University of California, San Francisco (UCSF) researchers focusing on immunotherapies that fight cancer center their attention on emerging engineered smart immune cells can zap solid cancerous tumors, opening the opportunity up to apply breakthrough immuno-oncology therapies targeting a number of cancers that up until now have been considered treatable with this powerful therapy harnessing the patient’s own immune system. Exemplified in two research papers published April 28, 2021 in Science Translational Medicine, the UCSF investigators suggest by “programming” basic computational abilities into immune cells engineered to zap cancerous tumors, they have figured out how to overcome considerable obstacles that have limited the use of these therapies in the clinic. Advanced-programmed “smart” therapies are more targeted, precise yet flexible than the previous generation of immuno-oncology approaches. Coming soon: clinical trials based on this breakthrough.
TrialSite breaks this potentially exciting information down for the community.
Who are the two research authors?
In the first paper, 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 smart system in glioblastoma, the most aggressive of brain cancer that affects adults and children. Physicians have yet to successfully treat immunotherapies due to the complexity of the 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 each year.
How does this new life science-based system work?
In the first paper, the authors explain how the system uses a two-step process to hunt down cancer cells and can completely clear human patient-derived tumors from the brains of mice without dangerous side effects or the high risk of recurrence currently associated with immunotherapy treatment in solid tumors.
Therapy like multipurpose ‘screw driver’
Authors Kole Roybal, PhD and Bin Liu, PhD led a study that revealed 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 many thousand annually.
How does this latest research address “T-cell exhaustion”?
First, a definition of this phenomenon representing a real challenge with immunotherapy targeting cancer. A long -standing challenge reports UCSF, in which traditional CAR-T cells, that is those reprogramed intruder-hunting cells behind some of the most promising cancer immunotherapies, tire out when engaged in prolonged battles against cancer. The novel smart cells remain consistently and continuously strong throughout the fight against the cancer. They are able to conserve their energy by switching to a form of “standby mode” when not directly engaged in the battle against cancer.
In this way, “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.”
Imminent Opportunity? A Treatment for Deadly Brain Cancer?
While glioblastomas (brain cancer) are like a death sentence, UCSF researchers such as Okada, an expert in brain cancer and partner Lim, who has been developing novel cell engineering technologies, hope to change all of that.
Why hasn’t immunotherapy worked against brain cancer?
To summarize in a nutshell, there are two primary reasons. Either the CAR-T cells couldn’t zap all molecules in the brain cancer hence allowing the cancer to survive the therapy and come back with a vengeance. On the other hand, targeting some of the other molecules found in glioblastoma cells are also found in healthy cells and hence there’s a risk of damaging the human body. This has meant a catch-22 situation.
Enter synNOTCH from Dr. Lim’s Lab
Welcome to the breakthrough that could potentially save many thousands of lives and hopefully someday protect our loved ones from what is today a death sentence. SynNOTCH is a customizable molecular detector that Lim’s lab has been perfecting for several years. The synNOTCH system lets scientists program CAR-T cells to detect specific molecules found on the surface of cancer cells, ensuring that CAR-Ts attack only when they encounter the molecules they’re programmed to target.
How did they Kill Glioblastoma cells?
The team took a novel, two-step approach, including 1) utilizing synNOTCH to give CAR-Ts the ability to carefully judge if they are a tumor versus other parts of the body, while another set of synNOTCH sensors ensures a strong and comprehensive killing response. So, once the CAR-T cells confirm they are in the tumor, then 2) a second set of sensors are activated, enabling CAR-T cells to detect and kill glioblastoma cells based on multiple brain-tumor molecules.
What is the result of this two-step process?
This two-step process leads to more complete tumor killing while in parallel prevents tumor cells from accumulating simple mutations that would allow them to evade CAR-Ts.
What did the researchers test synNOTCH on?
Preclinical studies—mice with human patient-derived glioblastomas. In this study, synNOTCH CAR-Ts wiped out tumors that were not cleared by normal T cells or traditional CAR-Ts, with no signs of dangerous effects.
What’s Dr. Lim’s perspective on this news?
“We’ve been saying for a while that we should think of these cells like computers — smart enough to integrate multiple data points and make complex choices,” said Lim, who also directs the Cell Design Institute at UCSF. “Now we’re seeing this working in a real-world model of a very deadly cancer for both adults and children.”
SynNOTCH, a Flexible Powerful system Enables Smarter Immunotherapies
The second paper further demonstrated the efficacy 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’s common to many forms of cancer, including the asbestos-driven mesothelioma as well as ovarian, pancreatic and testicular malignancies. Importantly, the molecule is rarely found in healthy tissue.
SynNOTCH maintains stable levels of activity throughout the cancer attack process
The researchers at UCSF write that they were pleased to find that synNOTCH CAR-Ts maintained stable levels of activity throughout the cancer killing process, eliminating the challenge of T-cell exhaustion, which hinders traditional CAR-T therapies. Researchers believe exhaustion occurs because traditional CAR-Ts are designed to continuously express a kill switch, meaning they are always on and eventually deplete their resources, leading to a “cell that isn’t doing much of anything,” declares Dr. Roybal.
This work was supported by the UCSF Glioblastoma Precision Medicine Project, the UCSF Cell Design Institute, the Parker Institute for Cancer Immunotherapy, the Howard Hughes Medical Institute, the Swedish Society for Medical Research, the Swedish Research Council, the UCSF Helen Diller Family Comprehensive Cancer Center, U54CA244438, CA196277, R35 NS105068, DP2 CA239143, P30 DK063720 and S10 Instrumentation Grant S10 1S10OD021822-01.
The University of California, San Francisco (UCSF) is exclusively focused on the health sciences and is dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. UCSF Health, which serves as UCSF’s primary academic medical center, includes top-ranked specialty hospitals and other clinical programs, and has affiliations throughout the Bay Area. UCSF School of Medicine also has a regional campus in Fresno.
Wendell Lim, PhD, chair and Byers Distinguished Professor of cellular and molecular pharmacology
Note that Dr. Liu is part of a startup cancer biotech called Vivace Therapeutics. Prior, he discovered a unique approach to treating prostate cancer and multiple myeloma that led to the formation of Fortis Therapeutics.
Hideho Okada, MD, PhD, the Kathleen M. Plant Distinguished Professor of neurological surgery
Call to Action: This breakthrough shows much promise. TrialSite will monitor.