People who are colorblind may be missing a life-saving warning sign of bladder cancer. Analysis of the electronic health records of hundreds of people found that those with color vision deficiency (CVD), or color blindness and bladder cancer had significantly worse outcomes than patients with normal vision, according to a study published in Nature Health.

Warning signs may go unnoticed

Bladder cancer is a major health concern and one of the most common cancers worldwide, according to the World Health Organization (WHO). For many individuals, the first warning sign is blood in their urine. However, people with color blindness may miss this early clue that something is wrong because they struggle to distinguish red from shades of brown or green. The study authors suspected that this blind spot in cancer detection leads to dangerous delays in seeking care.

To determine whether this was the case, the team analyzed data from the TriNetX electronic health records network. This is a massive global database of anonymous medical files.

The researchers compared 135 colorblind patients with bladder cancer to a group of 135 patients with the same condition but normal vision. Each pair had the same age, race, sex and even the same health histories, such as diabetes or high blood pressure. They also compared 187 matched pairs with colorectal cancer.

Increased risk

The researchers found that over a 20-year period, the CVD group experienced a 52% higher risk of death compared to the non-CVD group. According to the study, the possible explanation for this is not any difference in cancer biology, but the nature of the disease itself.

Bladder cancer is usually painless at first, meaning the red color of blood is often the only early warning a person receives. If someone doesn’t feel any pain and cannot see the color, they may not know anything is wrong until later, when the cancer has invaded deeper tissues and becomes harder to treat.

For colorectal cancer, there was no significant difference in survival between the two groups. The researchers believe this is because colorectal cancer is often caught through screening or because some symptoms are felt, such as stomach pain.

The study authors point out that their conclusions are not definitive proof but rather a starting point for more research. Even so, these findings could change the ways doctors treat colorblind patients, as they comment in their paper: “These hypothesis-generating findings should increase clinicians’ suspicion of bladder cancer among patients with CVD and nonspecific signs of malignancy.”

A News & Views article on the research is also published in Nature Health.

Stanford University-led researchers report that tumor cells hijack mitochondria from immune cells, reducing anti-tumor immune function and activating cGAS-STING and type I interferon signaling that promotes lymph node metastasis.

Lymph nodes hold dense networks of immune cells and can become a site of tumor colonization. Mechanisms that let tumor cells subvert tumor-immune microenvironments to favor spread to lymph nodes remain incompletely understood.

Mitochondrial transfer, the movement of mitochondria between cells, is a mode of intercellular communication that reshapes metabolism, stress responses, and cellular function across diverse physiological and pathological settings. Recruiting outside mitochondria into cancer cells can enhance oxidative phosphorylation, promote survival under metabolic stress, and influence therapy resistance.

Uncertainty remains around whether mitochondrial transfer from distinct cell types elicits unique features and clinical behaviors in cancer cells. The consequences of mitochondrial transfer and any impact on tumor dissemination have been poorly characterized.

Lymph node metastasis is a critical early step in cancer progression that can create a systemic impairment of tumor control. Mechanisms by which tumor cells subvert early immune surveillance in lymph nodes are also incompletely understood.

Previous reports have found that T cells and macrophages can transfer mitochondria to cancer cells. The extent of mitochondrial transfer by other immune cells remains unclear, along with any connections to lymph node colonization.

In the study, “Mitochondrial transfer from immune to tumor cells enables lymph node metastasis,” published in Cell Metabolism, researchers tracked mitochondrial movement from immune cells into tumor cells and tested whether that transfer links immune impairment with lymph node metastasis through cGAS-STING and type I interferon signaling.

Experiments set out to address uncertainty around how tumor cells subvert tumor-immune microenvironments to favor spread to lymph nodes, while also probing whether mitochondria arriving from immune cells carry consequences beyond metabolic support.

Flow cytometry and confocal microscopy tracked mitochondria movement into tumor cells after implantation of tagged colon, breast, and melanoma cancer cells into mitochondria reporter MtD2 mice.

