Affecting an estimated 100,000 people globally, cystic fibrosis (CF) cases stem from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. In the past several decades, scientists have successfully engineered various small-molecule therapies that lessen the severity of the disease. However there are still treatment challenges. Now, data from a new study in a cell model demonstrates that a gene therapy can successfully repair an “untreatable” mutation associated with a particularly severe form of the disease. Details of the potential therapy are published in a new Science Translational Medicine paper titled “Functional correction of the untreatable CFTR 1717-IG>A mutation through mRNA- and sgRNA-optimized base editing.”
Many current therapies benefit patients with the most common disease-associated mutation, F508del. However they often have little effect on patients who harbor other types of mutations. For example, some patients have a mutation named 1717-1G>A, which is relatively common but doesn’t have any approved therapies due to being a splicing mutation that results in little to no protein production. In fact, “about 10% of people with CF do not qualify for any of the available CFTR modulator therapies, particularly those people with severe splicing mutations that result in frameshifts and the formation of premature termination codons.”
The 1717-1G>A mutation is the target of the therapy described in the paper, which was written by scientists from the University of Trento and their collaborators elsewhere. Specifically, the team developed an “adenine base editing strategy to efficiently correct the 1717-1G>A mutation,” they wrote in Science Translational Medicine. “By harnessing the SpRY- ABE9 system, which we delivered as optimized RNAs for both the base editor and single guide RNA (sgRNA), we achieved functional correction in patient-derived models.”
Furthermore, the scientists note that they opted to use base editing rather than strategies like base editing because it has the advantage of “typically higher nucleotide modification efficiencies and a streamlined system requiring only the editor and an sgRNA” and because it has been used in other CF studies.
Using their ABE9 base editor and modified CRISPR-Cas9 tool, the scientists report successfully editing up to 30% of target DNA in human embryonic kidney cell lines and patient-derived airway epithelial cells with minimal off-target effects. It also corrected the mutation in intestinal organoids derived from CF patients as evidenced by restored CFTR activity.
Additional studies are needed, especially in animals, to fully assess the effectiveness of potential therapy but early results are promising. Overall, the approach achieved an editing efficiency of 13%. Prior studies showed that 10% efficiency may be enough for functional recovery. The results suggest that the therapy could benefit the subset of patients whose disease is caused by 1717-1G>A.
A study in 3,000 Punjabi Sikhs has identified previously unreported molecular pathways that contribute to cardiometabolic disease. Published today in PLOS Medicine, these findings highlight the benefits of including diverse participants in these types of studies, which have historically centered on individuals of European ancestry.
“Genetic mechanisms that predispose people to type 2 diabetes and cardiovascular disease remain poorly understood, partly because of a lack of sufficient data on non-European ethnic groups,” write the authors of the study, who were led by Dharambir K. Sanghera, PhD, director of the Genetic Epidemiology Laboratory at the University of Oklahoma Health Sciences Center. “Extending these evaluations to diverse cohorts is essential for gaining insights into the molecular pathways involved in disease.”
Sanghera and colleagues conducted a metabolite genome-wide association study to look for links between the human lipidome and cardiometabolic disorders in a Punjabi population originating from Northern India. Epidemiological studies have repeatedly shown that South Asians living abroad experience a higher incidence of type 2 diabetes and are more susceptible to cardiovascular disease compared to other ethnic groups. However, the exact mechanism responsible for this increased risk remains unknown and lipidomic and genome-wide data is lacking for Indian populations.
“Genome-wide studies have shown that genes influencing blood lipid metabolites are often linked to different diseases,” write the study authors. “However, most of this research has been done on people of European ancestry. Studying more diverse populations is important to better understand how these genetic pathways contribute to disease in different ethnic groups.”
The study looked at genetic influences on 516 lipids in 3,000 Punjabi Sikh individuals and then validated the results in larger cohorts, with both European and non-European ancestry, using data from UK Biobank, GeneRISK, DIAMANT, PROMIS, and other studies. After multiple rounds of testing and correction, results showed strong associations in 36 pairs of lipid metabolites and single nucleotide polymorphisms (SNPs). Among them, 33 had not been reported before, and three were confirmed to be ancestry-specific.
