets for the synNotch system. The researchers searched public cancer databases for molecules found in tumor cells that could be useful in CAR-T therapies against now intractable diseases. They found a molecule called ALPPL2 that is common in many cancers, including asbestos-induced mesothelioma, as well as ovarian, pancreatic and testicular malignancies. Importantly, the molecule is rarely found in healthy tissue.
Kole Roybal, PhD.
In tests of synNotch circuits designed to detect ALPPL2, CAR-T cells were able to recognize and kill mesothelioma and ovarian cancer cells with precision. “We can build cells that recognize ALPPL2 and then regulate other sensors against more common tumor antigens,” said Roybal, another founder of the Cell Design Institute. “This is a fully viable clinical grade antigen that we can use to develop cell therapies for use in humans.”
A striking finding from both studies is that synNotch CAR-Ts maintained stable activity levels throughout the cancer death process, eliminating the challenge of T cell depletion that hinders traditional CAR-T therapies. Researchers believe that depletion occurs because traditional CAR-Ts are designed to continuously push a kill switch, meaning they’re always on and eventually deplete their resources, leading to a “cell that doesn’t do much,” said Roybal.
“Amazingly, this was not the case in our synNotch systems,” he said. The researchers found that synNotch CAR-T cells remain in standby mode until they identify the cancer, saving their energy. “These papers show that there are several reasons why these synNotch T cells might be better than current state-of-the-art CAR T cell technology.”
Authors: In addition to Lim, Roybal, Okada and Liu, other researchers involved in the study were Joseph H. Choe, Payal B. Watchmaker, Milos S. Simic, Ryan D. Gilbert, Aileen W. Li, Nira A. Krasnow, Kira M. Downey, Wei Yu, Diego A. Carrera, Anna Celli, Juhyun Cho, Jessica D. Briones, Jason M. Duecker, Yitzhar E. Goretsky, Ruth Dannenfelser, Lia Cardarelli, Olga Troyanskaya, Sachdev S. Sidhu, Axel Hyrenius-Wittsten, Yang Su, Minhee Park, Julie M. Garcia, Josef Alavi, Nathaniel Perry, and Garrett Montgomery.
Financing: This work was supported by the UCSF Glioblastoma Precision Medicine Project, UCSF Cell Design Institute, Parker Institute for Cancer Immunotherapy, Howard Hughes Medical Institute, Swedish Society for Medical Research, Swedish Research Council, UCSF Helen Diller Family Comprehensive Cancer Center, U54CA244438, CA196277, R35 NS105068, DP2 CA239143, P30 DK063720 and S10 Instrumentation Fair S10 1S10OD021822-01.
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