Researchers tagged colon, breast, and melanoma cancer cells so donor mitochondria could be detected inside tumor cells. Mouse experiments paired those tagged cancer cells with mice carrying a mitochondria reporter signal, allowing host mitochondria to be seen inside cancer cells at tumor sites and in draining lymph nodes.

Bone marrow transplantation created chimeric mice where the mitochondria reporter signal stayed within immune cells, tightening donor identity to hematopoietic compartments. Genetic differences in mitochondrial DNA between mouse strains provided a second way to detect donor mitochondrial material inside tumors.

Co-culture experiments placed tumor cells and immune cells together to watch transfer during direct contact and to test conditions that altered transfer rates, including low oxygen and inflammatory stimulation. Disruption of physical contact and of cell-to-cell transfer structures tested dependence on direct interaction.

Immune donor cells were separated into groups that retained mitochondria or lost mitochondria during contact with tumor cells, followed by readouts tied to antigen presentation and cytotoxic function.

Tumor cells that received mitochondria were compared with tumor cells that did not for immune-evasion markers and for gene expression patterns linked to type I interferon signaling and cytosolic DNA sensing.

Mitochondria caught crossing into tumor cells

Tumor cells acquired mitochondria from host cells across colon, breast, and melanoma models. Immune cells were identified as a donor source in bone marrow chimera experiments that restricted the reporter signal to hematopoietic cells. Draining lymph nodes carried a higher fraction of tumor cells with immune-derived mitochondria than primary tumors.

Direct physical contact supported transfer, with higher transfer under hypoxic stress and inflammatory cues. Disruption of transfer structures and knockdown of a transfer-related factor reduced transfer, paired with reduced lymph node metastasis incidence in reported mouse experiments. mtDNA polymorphism tracing added a second line of evidence that donor mitochondrial DNA could be detected in tumor material.

Immune weakening meets tumor escape programs

Immune cells that lost mitochondria showed reduced antigen-presentation and co-stimulatory machinery, with reduced activation and cytotoxic capacity reported for natural killer and CD8 T cells. Changes aligned with impaired immune surveillance in the co-culture systems described.

Tumor cells that received immune-derived mitochondria showed features linked to lymph node metastasis, including increased immune-evasion marker expression and activation of type I interferon pathways tied to cGAS-STING signaling.

Mitochondrial fusion and mtDNA leakage into the cytosol linked mitochondrial transfer to cGAS-STING activation. Inhibition of mitochondrial transfer machinery or inhibition of cGAS, STING, or type I interferon reduced lymph node metastasis in experiments.

Analyses of human datasets associated higher mitochondrial transfer signatures with lymph node metastasis and cGAS-STING pathway activation. Receiver prediction was limited when mitochondrial coverage was low and cell numbers were small.

Targets along the transfer chain

Authors identify immune-to-tumor cell mitochondrial transfer as a central mechanism that facilitates lymph node colonization through two coordinated effects. Loss of mitochondria disables anti-tumor immunity by diminishing antigen presentation and impairing cytotoxic function across multiple immune lineages, while immune-derived mitochondria activate the cGAS-STING pathway in tumor cells and induce a type I interferon program that promotes immune evasion and lymph node colonization.

Targeting mitochondrial transfer or the resulting cGAS-STING signaling represents a promising strategy to restrict lymph node metastasis, a critical early step in systemic cancer progression.

Taking acetaminophen during pregnancy does not increase the risk of autism, attention-deficit hyperactivity disorder (ADHD), or intellectual disability among children. That is according to the most rigorous analysis of the evidence to date, published in The Lancet Obstetrics, Gynecology & Women’s Health, and led by researchers from City St George’s, University of London.

Researchers conducted a systematic review and meta-analysis of 43 existing studies to determine whether acetaminophen was safe to use in pregnancy or not. This was in response to public concerns following claims back in September 2025 that suggested taking acetaminophen during pregnancy might impact the neurodevelopment of those children and increase their risk of autism.

The claims were based on earlier studies that reported small associations between acetaminophen in pregnancy and increased risks of autism. However, these were often based on studies prone to biases, including being limited by the type of data collected and not exploring comparisons between siblings to account for family history, which is vital information.

