CAR-T Cell Therapies for Diffuse Midline Glioma: A Summary PDF

News in focus The trials were designed to test the therapy’s he has graduated from secondary school and solely where they are needed, making them safety rather than its effectiveness, and larger is now thriving at university. “All those normal less likely to become dysfunctional...

News in focus The trials were designed to test the therapy’s he has graduated from secondary school and solely where they are needed, making them safety rather than its effectiveness, and larger is now thriving at university. “All those normal less likely to become dysfunctional from trials are needed to know for sure whether the things mean so much more in this context,” “exhaustion”, a phenomenon known to limit treatments are beneficial. In the meantime, says Mahdi. “This reality wouldn’t have been the effectiveness of T-cell therapies, says researchers are eager to find ways to tweak his otherwise.” Hideho Okada, who studies immunotherapies their approach to maximize its reach. “We’re and is a lead investigator on the project. The seeing a glimpse of a signal” that the approach A menu of choices team treated its first clinical-trial participant — could work, says Jasia Mahdi, a paediatric The researchers are eager to find ways to an adult with an aggressive brain cancer called neurologist at Texas Children’s Hospital in extend these dramatic responses to more of glioblastoma — in June and plans to launch a Houston. “Our task now is to figure out how their study participants. Vitanza’s team has similar study in children next. we expand on that.” launched another trial that will test CAR T Such modifications to CAR-T-cell therapies cells that target four molecules found mainly are only the beginning, says Vitanza. Research- Tumour-finding T cells on brain and spinal tumours, in hopes that T ers are hunting for more ways to supercharge CAR-T-cell therapies consist of immune cells cells that recognize multiple targets will be CAR-T-cell therapies, and decades from now, called T cells that have been removed from more effective. physicians might be able to pick and choose the recipient and engineered to produce Another team at the University of Califor- from a variety of options that can be tailored molecules dubbed chimeric antigen recep- nia, San Francisco, is testing CAR T cells that for individual patients. “It’s so incredible that tors (CAR) on their surfaces. These T cells are express the cancer-seeking receptor only we’ve gotten to this point,” he says. “But in readministered into the body, where their when the cells are in the central nervous sys- 20 years, the CAR T cells we use for patients new receptors enable them to recognize and tem. The hope is that the T cells will be active will look very different from now.” destroy cancer cells. Despite lingering safety concerns, the approach has shown success in treating sev- MICE LIVE LONGER eral blood cancers and, in some cases, has produced remissions lasting more than a WHEN INFLAMMATION decade. But using CAR-T-cell treatments to treat solid tumours such as those of the brain and lung is more challenging. Solid tumours can contain various cells with different muta- tions and varying sensitivities to the therapy. Solid tumours can also be more difficult for the PROTEIN IS BLOCKED T cells to penetrate. Humans also have the protein, called IL-11, offering Even so, studies in mice have suggested that CAR T cells might work against diffuse midline hope for future longevity treatments. gliomas. New therapies for the cancer are By Heidi Ledford A desperately needed: the standard treatment “There’s a real opportunity here to translate is radiation occasionally paired with chemo- this into clinical therapies,” says Cathy Slack, therapy, but the cancer is fatal and median protein that promotes inflammation who studies the biology of ageing at the Uni- survival is about 13 months after diagnosis, could hold the key to a longer, health- versity of Warwick, UK. “And that’s where the says Vitanza. ier life. Blocking the protein, called field is kind of stuck at the moment.” IL-11, in middle-aged mice boosted Researchers have long known that chronic Success: a diploma metabolism, reduced frailty and inflammation contributes to diseases asso- Now, the first CAR-T therapy clinical trials increased lifespan by about 25%. ciated with ageing. As the body grows older against diffuse midline gliomas in children Although a research team tested for these and accumulates damaged proteins and have finished, and the results are promising. health effects only in mice, IL-11 and its other molecules, the immune system often At the meeting in Philadelphia, Vitanza pre- molecular partners — which include chemi- sees these as signs of a possible infection, sented data from a trial in which 21 children cal messengers for the immune system called says Stuart Cook, a medical researcher who with diffuse midline glioma were treated with interleukins — also exist in humans. And CAR T cells that target a protein called B7-H3, drug candidates that block IL-11 are already “There’s a real which is found predominantly on cancer cells. in human trials against cancer and fibrosis, Only one of those participants experienced a condition associated with ageing in which opportunity here to a severe reaction to the treatment itself, scar tissue replaces healthy tissue. translate this into and some have lived longer than expected, clinical therapies.” Vitanza says. Longevity effect Mahdi presented data from a clinical trial The results, reported on 17 July in