Complex Link Between Gut Microbiome and Immunotherapy Response in Advanced Melanoma

A large-scale meta-analysis has verified that the gut microbiome does influence patients' response to immune checkpoint inhibitor (ICI) therapy in advanced melanoma, but the relationship appears to be more complex than previously thought. Overall, researchers identified a panel of species, including Roseburia spp. and Akkermansia muciniphila, associated with responses to ICI therapy. However, no single species was a "fully consistent biomarker" across the studies, the authors explain. This "machine learning analysis confirmed the link between the microbiome and overall response rates (ORRs) and progression-free survival (PFS) with ICIs but also revealed limited reproducibility of microbiome-based signatures across cohorts," Karla A. Lee, PhD, a clinical research fellow at King's College London, UK, and colleagues report. The results suggest that "the microbiome is predictive of response in some, but not all, cohorts." The findings were published online February 28 in Nature Medicine. Despite recent advances in targeted therapies for melanoma, less than half of the those who receive a single-agent ICI respond and those who receive combination ICI therapy often suffer from severe drug toxicity problems. That is why finding patients more likely to respond to a single-agent ICI has become a priority. Previous studies have identified the gut microbiome as "a potential biomarker of response as well as a therapeutic target" in melanoma and other malignancies, but "little consensus exists on which microbiome characteristics are associated with treatment responses in the human setting," the authors explain. To further clarify the microbiome–immunotherapy relationship, the researchers performed metagenomic sequencing of stool samples collected from 165 ICI-naive patients with unresectable stage III or IV cutaneous melanoma from 5 observational cohorts in the Netherlands, United Kingdom, and Spain. These data were integrated with 147 samples from publicly available datasets. First, the authors highlighted the variability in findings across these observational studies. For instance, they analyzed stool samples from one UK-based observational study of patients with melanoma (PRIMM-UK) and found a small but statistically significant difference in the microbiome composition of immunotherapy responders vs nonresponders (P = .05) but did not find such an association in a parallel study in the Netherlands (PRIMM-NL, P = .61). The investigators also explored biomarkers of response across different cohorts and found several standouts. In trials using ORR as an endpoint, two uncultivated Roseburia species (CAG:182 and CAG:471) were associated with responses to ICIs. For patients with available PFS data, Phascolarctobacterium succinatutens and Lactobacillus vaginalis were "enriched in responders" across 7 datasets, and significant in 3 of the 8 meta-analysis approaches. A muciniphila and Dorea formicigenerans were also associated with ORR and PFS at 12 months in several meta-analyses. However, "no single bacterium was a fully consistent biomarker of response across all datasets," the authors wrote. Still, the findings could have important implications for the more than 50% of patients with advanced melanoma who don't respond to single-agent ICI therapy. "Our study shows that studying the microbiome is important to improve and personalize immunotherapy treatments for melanoma," study co-author Nicola Segata, PhD, principal investigator in the Laboratory of Computational Metagenomics, University of Trento, Italy, said in a press release. "However, it also suggests that because of the person-to-person variability of the gut microbiome, even larger studies must be carried out to understand the specific gut microbial features that are more likely to lead to a positive response to immunotherapy." Co-author Tim Spector, PhD, head of the Department of Twin Research & Genetic Epidemiology at King's College London, added that "the ultimate goal is to identify which specific features of the microbiome are directly influencing the clinical benefits of immunotherapy to exploit these features in new personalized approaches to support cancer immunotherapy." In the meantime, he said, "this study highlights the potential impact of good diet and gut health on chances of survival in patients undergoing immunotherapy." This study was coordinated by King's College London, CIBIO Department of the University of Trento and European Institute of Oncology in Italy, and the University of Groningen in the Netherlands, and was funded by the Seerave Foundation. Lee, Segata, and Spector have disclosed no relevant financial relationships.