The team looked at 43 studies with the highest quality and most rigorous research methods and compared pregnancies where the mother had taken acetaminophen to pregnancies where they had not taken the drug.

They pooled the results of sibling comparison studies that compared siblings born to the same mother, where one pregnancy involved acetaminophen exposure and another did not. This design helps control for shared genetics, family environment and long-term parental characteristics that traditional studies cannot fully account for.

Across the sibling-comparison studies, data included 262,852 children assessed for autism, 335,255 for ADHD and 406,681 for intellectual disability. When compared to pregnancies with no exposure to acetaminophen, it was confirmed that taking acetaminophen in pregnancy was not linked to childhood autism, ADHD or intellectual disability.

Professor Asma Khalil, professor of obstetrics and maternal fetal medicine at City St George’s, University of London and consultant obstetrician, who led the study, said, “Our findings suggest that previously reported links are likely to be explained by genetic predisposition or other maternal factors such as fever or underlying pain, rather than a direct effect of the acetaminophen itself.

“The message is clear: Acetaminophen remains a safe option during pregnancy when taken as guided. This is important as acetaminophen is the first-line medication we recommend for pregnant women in pain or with a fever, and so they should feel reassured that they still have a safe option to relieve them of their symptoms.”

All studies were assessed for their quality based on the Quality In Prognosis Studies (QUIPS) tool that evaluates numerous factors in the way the research has been conducted to determine the risk of bias, another strength of this work. The lack of association between taking acetaminophen during pregnancy and the risk of the child having autism, ADHD or intellectual disabilities also remained in the studies deemed to be at low risk of bias (and therefore highest quality), and in those which had a longer follow-up period of over five years.

The authors note that a limitation of the current study was that it was not possible to analyze smaller groups in the studies with sibling comparisons based on which trimester of pregnancy acetaminophen was consumed in, sex of the baby or how often acetaminophen was taken, because too few of the existing studies reported these data.

Overall, the findings of the study support the recommendations made by major medical organizations worldwide. The researchers hope that this gold-standard review will put an end to any skepticism about using acetaminophen during pregnancy, as avoiding acetaminophen for significant pain or fever can expose both mother and baby to known risks, particularly untreated maternal fever.

The investigational cancer vaccine, NOUS-209, was found to safely stimulate the immune system to target precancerous and cancerous cells in individuals with Lynch Syndrome (LS), according to a study from researchers at The University of Texas MD Anderson Cancer Center.

The results of a Phase Ib/II clinical trial, published today in Nature Medicine, provide early evidence that immune-based approaches, such as NOUS-209, may be able to intercept cancer before it develops, offering a potential new avenue for preventive care for high-risk individuals.

“Current management strategies for Lynch Syndrome patients—frequent screenings or elective preventive surgery—are life-changing interventions that help prevent cancer development but can significantly affect quality of life,” said principal investigator Eduardo Vilar-Sanchez, M.D., Ph.D., chair ad interim of Clinical Cancer Prevention. “By teaching the immune system to recognize and attack abnormal cells, this therapy offers a promising new approach to this patient population, who face a significantly higher risk of colorectal, endometrial, urothelial and other cancers.”

What is Lynch Syndrome?

Lynch syndrome is caused by inherited mutations in mismatch repair (MMR) genes, which normally help fix DNA errors. Patients with LS have a genetic predisposition to develop cancers with microsatellite instability and often develop cancers at a younger age than the general population, meaning they may benefit from increased screening and preventive strategies.

What is NOUS-209 and what did the researchers learn about the therapy in this study?

NOUS-209 is an experimental cancer vaccine that helps the immune system recognize cancer cells. It works by showing your immune system clear “practice targets” from cancer cells so it can learn to spot and attack the real ones in your body.

NOUS-209 was generally well tolerated, with no serious side effects related to treatment. All participants developed strong immune responses from T cells that recognize and attack cancer-related targets, and these responses increased further with annual retreatment. In laboratory testing, the vaccine-induced T cells were able to kill tumor cells and showed signs of long-lasting immune memory.

