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Risk of secondary cancers after CAR-T cell therapy low, according to large study

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Risk of secondary cancers after CAR-T cell therapy low, according to large study


A large study by researchers at Stanford Medicine has found that the risk of secondary blood cancers after CAR-T cell therapy — a cell-based cancer treatment that exploded on the scene in 2017 as a treatment for intractable blood cancers — is low, despite a Food and Drug Administration warning.

In November 2023, the FDA issued a warning about a risk of secondary cancers — particularly blood cancers — that may be associated with CAR-T cell therapy. The warning was preceded by a rising tide of concern following reports of patients diagnosed with T cell cancers unrelated to the cancer for which they had been treated.

However, the study of over 700 patients treated at Stanford Health Care indicated that the risk is low — around 6.5% in the three years after therapy. In the only case of fatal secondary T-cell cancer, researchers found it was likely due to the immunosuppression caused by CAR-T cell therapy, rather than the CAR-T cells. The compromised immune system allowed pre-existing, but not previously detected, cancer cells to grow explosively in the patient.

“We wanted to understand this one rare case, so we analyzed all the patients treated with CAR-T cell therapy at Stanford with wide breadth and studied this single case extraordinary depth,” said professor of medicine Ash Alizadeh, MD, PhD. “We compared protein levels, RNA sequences and DNA from single cells across multiple tissues and time points to determine that the therapy didn’t introduce the lymphoma into this patient; instead it was already brewing in their body at very low levels.”

The study’s conclusions may alleviate some concerns sparked by the FDA’s “black box”warning — a prominent box on medication labels that warns of risky side effects. More importantly, however, it may help researchers and clinicians identify prospective CAR-T cell therapy recipients who are at increased risk of secondary cancers. Although these patients are unlikely to forgo potentially lifesaving treatment to avoid a small risk of future cancer, they could be monitored more closely after receiving the therapy or screened thoroughly for other cancers before initiating CAR-T cell treatment.

Alizadeh, who is the Moghadam Family Professor and the leader of the Cancer Genomics Program at the Stanford Cancer Institute, and David Miklos, MD, PhD, professor of medicine and chief of bone marrow transplantation and cellular therapy, are the senior authors of the study, which will be published on June 13 in The New England Journal of Medicine. Postdoctoral scholars Mark Hamilton, MD, PhD; Takeshi Sugio, MD, PhD; and Troy Noordenbos, MD, PhD are the lead authors of the research.

The problem with cancer treatments

The idea of a cancer treatment causing other cancers is not new. The chemotherapy and radiation treatments that are standard for many types of cancers can cause genetic mutations in previously healthy cells that cause them to ignore the biological guardrails meant to keep cell division in check.

In CAR-T cell therapy, immune cells called T cells are isolated from a patient and genetically engineered to more efficiently seek out and kill cancer cells. To do so, researchers introduce a custom-made gene into the T cells’ DNA. This gene encodes instructions for a protein called a chimeric antigen receptor that recognizes and binds to cancer cells; when the protein is made by the T cells and affixed to their surfaces, they become efficient cancer-killing machines.

When researchers were designing the therapy, they used genetic engineering strategies to ensure that the inserted gene would generally not disrupt normal cellular functions. But if the gene for the new protein is mis-inserted in the genome it could inactivate or modify genes involved in key cellular pathways such as those that control cell growth. If this happens, the T cells that are meant to be curative may instead become cancerous.

After the FDA announced in November it was investigating the risk of secondary cancers, Miklos and his colleagues realized Stanford Medicine’s large biobank of tissue and blood samples from people receiving CAR-T cell therapy could hold vital answers, both about the relative risk and whether these cancers arose from the manipulated T cells. They partnered with researchers in Alizadeh’s laboratory to conduct an in-depth look at the DNA sequences, the RNA messages (which give a glimpse into the proteins a cell is making) and the proteins in the samples.