Nature, sug- of a T-cell therapy that targets a molecule gest that those potential treatments might studies IL-11 at Duke–National University of called GD2. In that trial, conducted at Stanford also have an impact on longevity (A. A. Widjaja Singapore Medical School. This can trigger University in California, nine people with dif- et al. Nature https://doi.org/gt4rpk; 2024), inflammatory responses that might cause fuse midline glioma received treatment, and but separate clinical trials are needed to be further damage and contribute to diseases tumours shrank by more than half in four of certain. such as cancer and autoimmune disorders. them. Still, IL-11’s clear path to testing in humans IL-11’s role in promoting inflammation has That trial also had an outlier: a young man distinguishes it from the crowd of other pro- also long been clear (S. A. Cook and S. Schafer whose cancer disappeared entirely and who teins and rejuvenation interventions, many Annu. Rev. Med. 71, 263–276; 2020). But the has remained cancer-free for the more than 30 of which have shown promise in animal mod- link between the protein and ageing was dis- months since his first treatment. In that time, els but stalled on the way to clinical trials. covered by accident when Cook’s colleague, 716 | Nature | Vol 631 | 25 July 2024  molecular biologist Anissa Widjaja, also at Duke–National University of Singapore Medi- cal School, was testing a method for detecting IL-11. She happened to include in her assay a sample of proteins taken from an old rat, and the test revealed that IL-11 levels were much higher in that sample than in those from younger rats. The result led the team, which had not pre- viously focused on longevity, to head in a new direction. The researchers tested a variety of samples from young and old mice and found that IL-11 was consistently more abundant in older mouse tissues, including skeletal mus- cle, fat and liver tissue. When they deleted the gene that codes for the IL-11 protein in some mice, the animals had improved healthspans — they were healthy for longer — and lived 25% longer than did mice with normal levels of IL-11. Next steps The team obtained similar results when, NIAID/NATIONAL INSTITUTES OF HEALTH/SPL for 25 weeks, they used an antibody against IL-11 to block the protein in mice that were 75 weeks old — roughly the equivalent of 55 years for a person. Similar antibodies are being tested in human trials against cancer and fibrosis. The magnitude of the response resem- bles that seen in some studies when mice are treated with rapamycin, a prominent drug in the anti-ageing field that is being A cell (red) infected with SARS-CoV-2 virus particles (blue). tested for its benefits. But rapamycin has LONG COVID LUNG been linked to unwanted side effects, says Cook, who co-founded a Singapore-based DAMAGE LINKED TO company called Enleofen that is developing drugs against fibrosis. “Rapamycin is good for IMMUNE RESPONSE lifespan, but not healthspan,” he says. The results are striking and should prompt further studies, says Dan Winer, who studies the role of the immune system in ageing at the Buck Institute for Research on Aging in Inhibiting a protein that drives chronic inflammation Novato, California. One important next step would be to test candidate IL-11 drugs in mice improves lung health in mice with COVID-19. with diverse genetic backgrounds and in mul- By Helena Kudiabor A tiple laboratories to be sure that the results after infection”, says study co-author Jie Sun, are reproducible, he says. an immunology researcher at the University signalling molecule that helps to of Virginia in Charlottesville. “In the future, we Drug candidates kick-start inflammation in the lungs could target this pathway for potential treat- Beyond that, determining the effect of could play a key part in aggravating ment of long COVID.” anti-IL-11 drug candidates on longevity in some long COVID symptoms, finds people could be a challenge. A clinical trial a study that analysed lung samples Inflammation protein examining the impacts on lifespan would be from people with the condition. IFN-γ is one of many proteins that the body long and expensive, and the results could be The findings, published in Science Trans- releases to fight infections. When released difficult to interpret because many confound- lational Medicine on 17 July1, could help sci- by white blood cells known as T cells, it sends ing factors can affect longevity. entists to develop more effective treatments signals to other immune cells and promotes Instead, Cook says, researchers might do for long COVID, which causes symptoms such inflammation. In the short term, this increases well to focus on a specific condition associ- as brain fog, fatigue, breathlessness and lung blood flow to the infected area to support the ated with ageing, such as loss of muscle mass, damage and can persist for months or years healing process — but chronic inflammation that would provide quicker results and a more after infection with SARS-CoV-2, the virus can cause damage to cells and tissues. specific outcome. behind COVID-19. Previous research has shown that people “Ageing is a tough field,” he adds. “But there By inhibiting the molecule — called interferon with long COVID have elevated levels of IFN-γ are a lot of therapeutic angles, and a lot more gamma (IFN-γ) — in mice with COVID-19, “we (ref. 2), and evidence also suggests that the biology left to understand.” were able to dampen the chronic conditions protein can contribute to injuries in the alveoli3 Nature | Vol 631 | 25 July 2024 | 717