One year after treatment, researchers observed fewer precancerous lesions and no new advanced polyps, providing early evidence that NOUS-209 may help stop cancer before it develops.

What are the limitations of this study?

The Phase Ib/II study was relatively small (45 patients) and designed to evaluate safety and immunogenicity, rather than definitive clinical outcomes.

Next, researchers will work to understand how NOUS-209 can induce immune responses in larger and higher-risk populations of LS carriers. Optimal dosing schedules and durability of immune protection over multiple years also is under investigation.

Sexual desire is a fundamental part of being human and a driving force in many relationships, yet we still don’t fully understand why it varies so much from person to person.

In a large-scale study published in the journal Scientific Reports, researchers are giving us some answers. One of the most surprising findings is that men’s desire peaks in their late 30s and early 40s, not in their teens or 20s, as previously assumed.

Researchers from the University of Tartu in Estonia analyzed data from 67,334 adults in the Estonian Biobank. This is a massive repository that contains biological samples and lifestyle information of some of the country’s adult population. The samples in the study represented about 7% of the country’s adults, with participants aged 18 to 89 years.

Levels of desire

The study authors asked these individuals to rate their general level of sexual desire and then compared their answers with a range of background information. This included age, gender, sexual orientation and even their jobs and level of education.

“Our large study considered the individual and interactive roles of several demographic factors in sexual desire, including age, gender, sexual orientation, relationship status, number of children, recent childbirth, educational attainment, and occupation,” wrote the scientists in their paper.

“The findings showed that demographic factors alone—even without accounting for psychological or relational influences—explained 28% of the variance in sexual desire.”

In other words, nearly one-third of the difference between one person’s sexual desire and another’s can be predicted just by looking at basic facts such as age, gender and family.

Key differences

The study also revealed a few more insights into the ways our lives shape our sexual desire. While it tends to dip for everyone as they get older, which was already common knowledge, it drops much more steeply in women.

Another major factor affecting desire is having children, which affects men and women differently. For women, having more children was linked to a lower sexual desire, while men with larger families, on the other hand, reported higher levels of desire.

And who has the highest levels of desire? According to the data, people who identify as bisexual or pansexual.

By providing more details about sexual desire, the researchers hope it will reduce the sense of distress in those who feel as though there is something wrong with them when their desire changes. They also want relationship counselors to use the data to help people understand that shifts in desire are often a natural response to life stages and circumstances.

Each year, more than two million people die from advanced chronic liver disease (ACLD). Previous research has linked gut microbiome disruptions to this condition and suggested that bacteria typically found in the mouth may colonize the gut.

A new study published in Nature Microbiology now shows that identical bacterial strains occur in both the mouth and gut of patients with advanced chronic liver disease and also reveals a mechanism by which oral bacteria affect gut health. The researchers also found that this process coincides with worsening liver health.

Unusual similarity between oral and gut microbiome

Researchers analyzed bacterial populations in saliva and stool samples from 86 patients. The team found that both the gut and oral microbiome undergo significant changes as liver disease worsened, where changes to the oral microbiome were already detectable at earlier disease stages.

In healthy individuals, bacterial communities differ substantially between body sites. In patients with liver disease, however, oral and gut microbiomes became increasingly similar as the disease progressed and nearly identical bacterial strains were recovered from the mouth and gut of patients.

“These strains are typically found in the mouth and are rarely present in the healthy gut. However, we observed increases in the absolute abundances of these oral bacteria in patients with advanced chronic liver disease. This strongly suggests that these bacteria translocate from the mouth and colonize the gut,” explains Melanie Schirmer, Professor of Translational Microbiome Data Integration at TUM.

Bacteria can damage the intestinal barrier

The team identified several oral bacterial species that colonized patients’ guts. They also found evidence that higher levels of these bacteria in stool samples were associated with damage to the intestinal barrier.

“To investigate this link, we performed a gene analysis,” says Shen Jin, one of the study’s first authors. “We discovered that these bacteria carry genes encoding collagen-degradation enzymes.”

