CAR T Design Targets Mesothelin’s “Stump”
A mesothelin-targeting CAR T cell designed to avoid the effects of shed antigen has shown activity in preclinical models of ovarian and pancreatic cancer.
The CAR, known as CAR 422, targets a short juxtamembrane “stump” of mesothelin that remains on the tumor-cell surface after most of the protein is cleaved and shed. Conventional mesothelin-directed CAR T cells often target membrane-distal regions that can be lost through shedding, while soluble mesothelin in the tumor microenvironment may act as a decoy and limit tumor engagement.
Researchers at the University of Pennsylvania used a canine antibody phage display library to identify stump-binding single-chain variable fragments, then screened candidate CAR T cells in vitro and in mouse models. CAR 422 emerged as the lead construct.
In an ovarian cancer peritoneal model designed to reflect high levels of shed mesothelin, CAR 422 controlled tumor growth and supported long-term survival, including after tumor rechallenge. The construct also showed activity in a pancreatic cancer model and retained specificity for human mesothelin in membrane proteome array testing. Source
Engineered Tregs Suppress Allergic Asthma in Mice
Engineered regulatory T cells reduced allergic asthma symptoms in mice, suggesting a possible cell therapy approach for severe allergies.
The study tested chimeric allergen receptor Tregs, or CAlleR Tregs, designed to recognize Bet v 1, the major allergen in birch pollen. Unlike conventional CAR T cells, which are typically built to attack cancer cells, these cells were engineered to suppress allergen-specific immune responses.
Researchers led by Yannick D. Muller at Lausanne University Hospital and the University of Lausanne generated the receptors using antibodies isolated from a birch-allergic donor. In mouse models of birch pollen–induced allergic airway inflammation, the cells reduced eosinophilic inflammation, mucus production, and airway hyperresponsiveness. When given before allergen exposure, they also helped prevent asthma-like symptoms from developing.
“Our study provides proof-of-concept and preclinical evidence that CAlleR Tregs redirected against a birch pollen allergen can downmodulate birch pollen–induced allergic asthma,” Muller said. Source
Radiopharmaceutical Boosts CAR T in Neuroblastoma Models
A targeted radiopharmaceutical improved the activity of CAR T cell therapy in preclinical models of neuroblastoma, according to a study.
Researchers at the University of Pittsburgh, UPMC Hillman Cancer Center, and the National Cancer Institute combined CAR T cells with [67Cu]Cu-LLP2A, a radiopharmaceutical that targets VLA-4 and delivers localized radiation to tumors and surrounding immune cells.
In mouse models of high-risk relapsed neuroblastoma, the combination produced greater tumor regression than either treatment alone. In radiation-sensitive tumors, the radiopharmaceutical directly damaged cancer cells and appeared to prime them for CAR T attack. In radiation-resistant tumors, it reshaped the tumor microenvironment, reducing suppressive macrophages and supporting cytotoxic CAR T cell niches. Source
Gene Therapy Shows Durable Effect in MMA Mouse Model
A single dose of a liver-directed lentiviral gene therapy produced durable therapeutic effects in mouse models of methylmalonic acidemia, according to preclinical data.
The therapy uses an immune-shielded lentiviral vector to deliver the MMUT gene to the liver. MMA is a rare inherited metabolic disorder most often caused by mutations affecting methylmalonyl-CoA mutase, leading to methylmalonic acid accumulation and damage to the brain, liver, kidneys, and other organs.
In the study, systemic administration of the vector led to sustained improvement in disease features over the average lifespan of laboratory mice. An optimized MMUT transgene improved efficacy, with dose-dependent effects on metabolomic biomarkers and gene transfer efficiency exceeding 80 percent of the liver.
Genespire is progressing its lead MMA candidate, GENE202, toward the clinic. Source
Gene Therapy Platform Targets Human Glia Across the Brain
Researchers have developed a gene therapy platform designed to deliver therapeutic genes broadly through the brain while preferentially targeting human glial cells.
The study pairs engineered AAV5 capsids with a delivery strategy that uses the brain’s glymphatic transport system. The approach is intended to address two barriers in neurological gene therapy: crossing or bypassing the blood-brain barrier and limiting unwanted exposure in peripheral organs.
Researchers at the University of Rochester Medical Center screened modified AAV5 vectors in mice engrafted with human glial progenitor cells, identifying variants with a preference for human glial cells and their descendants, including astrocytes and oligodendrocytes. The vectors were then delivered into the cisterna magna, with hypertonic treatment used to enhance spread through glymphatic pathways.
“Gene delivery to the brain has always faced two major obstacles,” said Steve Goldman, co-director of the University of Rochester Medicine Center for Translational Neuromedicine. “You need a way to get therapies into the brain selectively and efficiently, and you need vectors that can deliver those therapies to the right cells once they get there.” Source
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