Further investigation identified a causal association between type 2 diabetes and the metabolite LPC O-16:0, which was paired with a genetic variant in the gene encoding for CD45, a key regulator of immune signaling. Another possible causal relationship was found with PC 38:4, a metabolite shown to protect against coronary artery disease in Indian populations that was paired with a genetic variant in an untranslated region of the FADS1/2 genes.
“Our study has discovered new metabolite markers and genes that intersect with pathways of inflammation and immuno-vascular diseases, which have not been reported in previous European studies, specifically emphasizing how immune system signaling affects metabolic health,” state the authors. “By identifying unique genetic signatures in Asian Indians, the research advocates for ancestry-specific medical approaches to address chronic immuno-vascular conditions in cardiometabolic disease. These advances could be beneficial in clinical practice, enabling effective personalized therapies and preventive strategies.”
A genetic analysis of a large U.S. clinical trial suggests that vitamin D supplementation may reduce the risk of progression from prediabetes to type 2 diabetes, but only for those people who harbor specific variants of the vitamin D receptor gene. The study, led by researchers at Tufts University and published in JAMA Network Open, found that daily high-dose vitamin D lowered diabetes risk by 19% in participants with certain genotypes, opening the possibility of using vitamin D as a diabetes prevention strategy.
The new findings build on data from the Vitamin D and Type 2 Diabetes (D2d) clinical trial, a multi-site randomized study that enrolled more than 2,000 U.S. adults with prediabetes. Study participants were assigned to receive either 4,000 IU of vitamin D3 daily or a placebo. The subjects were then followed for a median of 2.5 years to assess progression to diabetes. The original trial did not show a statistically significant reduction in diabetes risk across all participants.
“But the D2d results raised an important question: Could vitamin D still benefit some people?” said lead author Bess Dawson-Hughes, MD, a senior scientist at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. “Diabetes has so many serious complications that develop slowly over years. If we can delay the time period that an individual will spend living with diabetes, we can stop some of those harmful side effects or lessen their severity.”
In their follow-on research, the Tufts noted that subsequent analysis of the D2d trial data showed that outcomes varied based on achieved blood levels of vitamin D in participants. The new study also found a genetic link to those who had improved outcomes.
To explore the role genetics might play, the investigators conducted a post hoc analysis of 2,098 D2d participants who consented to genetic testing. They focused on three common polymorphisms in the vitamin D receptor (VDR) gene: ApaI, BsmI, and FokI. The researchers first examined how vitamin D levels correlated with diabetes risk across genotypes, then evaluated how genetic variants influenced response to supplementation.
The data showed that the ApaI polymorphism is a key determinant of response. Participants with the AA genotype, which was about 30% of the cohort, did not experience a reduction in diabetes risk with vitamin D supplementation. By comparison, those with the AC or CC genotypes, the remaining 70% of participants, showed a 19% lower risk of developing diabetes when treated with vitamin D compared with placebo.
The biological basis for this effect is linked to the role the VDR gene plays in pancreatic β cells, where it influences insulin secretion and glucose regulation. Variations in the receptor may alter how effectively vitamin D exerts these effects, explaining why some individuals benefit from supplementation while others do not.
Earlier research has suggested there is a connection between vitamin D and diabetes risk. In earlier analyses of the D2d trial, participants who maintained higher blood levels of vitamin D experienced substantial reductions in diabetes incidence. These findings were supported by meta-analyses and observational studies, including research from the UK Biobank, which found that genetic variation in VDR could modify its activity.
“We hypothesized that VDR gene variants modify the association between achieved intratrial 25-hydroxyvitamin D (25(OH)D) level and diabetes risk and may modify the effect of vitamin D3 supplementation on the risk of developing diabetes,” the researchers wrote. 25(OH)D is the main form of vitamin D circulating in the blood.
The current study broadens knowledge on the role vitamin D can play in diabetes prevention by identifying the specific polymorphisms at play. The overlap between ApaI and BsmI variants provides further evidence of the role of VDR genetics, although the researchers noted that ApaI alone may be sufficient to identify likely responders.
“This genetic association analysis of the D2d study suggests that genetic variation in the VDR, specifically the ApaI polymorphism, is associated with diabetes risk at higher intratrial 25(OH)D levels and is associated with response to 4000 IU/d of vitamin D3 supplementation among adults with prediabetes,” the researchers wrote.