The team confirmed these enzymes were active by testing isolated bacteria from stool samples and synthesizing the enzyme.

“Collagen breakdown can compromise the gut barrier, potentially allowing bacteria and bacterial products to reach other organs, such as the liver. We believe this may worsen the disease,” explains Aurelie Cenier, a doctoral researcher and co-first author.

Experiments in a mouse model for liver disease supported this hypothesis: introducing these bacteria from human patients exacerbated gut barrier damage and worsened liver fibrosis.

Implications for diagnosis and treatment

“Our findings open potential new therapeutic strategies for people with advanced chronic liver disease. Protecting or restoring the gut barrier could help slow disease progression. Targeting the oral microbiome offers a way to positively influence the course of the disease and prevent clinical complications,” says Dr. Vishal Patel from King’s College London.

The study also suggests a new diagnostic approach. The team examined the bacterial gene involved in collagen degradation in more detail. Its abundance in stool samples could serve as a future disease marker. In the study, this marker reliably distinguished sick individuals from healthy ones.

A new randomized controlled trial has found promising evidence that the smoking cessation medication varenicline (Chantix/Champix) can help people with cannabis use disorder (CUD) to reduce cannabis use. CUD is a rising problem globally, partly due to recent legalization in several countries and US states, and until now no medications have been found to treat it.

CUD is characterized by continued use of cannabis despite “clinically significant impairment” such as ignoring important social, occupational, or recreational activities and persistent use despite physical or psychological problems associated with cannabis. Cannabis use is also associated with psychosis, sleep disorders, withdrawal, and mood and anxiety disorders.

Varenicline is an effective medication for quitting tobacco. This trial, conducted at the Medical University of South Carolina and published in Addiction, tested whether varenicline could help with CUD.

Results showed it helped men reduce cannabis use, but not women. (Varenicline works equally well for both sexes as a stop-smoking aid.)

The trial included 174 participants with CUD who used cannabis at least three days per week. Participants were randomized to varenicline (working up to a dose of 1 mg twice daily) or placebo for 12 weeks. Participants also received a weekly brief medical management session to encourage their adherence to both the medication and the treatment plan.

Key findings by gender

The men in the study who received varenicline used cannabis fewer times per week than the men on placebo. Specifically, the varenicline group averaged 7.9 cannabis sessions per week during the study and 5.7 sessions in the week following the study, compared with more than 12 weekly sessions for the placebo group. The male varenicline group also used cannabis an average of 3.8 days per week, compared with 4.7 days per week for the male placebo group.

The women in the study who received varenicline did not differ in their cannabis use from the women on placebo. The varenicline group averaged just over 10 sessions per week, compared with the placebo group’s 9.2 weekly sessions (which dropped to 8.2 in the week following the study). The female varenicline group used cannabis an average of 4.9 days per week, compared with 3.6 days for the female placebo group.

The female varenicline group showed higher withdrawal and craving scores and higher anxiety than any of the other groups. Perhaps connected with that, women receiving varenicline reported lower medication adherence than women receiving placebo.

Implications and next steps

Lead author Professor Aimee McRae-Clark says, “Cannabis use disorder is rising quickly in the United States. Current pharmacological treatment options are very limited, and so our ability to help people reduce their cannabis use is also limited. Our study found that varenicline, a drug that helps people to reduce or stop smoking, may be effective at reducing cannabis use as well, but only for men.

“Our next step is to further explore varenicline for cannabis use disorder, using a larger sample size of women, to better understand this sex difference in the treatment outcome. In the meantime, we are encouraged that varenicline shows potential promise in treating this fast-growing problem.”

Parental alienation is when one parent manipulates the child into distancing themselves from the other parent. But does this leave detectable biological evidence?

After a breakup, it is not at all uncommon for one parent to manipulate one or more of the former couple’s children into distancing themselves from the other parent. This is called parental alienation (PA). But this kind of manipulation is often difficult to prove. Can biological markers perhaps reveal it? An international research team from Norway, Ukraine and France wants to find out.

