PRESS-NEWS.org - Press Release Distribution
PRESS RELEASES DISTRIBUTION

Study offers a potential strategy to improve T cell therapy in solid tumors

Simultaneous knockout of two inflammatory regulators boosted T cell expansion in models

2023-03-15
(Press-News.org) PHILADELPHIA – A new approach that delivers a “one-two punch” to help T cells attack solid tumors is the focus of a preclinical study by researchers from the Perelman School of Medicine at the University of Pennsylvania. The findings, published in the Proceedings of the National Academy of Sciences (PNAS), showed that targeting two regulators that control gene functions related to inflammation led to at least 10 times greater T cell expansion in models, resulting in increased antitumor immune activity and durability.

CAR T cell therapy was pioneered at Penn Medicine by Carl H. June, MD, the Richard W. Vague Professor in Immunotherapy at Penn and director of the Center for Cellular Immunotherapies (CCI) at Abramson Cancer Center, whose work led to the first approved CAR T cell therapy for B-cell acute lymphoblastic leukemia in 2017. Since then, personalized cellular therapies have revolutionized blood cancer treatment, but remained stubbornly ineffective against solid tumors, such as lung cancer and breast cancer.   

“We want to unlock CAR T cell therapy for patients with solid tumors, which include the most commonly diagnosed cancer types,” said June, the new study’s senior author. “Our study shows that immune inflammatory regulator targeting is worth additional investigation to enhance T cell potency.”

One of the challenges for CAR T cell therapy in solid tumors is a phenomenon known as T cell exhaustion, where the persistent antigen exposure from the solid mass of tumor cells wears out the T cells to the point that they aren’t able to mount an antitumor response. Engineering already exhausted T cells from patients for CAR T cell therapy results in a less effective product because the T cells don’t multiply enough or remember their task as well.

Previous observational studies hinted at the inflammatory regulator Regnase-1 as a potential target to indirectly overcome the effects of T cell exhaustion because it can cause hyperinflammation when disrupted in T cells – reviving them to produce an antitumor response. The research team, including lead author David Mai, a Bioengineering graduate student in the School of Engineering and Applied Science, and co-corresponding author Neil Sheppard, DPhil, head of the CCI T Cell Engineering Lab, hypothesized that targeting the related, but independent Roquin-1 regulator at the same time could boost responses further. 

“Each of these two regulatory genes has been implicated in restricting T cell inflammatory responses, but we found that disrupting them together produced much greater anticancer effects than disrupting them individually,” Mai said. “By building on previous research, we are starting to get closer to strategies that seem to be promising in the solid tumor context.”

The team used CRISPR-Cas9 gene editing to knock out Regnase-1 and Roquin-1 individually and together in healthy donor T cells with two different immune receptors that are currently being investigated in Phase I clinical trials: the mesothelin-targeting M5 CAR (mesoCAR) and the NY-ESO-1-targeting 8F TCR (NYESO TCR). Neither engineered T cell product targets CD19, the antigen targeted by most approved CAR T cell therapies, as this antigen is not present in solid tumors.

After CRISPR editing, the T cells were expanded and infused in solid tumor mice models, where researchers observed the double knockout led to at least 10 times as many engineered T cells compared to disabling Regnase-1 alone, as well as increased antitumor immune activity and longevity of the engineered T cells. In some mice, it also led to overproduction of lymphocytes, causing toxicity.

“CRISPR is a useful tool for completely ablating the expression of target genes like Regnase and Roquin, resulting in a clear phenotype, however there are other strategies to consider for translating this work to the clinical setting, such as forms of conditional gene regulation,” Sheppard said. “We’re certainly impressed by the antitumor potency that was unleased by knocking out these two non-redundant proteins in combination. In solid tumor studies, we often see limited expansion of CAR T cells, but if we’re able to make each T cell more potent, and replicate them to greater quantities, we expect T cell therapies to have a better shot at attacking solid tumors.”

Additional authors include Omar Johnson, Jordan Reff, Ting-Jia Fan, and John Scholler. The research was supported by the National Institutes of Health (1P01CA214278, R01CA226983), the Parker Institute for Cancer Immunotherapy, the Emerson Collective, the Fontaine Fellowship, the Norman and Selma Kron Research Fellowship, and the Robert Wood Johnson Foundation Health Policy Research Scholars.