The implications for clinical care include the potential use of genetic testing to guide preventive treatment. A single test for the ApaI polymorphism could help identify patients with prediabetes who are most likely to benefit from higher-dose vitamin D supplementation.
While the results have established a link between variations in the VDR gene and diabetes development, the research noted that the study was not designed to assess the mechanisms underlying the genetic effects. Further, its sample size limited subgroup analyses by race and ethnicity.
“Our findings suggest we may eventually be able to identify which patients with prediabetes are most likely to benefit from additional vitamin D supplementation,” Dawson-Hughes said. “In principle, this could involve a single, relatively inexpensive genetic test.”
Next steps in this line of research include replicating the findings in independent cohorts and conducting prospective trials designed to test genotype-guided supplementation strategies.
A generative AI tool for molecular design has created a new antibiotic that has shown promising preclinical results against methicillin-resistant Staphylococcus aureus (MRSA).
The SyntheMol-RL generative model, described in Molecular Systems Biology, could speed drug discovery and help in the fight against antibiotic resistance.
The algorithm uses reinforcement learning to rapidly design easily synthesizable small-molecule drug candidates from a massive chemical space of 46 billion compounds.
It created a compound that the researchers named synthecin, which was effective against MRSA wound infection in a mouse model, showing its utility for real-world drug discovery.
“We used our model to design new antibiotics, but it’s capable of so much more,” said researcher Jon Stokes, PhD, from McMaster University.
“We built it to be disease agnostic, meaning it could just as easily generate novel drug candidates for diabetes or cancer or other indications.”
The rapid spread of antibiotic resistance is a critical challenge facing modern medicine. In 2019, just under five million deaths were linked with drug-resistant bacteria and this number is expected to more than double by 2050 if the emergence of antimicrobial resistance continues to outpace the creation of new antibiotics.
Stokes and team examined whether SyntheMol-RL could identify potential antibiotics for MRSA, an infection listed by the World Health Organization as a high priority for new antibiotics.
It replaces SyntheMol, a previous incarnation that was not as effective for exploring the chemical space and was not able to optimize more than one molecular property, which is a necessity in real-world drug discovery.
The second-generation model uses reinforcement learning, which enables it to rapidly explore massive combinatorial chemical spaces with tens of billions of molecules for promising compounds that are easy to synthesize.
The researchers deployed SyntheMol-RL to identify compounds that simultaneously possessed the multiple drug-like properties of antibacterial activity against MRSA and aqueous solubility.
Next, they synthesized and experimentally tested 79 compounds designed by two variants of SyntheMol-RL and found a corresponding two and 11 potent hits.
One of these compounds, which they named synthecin, was able to fully arrest the growth of MRSA in a murine wound infection model.
“These results demonstrate that SyntheMol-RL is an effective and flexible framework for drug design applications,” the authors maintained.
They added: “SyntheMol-RL is compatible with any property predictor and combinatorial chemical space, it can be readily extended to a wide variety of drug discovery and molecular design problems.”
From stem cells to platelet-rich plasma, regenerative medicine is often positioned as the future of healthcare. But not all approaches deliver on that promise. As interest grows, so do questions regarding what actually works. GEN’s Editor in Chief John Sterling spoke with Thomas Buchheit, MD, founder and medical director of the Triangle Regen Medicine and Biologics Center in Chapel Hill, NC, in relation to the science, the hype, and the realities shaping the field today.
GEN: How do you define regenerative medicine?
Buchheit: Many people think of regenerative medicine as growing new organs, but I define it more broadly as any therapy that improves tissue health or function. With that definition, we can include platelet-rich plasma (PRP), stem cells, and autologous conditioned serum (ACS). These approaches aim to enhance tissue health and improve function.
GEN: The field is promising, but also sometimes criticized as overhyped. Which areas deserve that criticism, and which have gained credibility through clinical validation?
Buchheit: Some criticism is valid, especially around stem cells. We’ve all seen claims over “miracle” stem cells that regrow cartilage. In reality, while these cells can be therapeutic, they typically don’t survive long after injection. Instead, they work by activating the body’s immune-based healing mechanisms. They can improve tissue health, but they’re not the miracle cures they were once portrayed to be.
On the other hand, therapies like PRP and ACS have gained credibility when properly applied and studied, particularly in musculoskeletal conditions.