The researchers analyzed the outcomes for 724 people treated with CAR-T cell therapy at Stanford Health Care between 2016 and 2024. Among those people, the incidence of secondary blood cancers approached 6.5% over a median of three years of follow-up, which is roughly similar to patients who underwent stem cell transplantation rather than CAR-T cell therapy to treat their cancers. Only one person rapidly developed and died from a T cell cancer called a T cell lymphoma shortly after CAR-T cell therapy.

The researchers used molecular, cellular and genetic analyses — including several novel genetic profiling techniques developed in Alizadeh’s laboratory — to compare all 724 patients’ tumors, their CAR-T cells and their healthy cells at multiple time points before and after CAR-T cell treatment.

“This was a tour de force effort from the study’s first authors, working feverishly as a team from just before Thanksgiving through Christmas,” Alizadeh said.

The analysis found no evidence that the T cells responsible for the patient’s second cancer were the T cells engineered for the CAR-T cell therapy — they were molecularly and genetically distinct. However, both sets of T cells were infected with a virus known to play a role in cancer development. Furthermore, the patient had a history of autoimmune disease in the years prior to their first cancer diagnosis.

The study’s findings suggest that secondary cancers arising after CAR-T cell therapy may be due to baseline immunosuppression or the side effects of the treatment, rather than the mis-insertion of the gene for the chimeric antigen receptor during the genetic engineering of the T cells.

“These results may help researchers focus on the immune suppression that can precede and often follows CAR-T cell therapy,” Miklos said. “Understanding how it contributes to cancer risk is particularly important as the CAR-T cell field pivots from treating high-risk, refractory blood cancers to lower risk, but clinically important, disorders including autoimmune diseases.”

“This study could serve as a blueprint for how to capture and characterize the outcomes of CAR-T therapies so we can develop a very clear understanding of their risks and benefits,” Alizadeh said. “These are lifesaving therapies that come with a very low risk of secondary cancers. The challenge lies in how to predict which patients are at higher risk, and why.”

The study was funded by the National Institutes of Health (grants R01CA233975, NCI P01 CA049605), the Leukemia and Lymphoma Society, the Lymph&Co Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, Kite-Gilead, and Adaptive Biotechnologies.



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Early dark energy could resolve cosmology’s two biggest puzzles

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Risk of secondary cancers after CAR-T cell therapy low, according to large study


A new study by MIT physicists proposes that a mysterious force known as early dark energy could solve two of the biggest puzzles in cosmology and fill in some major gaps in our understanding of how the early universe evolved.

One puzzle in question is the “Hubble tension,” which refers to a mismatch in measurements of how fast the universe is expanding. The other involves observations of numerous early, bright galaxies that existed at a time when the early universe should have been much less populated.

Now, the MIT team has found that both puzzles could be resolved if the early universe had one extra, fleeting ingredient: early dark energy. Dark energy is an unknown form of energy that physicists suspect is driving the expansion of the universe today. Early dark energy is a similar, hypothetical phenomenon that may have made only a brief appearance, influencing the expansion of the universe in its first moments before disappearing entirely.

Some physicists have suspected that early dark energy could be the key to solving the Hubble tension, as the mysterious force could accelerate the early expansion of the universe by an amount that would resolve the measurement mismatch.

The MIT researchers have now found that early dark energy could also explain the baffling number of bright galaxies that astronomers have observed in the early universe. In their new study, reported in the Monthly Notices of the Royal Astronomical Society, the team modeled the formation of galaxies in the universe’s first few hundred million years. When they incorporated a dark energy component only in that earliest sliver of time, they found the number of galaxies that arose from the primordial environment bloomed to fit astronomers’ observations.

You have these two looming open-ended puzzles,” says study co-author Rohan Naidu, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research. “We find that in fact, early dark energy is a very elegant and sparse solution to two of the most pressing problems in cosmology.”

The study’s co-authors include lead author and Kavli postdoc Xuejian (Jacob) Shen, and MIT professor of physics Mark Vogelsberger, along with Michael Boylan-Kolchin at the University of Texas at Austin, and Sandro Tacchella at the University of Cambridge.

Big city lights

Based on standard cosmological and galaxy formation models, the universe should have taken its time spinning up the first galaxies. It would have taken billions of years for primordial gas to coalesce into galaxies as large and bright as the Milky Way.