###

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $9.9 billion enterprise.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $546 million awarded in the 2021 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: the Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center—which are recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report—Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the nation’s first hospital, founded in 1751. Additional facilities and enterprises include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is powered by a talented and dedicated workforce of more than 47,000 people. The organization also has alliances with top community health systems across both Southeastern Pennsylvania and Southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2021, Penn Medicine provided more than $619 million to benefit our community.

END



ELSE PRESS RELEASES FROM THIS DATE:

Uncovering the ritual past of an ancient stone monument in Saudi Arabia

Uncovering the ritual past of an ancient stone monument in Saudi Arabia
2023-03-15
A comprehensive analysis of an archaeological site in Saudi Arabia sheds new light on mustatils—stone monuments from the Late Neolithic period thought to have been used for ritual purposes. Melissa Kennedy of the University of Western Australia, Perth, and colleagues, in conjunction with The Royal Commission for AlUla present these findings in the open-access journal PLOS ONE on March 15, 2023. Built around 7,000 years ago, mustatils are rectangular, low-walled, stone structures that range from 20 to 600 meters in length. Researchers first discovered them in the 1970s, and more than 1,600 mustatils have now been discovered, primarily concentrated in northern ...

The WWII shipwreck of the SS Thistlegorm, now a popular Red Sea dive site, has formed an artificial coral reef for a diverse community of fish, according to data gathered by volunteer divers

The WWII shipwreck of the SS Thistlegorm, now a popular Red Sea dive site, has formed an artificial coral reef for a diverse community of fish, according to data gathered by volunteer divers
2023-03-15
Article URL:  https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282239 Article Title: Eight years of community structure monitoring through recreational citizen science at the “SS Thistlegorm” wreck (Red Sea) Author Countries: Italy Funding: STE project was funded by Project AWARE Foundation, ASTOI Association, Ministry of Tourism of the Arab Republic of Egypt, Settemari S.p.A Tour Operator, Scuba Nitrox Safety International, Viaggio nel Blu Diving Center. The funders had no role in study design, data collection ...

Analysis links specific skills taught by US undergraduate degree courses with graduate earnings

Analysis links specific skills taught by US undergraduate degree courses with graduate earnings
2023-03-15
Article URL: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0282323 Article Title: Connecting higher education to workplace activities and earnings Author Countries: USA Funding: This research is supported in part by the University of Pittsburgh Pitt Momentum Fund and the Center for Research Computing. This work has been supported (in part) by # 2109-33808 from the Russell Sage Foundation. Any opinions expressed are those of the principal investigator(s) alone and should not be construed as representing the opinions of the Foundation. The funders had no role in study design, data collection ...

Estrogen possible risk factor in disturbed heart rhythm

Estrogen possible risk factor in disturbed heart rhythm
2023-03-15
The sex hormone estrogen has a negative impact on heartbeat regulation, according to an experimental study from Linköping University, Sweden, published in Science Advances. Estrogen impact seems to interact with hereditary changes causing a heart disease disturbing the heart’s rhythm, while other endogenous substances may have a protecting effect. In a lifetime, the heart beats around 2.5 billion times. Each heartbeat is triggered by an electrical impulse that causes the heart muscle to contract in a very well-coordinated movement. ...

Radar images record potential volcanic activity on Venus

2023-03-15
Researchers have identified evidence they interpret as active volcanism on the surface of Venus, according to a new analysis of radar images from the Magellan spacecraft. The images reveal a vent that changed shape on Venus, which they believe points to ongoing volcanic activity there. Many volcanoes have been identified on the surface of Venus, but evidence of recent volcanic activity on the planet has been lacking. As a result, it was unknown whether the prominent volcanic features of Venus’ geologically young surface are a product of ongoing active volcanism ...

AJR on a decade of lung cancer screening in American newspapers

AJR on a decade of lung cancer screening in American newspapers
2023-03-15
Leesburg, VA, March 15, 2023—According to an accepted manuscript published in ARRS’ own American Journal of Roentgenology (AJR), sentiment of U.S. newspaper articles covering lung cancer screening (LCS) from 2010 to 2022 was overall positive; however, certain key elements of LCS were infrequently mentioned. “The findings highlight areas for potential improvement of LCS media coverage; radiologists have an opportunity to take a more active role in this coverage,” concluded first author Brent P. Little, MD, of Mayo Clinic Florida in Jacksonville. Little et al. searched the ProQuest U.S. Newsstream ...