GEN: How do you incorporate regenerative medicine into your practice?
Buchheit: I focus on patient function—what people can do now and what they want to achieve. Then tailor therapies accordingly. I prioritize treatments with strong evidence. One example is ACS, also known as the Regenokine* program. It’s highly standardized and supported by over 20 years of research in osteoarthritis, sciatica, and radiculopathy.
Thomas Buchheit, MD
I also use PRP, which can be effective, but only when properly dosed. That’s been a major challenge since there are many ways to prepare PRP. We now know that dose matters. For example, treating knee osteoarthritis typically requires close to 10 billion platelets. At our clinic, we measure platelet counts before and after preparation to ensure accuracy, something often not done enough or at all.
GEN: Where did these approaches originate, and how widely are they used?
Buchheit: ACS originated in Germany in the 1990s with Dr. Peter Wehling. It was initially developed as an alternative to steroids for treating sciatica. The process involves incubating whole blood under controlled conditions, which stimulates the release of anti-inflammatory proteins, growth factors, and exosomes.
It became popular as patients, including athletes, traveled to Germany for treatment. Today, it’s available in the United States, though still more common in Europe. We now better understand how it works. Our research shows that exosomes play a key role in long-term benefits. If you remove them, effectiveness drops significantly.
GEN: Your new book Healing Joints and Nerves—who is it for?
Buchheit: It’s written for patients and a broad audience. I focused on authoring a book on regenerative medicine based on scientific accuracy and depth. I wanted to create a resource that explains these therapies clearly and truthfully—what they can and cannot do. It took over six years to complete. The book covers the history of stem cells and concludes with ACS, including both research and my personal experience with it as an avid runner and bicycle rider.
GEN: You often mention “good” vs. “bad” inflammation. What’s the difference?
Buchheit: Chronic inflammation is harmful. It damages tissue, drives pain, and contributes to diseases like osteoarthritis. But acute, controlled inflammation is essential for healing. It triggers the body’s repair processes. Exercise is a good example. It creates cycles of inflammation and recovery that make us stronger. Regenerative therapies aim to harness this same mechanism.
Interestingly, suppressing inflammation too aggressively can backfire. Studies show that patients who take anti-inflammatories after acute injuries may have a higher risk of chronic pain. Repeated steroid injections can also worsen joint damage over time.
GEN: Does all PRP work for osteoarthritis?
Buchheit: No. PRP must contain a sufficient platelet dose to be effective. Research shows that below approximately three billion platelets, it’s unlikely to work. Above four billion, effectiveness improves, and near 10 billion provides optimal results.
A practical tip: patients should ask how much blood is drawn. If only 10 mL is used to produce PRP, it’s mathematically impossible to achieve a high dose. Proper preparation typically requires 60–120 mL. Patients should also ask whether platelet counts are measured.
GEN: Please talk a bit more about Regenokine.
Buchheit: The program is based on ACS, enhanced through a controlled incubation process. This stimulates cells to release anti-inflammatory proteins, growth factors, and exosomes. Treatment typically takes roughly a week. Patients often come to the clinic for that duration. We’ve seen strong results in osteoarthritis and spine conditions, especially in patients who haven’t responded to other treatments, including stem cells.
GEN: What about safety, efficacy, and durability of results?
Buchheit: Outcomes vary by patient, but the primary goal is restoring function—whether that’s walking a dog or running a marathon. My approach is to stay as evidence-based as possible. That’s critical in a field where there is some overpromise or poorly validated treatments.
There are real concerns regarding product quality, sourcing, and transparency in some parts of the market. We need to know exactly what we’re using, how it works, and what evidence supports it. That’s how regenerative medicine will continue to advance responsibly.
Thomas Buchheit, MD, founded the Triangle Regen Medicine and Biologics Center in Chapel Hill, NC, to bring a range of regenerative therapies to patients. He now serves as an adjunct associate professor at Duke and continues to work with scientists at the Center for Translational Pain Medicine.
Buchheit began studying nerve injury pain and served as chief of pain medicine at Duke University Medical Center. He investigated the immune basis of pain relief following injury and the mechanisms behind regenerative therapies, including platelet-rich plasma, stem cells, and autologous conditioned serum. He has led several studies funded by the NIH and the Department of Defense.