Monkeypox Vaccines: Q&A With the CDC's Agam Rao, MD

Two vaccines are available for monkeypox. Vaccine expert Agam Rao, MD, medical officer in CDC's Poxvirus and Rabies Branch, answers questions about their effectiveness and dosing. How effective is the smallpox vaccine against monkeypox, and how was it identified as potentially protective against monkeypox? Smallpox is the illness that is caused by variola virus, a member of the genus Orthopoxvirus. Monkeypox virus is in that same genus. For viruses within the same genus, we expect that a vaccine against one will be effective against the other. There are actually several different vaccines worldwide that are used for smallpox and other similar viruses. In the United States, we have two vaccines that are licensed for the prevention of smallpox: ACAM2000 and JYNNEOS. JYNNEOS happens to be licensed by the US Food and Drug Administration (FDA) for prevention of monkeypox as well. We don't have any reason to believe that either of these vaccines would differ in effectiveness for monkeypox vs smallpox because the two viruses are related. Do you have any data on how effective ACAM2000 and JYNNEOS are in preventing smallpox? JYNNEOS is a new vaccine and therefore was not used during the eradication campaign for smallpox, so we don't have any real-world data on how effective it would be in preventing smallpox. In terms of ACAM2000, its precursor, a drug called Dryvax, was used during the eradication campaign, and data indicated that it was 85% effective at preventing smallpox if it was given as postexposure prophylaxis within 4 days of an exposure. Even beyond that, if the drug was given up to 14 days after an exposure, it would then at least lessen the symptoms. We don't have data about the real-world effectiveness of these vaccines to prevent monkeypox, particularly in this outbreak. Have there been monkeypox cases in older individuals who had been given the smallpox vaccine? There have been cases of people who have gotten monkeypox despite being vaccinated as children or being vaccinated in the past. Vaccine effectiveness probably wanes over time. We are also aware of monkeypox cases in people who had received the JYNNEOS or ACAM2000 vaccine as part of the current outbreak. There's really no vaccine that's 100% effective. There are always going to be people who don't mount an appropriate immune response, either because they're immunocompromised or for any other reason. What data did the FDA look at to approve JYNNEOS for the prevention of smallpox and monkeypox? In addition to the FDA approving the vaccine, the Advisory Committee on Immunization Practices, which is a group of vaccine experts who assemble to provide guidance to the CDC director for national vaccine recommendations, also recommended the JYNNEOS vaccine for the prevention of Orthopoxvirus infection for people with occupational risk. This was in November of last year and was unrelated to the current outbreak.

Pediatricians Urge Flu Vaccine for Kids

Attention parents: The nation's leading pediatric medical society is urging you to make sure your children get a flu shot this fall to prevent and control the spread of the illness. The American Academy of Pediatrics this week called on parents and caregivers to seek flu vaccines for their kids as soon as they are available in the fall. The group is encouraging parents to catch up on all other vaccines for their children, too. "As a pediatrician and a parent, I consider the flu vaccine as critical for all family members," Kristina A. Bryant, MD, said in a statement about the academy's recommendations. "We should not underestimate the flu, especially when other respiratory viruses like COVID-19 are circulating within our communities. Besides making your child miserable and wreaking havoc on your family's routine, influenza can also be serious and even deadly in children." Only 55% of children ages 6 months to 17 years had been vaccinated against influenza as of early April – down 2% from the previous April – and coverage levels were 8.1% lower for Black children compared with non-Hispanic white children, according to the CDC. In the 2019-2020 flu season, 188 children in the United States died of the infection, equaling the high mark for deaths set in the 2017-2018 season, the agency reported. American Academy of Pediatrics guidelines recommend children ages 6 months and older be vaccinated with the flu vaccine every year. Depending on the child's age and health, they may receive either a shot, which has an inactive version of the flu virus, or the nasal spray, which has a weakened form of the virus. (The academy has more information about the different vaccines here.) Children ages 6 to 8 months old who are getting flu vaccines for the first time should receive two doses at least 4 weeks apart. Pregnant women can get the flu vaccine any time in their pregnancy. Influenza vaccines are safe for developing fetuses, according to the academy. The group stressed the importance of flu vaccines for high-risk and medically vulnerable children and acknowledged the need to end barriers to immunizations for all people, regardless of income or insurance coverage. In 2020, an estimated 16.1% of children in the United States were living in poverty, up from 14.4% in 2019, according to the U.S. Census Bureau. Sources American Academy of Pediatrics: "American Academy of Pediatrics Urges Families to Get Children Vaccinated for Influenza to Prevent and Control Illness in 2022-23." HealthyChildren.org: "Which Flu Vaccine Should Children Get?" CDC: "2019-20 Season's Pediatric Flu Deaths Tie High Mark Set During 2017-18 Season." U.S. Census Bureau: "Income and Poverty in the United States: 2020."

Amazon Involved With New Cancer Vaccine Clinical Tria

Amazon is working with the Fred Hutchinson Cancer Research Center to develop cancer vaccines in a new clinical trial. The trial is aimed at finding "personalized vaccines" to treat breast cancer and melanoma, a form of skin cancer. The phase 1 trial is recruiting 20 people over age 18 years to study the safety of the vaccines, according to CNBC. The Fred Hutchinson Cancer Research Center and University of Washington Cancer Consortium are listed as the researchers of the clinical trial, and Amazon is listed as a collaborator, according to a filing on the ClinicalTrials.gov database. "Amazon is contributing scientific and machine learning expertise to a partnership with Fred Hutch to explore the development of a personalized treatment for certain forms of cancer," an Amazon spokesperson told CNBC. "It's very early, but Fred Hutch recently received permission from the US Food and Drug Administration to proceed with a phase 1 clinical trial, and it's unclear whether it will be successful," the spokesperson said. "This will be a long, multiyear process — should it progress, we would be open to working with other organizations in healthcare and life sciences that might also be interested in similar efforts." In recent years, Amazon has grown its presence in the healthcare industry, CNBC reported. The company launched an online pharmacy in 2020, developed a telehealth service called Amazon Care, and released its own COVID-19 test during the pandemic. A research and development group inside Amazon, known as Grand Challenge, oversaw the company's early cancer vaccine effort, according to Business Insider. It's now under the purview of a cancer research team that reports to Robert Williams, the company's vice president of devices. The study was first posted on ClinicalTrials.gov in October 2021 and began recruiting patients on June 9, according to the filing. The phase 1 trial is expected to run through November 2023. The phase 1 trial will study the safety of personalized vaccines to treat patients with late-stage melanoma or hormone receptor-positive HER2-negative breast cancer, which has either spread to other parts of the body or doesn't respond to treatment. More information about the study can be found on ClinicalTrials.gov under the identifier NCT05098210. Sources CNBC: "Amazon launches cancer vaccine clinical trial in partnership with Fred Hutchinson." ClinicalTrials.gov: "Personalized Neo-Antigen Peptide Vaccine for the Treatment of Stage IIC-IV Melanoma or Hormone Receptor Positive Her2 Negative Metastatic Refractory Breast Cancer," NCT05098210. Business Insider: "Amazon is quietly developing cancer vaccines in partnership with Fred Hutchinson and recruiting patients for a new clinical trial."