Resilient bug-sized robots keep flying even after wing damage

Resilient bug-sized robots keep flying even after wing damage
2023-03-15
Bumblebees are clumsy fliers. It is estimated that a foraging bee bumps into a flower about once per second, which damages its wings over time. Yet despite having many tiny rips or holes in their wings, bumblebees can still fly. Aerial robots, on the other hand, are not so resilient. Poke holes in the robot’s wing motors or chop off part of its propellor, and odds are pretty good it will be grounded. Inspired by the hardiness of bumblebees, MIT researchers have developed repair techniques that enable a bug-sized aerial robot to sustain severe damage to the actuators, or artificial muscles, that power its wings — but to still fly effectively. They optimized these artificial muscles ...

Psychological intervention reduced stress during COVID lockdown

2023-03-15
Resilience and well-being in difficult times can be developed via online interventions in the workplace. An international team of researchers from France, the UK and Russia (with the participation of researchers from the HSE International Laboratory of Positive Psychology of Personality and Motivation) studied the effectiveness of SPARK Resilience, a programme for developing resilience, at the beginning of the COVID-19 pandemic. The results of the study were published in the PLOS One journal. By creating the SPARK Resilience programme, psychologists focused on helping people gain ...

Biotechnologies harnessing microbes might enable us to extract rare elements and minerals, chemicals and fuels from wastewater

2023-03-15
Biotechnologies harnessing microbes might enable us to extract rare elements and minerals, chemicals and fuels from wastewater. #### Article URL: https://journals.plos.org/water/article?id=10.1371/journal.pwat.0000105 Article Title: Environmental biotechnologies can make water pollutants part of the path to mitigating climate change Author Countries: USA Funding: The author received no specific funding for this work.   END ...

Vitamin A may reduce pancreatitis risk during ALL treatment

Vitamin A may reduce pancreatitis risk during ALL treatment
2023-03-15
Consuming a diet rich in vitamin A or its analogs may help prevent children and young adults with acute lymphoblastic leukemia (ALL) reduce their risk of developing painful pancreas inflammation during chemotherapy treatment. Details about this potential dietary solution to prevent a potentially life-threatening adverse event were published March 15, 2023, in Science Translational Medicine. The research team was led by Sohail Husain, MD, chief of Pediatric Gastroenterology, Hepatology, and Nutrition at Stanford University and Anil Goud Jegga, DVM, MRes, a computational ...

LAST 30 PRESS RELEASES:

Quantum computing will radically alter the application of copyright law, study says

Ochsner Health & Wellness Day in New Orleans East set for March 9

Protecting joints from bacteria with mussels

Researchers investigate immune response of a man who received 217 Covid vaccinations

Proceed with caution – the meteoric rise of zero-alcohol drinks

USC collaborates with startup supporter Techstars to encourage intellectual property development

Who military service members see as credible to discuss secure firearm storage for suicide prevention

Low birthweight coupled with overweight in 20s linked with ‘massive risk’ of early type 2 diabetes in men

DNA aptamer drug sensors can instantly detect cocaine, heroin and fentanyl – even when combined with other drugs

New project will use next-gen at-home rapid test to track COVID-19, RSV, and flu

SRI relaunches the PARC Forum event series as it celebrates the first anniversary of acquiring the storied Palo Alto Research Center

An inside look at Beech tree disease

New AI model draws treasure maps to diagnose disease

Breastfeeding after COVID-19 booster can give babies antibodies

Researchers closing in on genetic treatments for hereditary lung disease, vision loss

COVID-19 associated with increased risk for autoimmune inflammatory rheumatic diseases up to a year after infection

UC Irvine receives $15 million NSF grant for integrative movement research

University of Houston engineer Metin Akay featured in study highlighting 50 scientists' contributions to biomedical engineering advancements

JWST captures the end of planet formation

Good news—MS drugs taken while breastfeeding may not affect child development

Programs intended to reduce health insurance premiums may make coverage less affordable for the middle class

PrEP discontinuation in a US national cohort of sexual and gender minority populations, 2017–22

USC Study: Medicare Part D plans increased restrictions on drug coverage

Sacituzumab govitecan plus platinum-based chemotherapy in breast, bladder, and lung carcinomas

Global study unveils "problematic" use of porn

Newly discovered protein prevents DNA triplication

Less ice in the arctic ocean has complex effects on marine ecosystems and ocean productivity

Antarctica’s coasts are becoming less icy

New research shows migrating animals learn by experience

Modeling the origins of life: New evidence for an “RNA World”

[Press-News.org] Study offers a potential strategy to improve T cell therapy in solid tumors
Simultaneous knockout of two inflammatory regulators boosted T cell expansion in models