“We are presenting a proposal for how we can develop molecular tests to identify parental alienation,” says Professor Denis Kainov at the Department of Clinical and Molecular Medicine at NTNU.

The researchers have published a paper on this topic in Cellular and Molecular Life Sciences.

Testing for biological markers

“Chronic stress in children who are exposed to parental alienation leaves measurable biological traces,” the paper says.

The researchers have identified different biological markers that could be tested for. These markers relate to six interconnected biological processes: activation of hormones, neurotransmitters, inflammation, substances that are secreted by stress, changes in the gut flora and chemical markers that regulate gene activity.

“If we achieve this, the findings can help clinicians detect harm earlier and provide the courts with objective documentation in parental disputes with a high degree of conflict,” says Kainov.

Parental alienation a controversial hypothesis

However, parental alienation as an identifiable biological condition is not supported by all research communities. The Swedish Wikipedia page even calls it a “pseudoscientific research model.”

“Parental alienation is not recognized in many countries. But this is a new step to raise awareness of the problem. We have to start somewhere. If this is possible, GPs could take samples in connection with divorce or other parental conflicts to protect the children,” says Professor Magnar Bjørås at the Department of Clinical and Molecular Medicine at NTNU.

The researchers emphasize that there are currently few long-term studies that are specific to parental alienation. They therefore believe that the next step must be to develop standardized protocols for children, test the findings in larger patient groups and strengthen the collaboration between doctors, psychologists and legal professionals. This would enable the tests to later be used in practice.

Apathy, social withdrawal, and loss of motivation—the so-called ”negative” symptoms of schizophrenia—are among the most disabling and hardest to treat. A team from the University of Geneva (UNIGE) has uncovered the unexpected role of the cerebellum in the emergence of these symptoms, through its ability to modulate the brain’s reward system. This mechanism, which has remained largely unexplored until now, opens the door to new targeted and noninvasive therapeutic approaches. The study is published in Biological Psychiatry.

Schizophrenia is a neuropsychiatric disorder that affects around 1% of the population and is best known for its hallucinatory and delusional symptoms. However, it is also marked by profound apathy, a reduced ability to experience pleasure, and progressive social withdrawal. These so-called “negative” symptoms—for which no effective treatment currently exists—are particularly disabling.

Several studies have shown that abnormalities in the brain’s reward system—particularly in the dopamine-producing ventral tegmental area (VTA)—are associated with these symptoms. In people with schizophrenia, the VTA is believed to be overactive, leading to a blunted perception of salience, where “everything feels the same,” and resulting in a lack of motivation.

The cerebellum, a hidden regulator

In an innovative study, a team from the University of Geneva (UNIGE) and the Geneva University Hospitals (HUG) has shown that the cerebellum plays a key role in regulating—or dysregulating—this mechanism via the VTA.

“What is sometimes called our ‘little brain’ actually contains 50% of all our neurons. Although it was long considered to have a purely motor function, we are now discovering that it also plays important emotional and cognitive roles,” explains Indrit Bègue, assistant professor in the Laboratory of Neuroimaging and Translational Psychiatry in the Department of Psychiatry at the UNIGE Faculty of Medicine, researcher at the Synapsy Center for Neuroscience Research in Mental Health, and University hospital physician in the Department of Adult Psychiatry at HUG, who led the study.

By following 146 patients over a period of 3 to 9 months, and by analyzing an independent validation cohort, the team was able to observe and describe for the first time the functional connection between the cerebellum and the VTA in the context of schizophrenia.

“We show that stronger cerebellar regulation of the reward system is associated with a reduction in negative symptoms—and conversely, weaker regulation with an increase in symptoms. This newly identified mechanism opens up promising avenues for targeted therapeutic interventions,” explains Jade Awada, a doctoral student in Bègue’s team at the Laboratory of Neuroimaging and Translational Psychiatry in the Department of Psychiatry at the UNIGE Faculty of Medicine, researcher at the Synapsy Center for Neuroscience Research in Mental Health, and first author of the study.

The analyses were carried out by Jade Awada and Farnaz Delavari, co-first author of the study and researcher in Professor Stephan Eliez’s laboratory.