*Regenokine was developed by Peter Wehling, MD, in Germany, originally in the 1990s. It utilizes a patient’s own blood to create a serum rich in anti-inflammatory proteins, particularly the interleukin 1 receptor antagonist (IL-1Ra), which helps reduce inflammation and promote healing in joints and tendons. The treatment is used for conditions like osteoarthritis and has gained popularity among athletes seeking pain relief. While it has shown promise in small studies, it is not yet FDA-approved and is not covered by insurance in the United States.
Legislators in two states have resisted efforts to restrict prescription drug affordability boards, the controversial panels that are designed to function as rate-setting authorities and place limits on the cost of prescription medicines.
In Virginia, the General Assembly unanimously rejected a move by Gov. Abigail Spanberger (D) to delay a key provision of two bills that would create a board and allow it to place price caps that mirror the negotiated prices paid by Medicare. Spanberger must now either accept or veto the legislation as originally intended.
In Colorado, the House Health and Human Services Committee postponed consideration of a bill that would exempt orphan drugs, which are used to treat rare diseases, from pricing caps that might be pursued by the state board. By delaying action until the end of the legislative session, the bill is effectively dead.
The intersection of geography and oncology is no longer a speculative frontier—it is rapidly becoming the new standard in understanding who gets cancer, who survives it, and why. At a recent session at AACR 2026 bringing together leading researchers from the Fred Hutch Cancer Center, Harvard, and UCSF, the consensus was clear: geospatial methods are fundamentally altering how epidemiologists interrogate the cancer continuum, from incidence to mortality, from prevention to palliative care.
Trang VoPham, PhD, from Fred Hutch opened proceedings with a sweeping overview of how location data is being weaponized against cancer disparities. Her team’s work exemplifies the field’s evolution beyond crude ecological fallacies toward granular, individual-level exposure assessment. “We linked geospatial data on agricultural pesticide operations with all death certificates in the U.S. from 1989 to 2023,” she explained, detailing their findings that higher linuron use correlated with a 16% increased risk of colorectal cancer mortality among under-50s—higher than the 11% seen in older populations. The precision matters: “It is absolutely critical… can you access or generate residential address histories, not just baseline, not just at diagnosis, to consider life course exposures, timing of exposures, during relevant and critical time periods?”
Trang VoPham, PhD, Fred Hutch Cancer Center
VoPham’s lab is already translating these insights into population health interventions. Their GeoXMap web application—developed with community advisory boards across Washington State—enables neighborhood-level mapping of over 175 health variables, each paired with actionable mitigation strategies. “When you map radon, you can click on the tips button and see strategies for exposure mitigation, like where to get free radon test kits,” she noted. During 2023’s wildfire season, her team used Epic electronic health records to identify and contact 64,000 high-risk patients, resulting in over 4,000 same-day virtual primary care appointments. “This approach could absolutely be scaled to target other populations… to empower high-risk patients with information to help protect themselves from environmental hazards.”
Jaime Hart, ScD, from Harvard, shifted focus to the atmospheric dimensions of cancer risk, tracing how air pollution research has matured since IARC’s 2013 carcinogen declaration. She noted that evidence at the time was largely restricted to lung cancer data. Today, the picture has broadened considerably. Hart highlighted recent consortium work linking traffic-related nitrogen dioxide with premenopausal and Black women’s breast cancer risk—”mostly being driven by premenopausal breast cancer and breast cancer among Black women and non-Hispanic white women”—while PM2.5 associations remain more equivocal for this site.
Jaime Hart, ScD, Harvard T.H. Chan School of Public Health
The mechanistic sophistication has advanced in parallel. Hart detailed how particulate matter can “translocate across your lungs, get into your circulation and deposit in every tissue in your body,” even ascending the nasal pathway to breach the blood-brain barrier. Her collaboration with VoPham on wildfire-specific PM2.5 revealed that “even for the same increase in air pollution exposure… if that PM2.5 is coming more from wildfires than not, you saw an elevated risk,” suggesting source-specific toxicity profiles that carry profound regulatory implications.