But in 2023, NASA’s James Webb Space Telescope (JWST) made a startling observation. With an ability to peer farther back in time than any observatory to date, the telescope uncovered a surprising number of bright galaxies as large as the modern Milky Way within the first 500 million years, when the universe was just 3 percent of its current age.

“The bright galaxies that JWST saw would be like seeing a clustering of lights around big cities, whereas theory predicts something like the light around more rural settings like Yellowstone National Park,” Shen says. “And we don’t expect that clustering of light so early on.”

For physicists, the observations imply that there is either something fundamentally wrong with the physics underlying the models or a missing ingredient in the early universe that scientists have not accounted for. The MIT team explored the possibility of the latter, and whether the missing ingredient might be early dark energy.

Physicists have proposed that early dark energy is a sort of antigravitational force that is turned on only at very early times. This force would counteract gravity’s inward pull and accelerate the early expansion of the universe, in a way that would resolve the mismatch in measurements. Early dark energy, therefore, is considered the most likely solution to the Hubble tension.

Galaxy skeleton

The MIT team explored whether early dark energy could also be the key to explaining the unexpected population of large, bright galaxies detected by JWST. In their new study, the physicists considered how early dark energy might affect the early structure of the universe that gave rise to the first galaxies. They focused on the formation of dark matter halos — regions of space where gravity happens to be stronger, and where matter begins to accumulate.

“We believe that dark matter halos are the invisible skeleton of the universe,” Shen explains. “Dark matter structures form first, and then galaxies form within these structures. So, we expect the number of bright galaxies should be proportional to the number of big dark matter halos.”

The team developed an empirical framework for early galaxy formation, which predicts the number, luminosity, and size of galaxies that should form in the early universe, given some measures of “cosmological parameters.” Cosmological parameters are the basic ingredients, or mathematical terms, that describe the evolution of the universe.

Physicists have determined that there are at least six main cosmological parameters, one of which is the Hubble constant — a term that describes the universe’s rate of expansion. Other parameters describe density fluctuations in the primordial soup, immediately after the Big Bang, from which dark matter halos eventually form.

The MIT team reasoned that if early dark energy affects the universe’s early expansion rate, in a way that resolves the Hubble tension, then it could affect the balance of the other cosmological parameters, in a way that might increase the number of bright galaxies that appear at early times. To test their theory, they incorporated a model of early dark energy (the same one that happens to resolve the Hubble tension) into an empirical galaxy formation framework to see how the earliest dark matter structures evolve and give rise to the first galaxies.

“What we show is, the skeletal structure of the early universe is altered in a subtle way where the amplitude of fluctuations goes up, and you get bigger halos, and brighter galaxies that are in place at earlier times, more so than in our more vanilla models,” Naidu says. “It means things were more abundant, and more clustered in the early universe.”

“A priori, I would not have expected the abundance of JWST’s early bright galaxies to have anything to do with early dark energy, but their observation that EDE pushes cosmological parameters in a direction that boosts the early-galaxy abundance is interesting,” says Marc Kamionkowski, professor of theoretical physics at Johns Hopkins University, who was not involved with the study. “I think more work will need to be done to establish a link between early galaxies and EDE, but regardless of how things turn out, it’s a clever — and hopefully ultimately fruitful — thing to try.”

We demonstrated the potential of early dark energy as a unified solution to the two major issues faced by cosmology. This might be an evidence for its existence if the observational findings of JWST get further consolidated,” Vogelsberger concludes. “In the future, we can incorporate this into large cosmological simulations to see what detailed predictions we get.”

This research was supported, in part, by NASA and the National Science Foundation.



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Plant-derived secondary organic aerosols can act as mediators of plant-plant interactions

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Risk of secondary cancers after CAR-T cell therapy low, according to large study


A new study published in Science reveals that plant-derived secondary organic aerosols (SOAs) can act as mediators of plant-plant interactions. This research was conducted through the cooperation of chemical ecologists, plant ecophysiologists and atmospheric physicists at the University of Eastern Finland.