A more accessible therapeutic target?

Unlike the VTA, which lies deep within the brain, the cerebellum is located on the surface, at the back of the skull. This makes it far more accessible—and a promising target for noninvasive interventions such as transcranial magnetic stimulation (TMS).

“This technique involves generating magnetic fields near the targeted brain area—in this case, the cerebellum—in order to stimulate and strengthen its activity. We are currently evaluating the potential of this approach to ‘treat’ the circuit between the cerebellum and the VTA that we identified in our study,” explains Bègue.

A randomized controlled trial is already under way with a cohort of patients at Campus Biotech. Results are expected in 2028.

According to a Phase I study led by researchers at The University of Texas MD Anderson Cancer Center, published in Nature Medicine, the novel monoclonal antibody linavonkibart has demonstrated the potential to overcome treatment resistance to anti-PD-1 immune checkpoint inhibitors in multiple cancer types.

The trial was led by Timothy Yap, M.B.B.S., Ph.D., professor of Investigational Cancer Therapeutics and vice president and head of clinical development in MD Anderson’s Therapeutics Discovery division.

“This is a very exciting trial because we’ve been trying to effectively target this protein, called transforming growth factor-beta 1, for a long time,” Yap said. “We’ve known that it helps tumors evade the immune system and develop resistance to immunotherapies but, until now, attempts to target it have failed. This is potentially a significant step in helping patients overcome resistance and benefit further from immunotherapies.”

Significance of linavonkibart clinical trial

Despite the tremendous impact that immunotherapies like pembrolizumab have had, many cancers are either unresponsive or develop treatment resistance. Research has found that often this resistance involves a protein called transforming growth factor-beta 1 (TGFβ1).

There have been previous efforts to develop therapies targeting TGFβ1, but most initial treatments also blocked TGFβ2 and TGFβ3, instead of just selectively blocking TGFβ1. Researchers found that TGFβ2 and TGFβ3 are essential for normal body functions, and so previous efforts were met with significant dose-limiting toxicities.

Linavonkibart is a first-in-class selective immunotherapy that aims to overcome resistance by targeting and preventing activation of only TGFβ1. Linavonkibart attaches itself to the protein in its “off” position, which then makes it unable to switch “on.”

Linavonkibart also is a “fully human” antibody, meaning it is built exclusively from structures found naturally in the human body. This should make it safer and less likely to initiate an immune response against it, and the initial clinical data support this theory.

This Phase I DRAGON trial was divided into three parts:

• Single-agent dose escalation arm (19 patients with a median age of 66 and four prior lines of therapy)
• Combination dose escalation arm (15 patients, median age of 65 and four prior lines) with linavonkibart combined with pembrolizumab
• Combination dose expansion arm (78 patients, median age of 65 and three prior lines)

The safety profile was manageable overall, and the combination therapy showed side effects consistent with the safety profile of pembrolizumab as a monotherapy, with only dermatologic reactions identified as an additional risk. No grade four or five or dose-limiting toxicities were observed in either dose escalation cohort. In the dose expansion cohort, the most common adverse effect at grade three or higher was rash, with only four patients experiencing any grade four adverse effects.

In the dose expansion cohort of 78 heavily pre-treated patients who were progressing on prior immune checkpoint therapy, physicians observed multiple objective responses. Especially notable was a 20% objective response rate in patients with heavily pretreated advanced clear cell renal cell cancer. Interestingly, the exploratory biomarker studies have uncovered a potential patient selection strategy for that subgroup to enrich for patient benefit. Responses also were observed in melanoma, head and neck squamous cell cancer, and urothelial cancer.

Assessing linavonkibart

According to Yap, there are multiple next steps to assess linavonkibart, including investigating whether it may be even more effective as an earlier-line treatment.

“It’s notable that our Phase I trial involved a very heavily pretreated population with a prognosis of just over three months,” Yap said. “We believe that this linavonkibart combination will be even more effective when given in earlier treatment settings, before significant resistance to immunotherapy has developed.”

Early data from this trial were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.