Iona Cheng, PhD, from University of California, San Francisco, anchored the session in the structural determinants that underlie these spatial patterns. Her work on redlining—historical mortgage discrimination encoded into contemporary health disparities—demonstrates how geospatial tools can excavate systemic injustice. “In Detroit… about 70% [of non-Hispanic white men with prostate cancer] do live in an area that has not been redlined, in contrast to about 30%,” she reported, whereas “almost 60%” of African American patients resided in the most heavily denied neighborhoods. The mortality gradient was stark: “Higher prostate cancer mortality, or lower survival, associated with living in neighborhoods with more redlining, for both Black and white men.”
Iona Cheng, PhD, University of California, San Francisco
Cheng emphasized that these are not proxy measures for individual behavior but independent contextual effects. “We do see that the neighborhood itself has contributions,” she said, describing how her team is developing racially-ethnic-specific composite indices of structural racism across housing, education, employment, and judicial domains. The community-engaged methodology proved essential: working with Hawaiian advisory boards revealed that non-Hispanic white reference groups made little demographic sense for the islands, prompting recalibration.
The session closed with a palpable sense of acceleration. From Google’s nascent geospatial reasoning AI to wearable sensor validation of satellite models; from street-view imagery classifying 350 million U.S. locations to ecological momentary assessment tracking real-time exposures, the toolkit is expanding exponentially. As Hart observed: “The places where we live, work, and play influence our risk of cancer, impose diagnostic outcomes. There are robust biological mechanisms that underlie this.” The geospatial revolution in cancer epidemiology, it seems, is only getting started.
Genotyping could help identify people who would most benefit from vitamin D supplements to prevent their progression to diabetes, further analysis of a clinical trial suggests.
The genetic association study indicated that individuals with glycemic indicators of prediabetes could benefit from supplementation with 4000 IU/d of vitamin D3 if they carried specific genetic polymorphisms.
Two genotypes of the ApaI vitamin D receptor polymorphism (VDR) were linked to a risk reduction when these vitamin supplements were taken compared with placebo, according to the report in JAMA Open.
“Our exploratory findings, if confirmed, hold promise for high-dose vitamin D3 as a targeted, personalized approach to reducing the risk of type 2 diabetes among selected adults with prediabetes,” reported Bess Dawson-Hughes, MD, from the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, and co-workers.
“The magnitude of the observed risk reduction among participants with AC and CC alleles of the ApaI polymorphism, if confirmed in an independent clinical trial, would have clinical implications for the management of prediabetes.”
There are four major polymorphisms in the vitamin D receptor: FokI, BsmI, ApaI, and TaqI. While the FokI polymorphism produces a shorter vitamin D receptor with enhanced transcriptional activity, the BsmI, ApaI, and TaqI polymorphisms influence mRNA stability, posttranscriptional regulation, and translational efficiency.
ApaI is strongly associated with metabolic syndrome and obesity, which are both major risk factors for type 2 diabetes.
In an extended analysis of the Vitamin D and Type 2 Diabetes (D2d) trial, researchers examined whether VDR gene variants modified the results of the trial.
The primary outcome of the original trial, conducted in people who achieved at least two of the three glycemic criteria for prediabetes, did not reach statistical significance in the intention-to-treat analysis. However, further examination revealed that the effect of vitamin D3 depended on the achieved intratrial serum 25-hydroxyvitamin D (25[OH]D) levels.
Dawson-Hughes and team therefore examined common VDR polymorphisms in the D2d trial to see whether these polymorphisms were associated with reduced diabetes risk among participants who achieved higher intratrial mean 25(OH)D level, in a discovery-level analysis.
They then conducted a test phase to determine whether participants’ VDR genetic profile modified the response to vitamin D3 supplementation compared with placebo.
Among 2098 participants in the D2d trial, the 618 carrying the AA alleles experienced no reduction in risk of progression to type 2 diabetes either when achieving higher intratrial 25(OH)D concentrations or when using vitamin D3 4000 IUs per day for a median of 2.5 years after adjusting for race, sex, and body mass index, among other variables.
However, the 1480 participants with ApaI AC and CC genotypes—representing 71% of the study population—had a progressively lower risk of type 2 diabetes at intratrial 25(OH)D levels of 40 ng/ml or higher.
Participants with these genotypes had a 19% reduction in the risk of progressing to type 2 diabetes over the same period (Hazard ratio=0.81).
“If confirmed, a 19% risk reduction in conversion to type 2 diabetes with vitamin D3 supplementation would not be trivial,” the authors concluded, noting that assessment of a single VDR polymorphism is inexpensive and now widely available.