It is well known that plants release volatile organic compounds (VOCs) into the atmosphere when damaged by herbivores. These VOCs play a crucial role in plant-plant interactions, whereby undamaged plants may detect warning signals from their damaged neighbours and prepare their defences. “Reactive plant VOCs undergo oxidative chemical reactions, resulting in the formation of secondary organic aerosols (SOAs). We wondered whether the ecological functions mediated by VOCs persist after they are oxidated to form SOAs,” said Dr. Hao Yu, formerly a PhD student at UEF, but now at the University of Bern.

The study showed that Scots pine seedlings, when damaged by large pine weevils, release VOCs that activate defences in nearby plants of the same species. Interestingly, the biological activity persisted after VOCs were oxidized to form SOAs. The results indicated that the elemental composition and quantity of SOAs likely determines their biological functions.

“A key novelty of the study is the finding that plants adopt subtly different defence strategies when receiving signals as VOCs or as SOAs, yet they exhibit similar degrees of resistance to herbivore feeding,” said Professor James Blande, head of the Environmental Ecology Research Group. This observation opens up the possibility that plants have sophisticated sensing systems that enable them to tailor their defences to information derived from different types of chemical cue.

“Considering the formation rate of SOAs from their precursor VOCs, their longer lifetime compared to VOCs, and the atmospheric air mass transport, we expect that the ecologically effective distance for interactions mediated by SOAs is longer than that for plant interactions mediated by VOCs,” said Professor Annele Virtanen, head of the Aerosol Physics Research Group. This could be interpreted as plants being able to detect cues representing close versus distant threats from herbivores.

The study is expected to open up a whole new complex research area to environmental ecologists and their collaborators, which could lead to new insights on the chemical cues structuring interactions between plants.



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Folded or cut, this lithium-sulfur battery keeps going

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Most rechargeable batteries that power portable devices, such as toys, handheld vacuums and e-bikes, use lithium-ion technology. But these batteries can have short lifetimes and may catch fire when damaged. To address stability and safety issues, researchers reporting in ACS Energy Letters have designed a lithium-sulfur (Li-S) battery that features an improved iron sulfide cathode. One prototype remains highly stable over 300 charge-discharge cycles, and another provides power even after being folded or cut.

Sulfur has been suggested as a material for lithium-ion batteries because of its low cost and potential to hold more energy than lithium-metal oxides and other materials used in traditional ion-based versions. To make Li-S batteries stable at high temperatures, researchers have previously proposed using a carbonate-based electrolyte to separate the two electrodes (an iron sulfide cathode and a lithium metal-containing anode). However, as the sulfide in the cathode dissolves into the electrolyte, it forms an impenetrable precipitate, causing the cell to quickly lose capacity. Liping Wang and colleagues wondered if they could add a layer between the cathode and electrolyte to reduce this corrosion without reducing functionality and rechargeability.

The team coated iron sulfide cathodes in different polymers and found in initial electrochemical performance tests that polyacrylic acid (PAA) performed best, retaining the electrode’s discharge capacity after 300 charge-discharge cycles. Next, the researchers incorporated a PAA-coated iron sulfide cathode into a prototype battery design, which also included a carbonate-based electrolyte, a lithium metal foil as an ion source, and a graphite-based anode. They produced and then tested both pouch cell and coin cell battery prototypes.

After more than 100 charge-discharge cycles, Wang and colleagues observed no substantial capacity decay in the pouch cell. Additional experiments showed that the pouch cell still worked after being folded and cut in half. The coin cell retained 72% of its capacity after 300 charge-discharge cycles. They next applied the polymer coating to cathodes made from other metals, creating lithium-molybdenum and lithium-vanadium batteries. These cells also had stable capacity over 300 charge-discharge cycles. Overall, the results indicate that coated cathodes could produce not only safer Li-S batteries with long lifespans, but also efficient batteries with other metal sulfides, according to Wang’s team.

The authors acknowledge funding from the National Natural Science Foundation of China; the Natural Science Foundation of Sichuan, China; and the Beijing National Laboratory for Condensed Matter Physics.



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