In a Commentary article accompanying the study, Michael Holick, PhD, and Arash Shirvani, PhD, both from Boston University, added: “The enormity of the disease burden of diabetes worldwide and the confirmation that vitamin D supplementation of 4000 IUs per day markedly reduces risk of developing it should be a wake-up call and the impetus for health organizations to develop strategies to improve vitamin D status for children and adults with food fortification programs, implementation of supplementation, and sensible sun exposure recommendations for those who are at risk.”
CAR T cell therapies have revolutionized outcomes for certain blood cancers, yet their impact on solid tumors has lagged. The field has long wrestled with T cell exhaustion—a state in which engineered cells lose their potency and fail to sustain an anti‑tumor response.
At this year’s AACR annual meeting in San Diego, researchers from the Perelman School of Medicine at the University of Pennsylvania presented first‑in‑human Phase I data pointing to a possible solution. Their novel “KIR‑CAR” T cell therapy demonstrated a favorable safety profile and early signals of activity across multiple solid tumor types.
The investigational therapy, SynKIR-110, represents a departure from traditional CAR T designs. Rather than using a single-chain receptor, the therapy is modeled after natural killer (NK) cell receptors and uses a “multi-chain” architecture.
This design separates tumor recognition from activation, effectively creating an intrinsic “on-off” mechanism. The T cell remains in a resting state until it encounters its target, at which point the receptor components assemble to trigger an immune attack.
“The KIR-CAR design provides a natural ‘on-off’ mechanism, which helps avoid the problem of T cell exhaustion,” said Janos L. Tanyi, MD, PhD, principal investigator of the study. “The CAR turns on when it finds its target, kills it, and then rests, rather than constantly burning energy.”
This contrasts with conventional CAR T cells, which remain continuously active and can become depleted over time, limiting their effectiveness—particularly in the more complex microenvironment of solid tumors.
The Phase I dose-escalation trial enrolled nine patients with advanced, mesothelin-expressing cancers, including ovarian cancer, mesothelioma, and cholangiocarcinoma. These patients had limited treatment options, having received an average of four prior lines of therapy.
Although the primary goal of the study was to assess safety, early signs of efficacy were observed. Disease stabilization was reported in four patients, and one patient in the highest dose cohort achieved an ongoing partial response.
“These are cancer types that have never had an approved cell therapy,” Tanyi said. “We’re seeing good efficacy signals, even at low doses, and limited toxicity.”
The results suggest that the therapy may be able to generate meaningful anti-tumor responses even in heavily pretreated populations.
Safety has been another major barrier for CAR T therapies, particularly in solid tumors. However, the KIR-CAR approach appears to mitigate some of these concerns.
No dose-limiting toxicities were observed in the initial cohorts. Cytokine release syndrome (CRS), a common side effect of CAR T therapy, occurred in 33% of patients but was limited to low-grade events. Notably, there were no cases of immune effector cell-associated neurotoxicity syndrome (ICANS), a more severe complication sometimes seen with CAR T therapies.
The ability to limit toxicity while maintaining activity is a key step toward broader application of cell therapies in solid tumors.
SynKIR-110 targets mesothelin, a protein expressed on the surface of several solid tumors but largely absent from normal tissues. This makes it an attractive target for immunotherapy, particularly in cancers such as ovarian cancer and mesothelioma, where treatment options are limited.
The trial results indicate that the therapy’s activity is not confined to a single tumor type, raising the possibility of broader applicability across mesothelin-expressing cancers.
The findings come amid growing efforts to adapt CAR T technology for solid tumors. While the approach has revolutionized hematologic malignancies, solid tumors present additional challenges, including immunosuppressive microenvironments, physical barriers to T cell infiltration, and antigen heterogeneity.
Researchers are exploring multiple strategies to address these barriers, including improved targeting, combination therapies, and next-generation receptor designs such as KIR-CAR.
As noted by CAR T pioneer Carl June, MD, advancing cellular therapies into solid tumors remains a central goal for the field.
The Phase I study continues to enroll patients, aiming for a 42‑person cohort to define the maximum tolerated dose ahead of Phase II. Early readouts show that CAR T expansion rises with dose, a pattern that may translate into stronger anti‑tumor activity at higher levels.
While still preliminary, the findings highlight the potential of multi‑chain CAR designs to sustain activity without added toxicity. If confirmed, KIR‑CAR therapies could usher in a new generation of engineered immune cells that more closely mirror natural immune regulation.
For now, the data offer a promising sign that CAR T innovation may finally be gaining ground in solid tumors.
Researchers at Memorial Sloan Kettering (MSK) Cancer Center have identified the earliest cellular and molecular events that create the needed conditions for lung cancer cells to begin their growth into a tumor. The study, published in Nature, describes how cells with cancer-causing mutations initiate a coordinated chain of events to involve nearby fibroblasts and immune cells to create a microenvironment conducive to tumor growth at the very start of disease.
“We also found that this transformation of the local neighborhood is reversible, if caught early enough. This opens the door to new treatment and prevention strategies,” said senior author Joo-Hyeon Lee, PhD, an associate member in the developmental biology program at MSK.
The research focused on lung alveolar type II (AT2) stem cells that acquire mutations in the KRAS gene. Rather than simply proliferating, the mutant cells enter a regenerative-like state that resembles tissue repair. In this state, they produce amphiregulin (AREG), a signaling molecule that initiates communication with surrounding cells. AREG activates nearby fibroblasts through EGFR signaling, which prompts them to adopt a fibrotic, injury-like state which results in a remodeling of the extracellular matrix.
Within the microenvironment created, fibroblasts play a central role in shielding emerging tumor cells by producing a fibrous scaffold that supports tumor growth while also releasing signals that alter the activity of immune cells. Macrophages recruited to the site undergo reprogramming, shifting away from fighting the tumor toward phenotypes that suppress immune responses. Neutrophils and regulatory T cells are also recruited, further dampening anti-tumor immunity. This coordinated activity creates a protective niche in which the cells with the KRAS mutation can grow without being eliminated.
“These reciprocal interactions establish a self-sustaining epithelial–stromal–immune circuit that generates a tumor-permissive niche before malignant outgrowth,” the researches wrote. This loop reinforces itself: mutant cells sustain fibroblast activation, fibroblasts reshape immune responses, and immune cells further support tumor-promoting conditions.
The study builds on prior research in the Lee lab into lung injury and repair, which showed that normal regenerative programs involve temporary activation of stem cells and fibroblasts. In cancer, however, this process becomes dysregulated. Mutant cells remain locked in a regenerative state, continuously signaling to their environment. Earlier work by the same group had identified these regenerative states as a feature of early tumorigenesis.
To identify the mechanisms involved, the MSK first used mouse models of lung cancer carrying KRAS mutations. Through lineage tracing and single-cell analyses, they tracked individual cells to map how interactions with fibroblasts and immune cells evolved over time. They then used tissue samples from patients with early-stage lung adenocarcinoma and found returned the same result of cancer cells producing high levels of AREG and adjacent fibrotic fibroblasts.
Importantly, the team demonstrated that disrupting this communication network can prevent tumor formation. Blocking AREG signaling with an EGFR inhibitor kept fibroblasts and immune cells in their normal states and significantly impaired tumor development. Similarly, removing the AREG gene from mutant cells prevented the formation of the tumor-supportive niche. Even after early lesions had formed, inhibiting KRAS activity reversed many of the changes that had already occurred in the microenvironment.
The implications of this research to influence for cancer care are substantial. The identification of early signaling events and microenvironmental changes suggests new biomarkers for detecting lung cancer before it becomes advanced. High levels of AREG or evidence of fibroblast activation could indicate the presence of precancerous lesions, which could be particularly important for screening those at high risk of developing cancer, such as long-term smokers.
The findings also suggest there could be the development of new therapeutics aimed at preventing cancer development as opposed to treating it once it is established. By targeting the AREG–EGFR signaling axis or disrupting fibroblast activation, clinicians may be able to block tumor development at its earliest stages. Because the team showed these processes can be reversed, there is a window for intervention before the disease becomes resistant to treatment.
“The reversibility of these preneoplastic circuits defines a therapeutic window before progression to treatment-resistant disease,” the researchers wrote.
Next steps for the team include validating biomarkers in clinical populations, refining organoid models to study patient-specific tumor development, and testing preventive therapies that target these newly identified early signaling pathways.