Overall Survival Dips With Vitamin D Deficiency in Melanoma

Patients with melanoma who are deficient in vitamin D have significantly worse overall survival than those with higher levels, according to research presented at the 31st Congress of the European Academy of Dermatology and Venereology. Whereas the 5-year overall survival was 90% when vitamin D serum levels were above a 10 ng/mL threshold, it was 84% when levels fell below it. Notably, the gap in overall survival between those above and below the threshold appeared to widen as time went on. Dr Inés Gracia-Darder The research adds to existing evidence that "vitamin D levels can play an important and independent role in patients' survival outcomes," study investigator Inés Gracia-Darder, MD, told Medscape Dermatology. "The important application in clinical practice would be to know if vitamin D supplementation influences the survival of melanoma patients," said Gracia-Darder, a clinical specialist in dermatology at the Hospital Universitari Son Espases, Mallorca, Spain. Known Association, but Not Much Data "It is not a new finding," but there are limited data, especially in melanoma, said Julie De Smedt, MD, of KU Leuven in Leuven, Belgium, who was asked to comment on the results. Other groups have shown, certainly for cancer in general, that vitamin D can have an effect on overall survival. "Low levels of vitamin D are associated with the pathological parameters of the melanoma, such as the thickness of the tumor," De Smedt said in an interview, indicating that it's not just overall survival that might be affected. "So we assume that also has an effect on melanoma-specific survival," she added. That assumption, however, is not supported by the data Gracia-Darder presented, as there was no difference in melanoma-specific survival among the two groups of patients that had been studied. Retrospective Cohort Analysis Vitamin D levels had been studied in 264 patients who were included in the retrospective cohort analysis. All had invasive melanomas, and all had been seen at the Hospital Clinic of Barcelona between January 1998 and June 2021. Their mean age was 57 years, and the median follow-up was 6.7 years. 0

Brain activity patterns during sleep shed light on the neurobiology behind 22q11.2 Deletion Syndrome

The brain activity patterns during sleep shed light on the neurobiology behind a genetic condition called 22q11.2 Deletion Syndrome (22q11.2DS) and could be used as a biomarker to detect the onset of neuropsychiatric disorders in people with 22q11.2DS. 22q11.2DS is caused by a gene deletion of around 30 genes on chromosome 22 and occurs in 1 in 3000 births. It increases the risk of intellectual disability, autism spectrum disorder (ASD), attention-deficit hyperactivity disorder (ADHD) and epileptic seizures. It is also one of the largest biological risk factors for schizophrenia. However, the biological mechanisms underlying psychiatric symptoms in 22q11.2DS are unclear. We have recently shown that the majority of young people with 22q11.2DS have sleep problems, particularly insomnia and sleep fragmentation, that are linked with psychiatric disorders. However, our previous analysis was based on parents reporting on sleep quality of their children, and the neurophysiology – what's happening to brain activity – has not yet been explored." Marianne van den Bree, co-senior author, Professor of Psychological Medicine at Cardiff University, UK An established way of measuring brain activity during sleep is an electroencephalogram (EEG). This measures electrical activity during sleep and features patterns called spindles and slow-wave (SW) oscillations. These features are hallmarks of non-rapid eye movement (NREM) sleep and are thought to aid memory consolidation and brain development. "Because sleep EEG is known to be altered in many neurodevelopmental disorders, the properties and coordination of these alterations can be used as biomarkers for psychiatric dysfunction" explained lead author Nick Donnelly, Clinical Lecturer in General Adult Psychiatry at the University of Bristol, UK To explore this in 22q11.2DS, the team recorded sleep EEG over one night in 28 young people aged 6-20 years old with the chromosome deletion and in 17 unaffected siblings, recruited as part of the Cardiff University Experiences of Children with copy number variants (ECHO) study, led by Prof. van den Bree. They measured correlations between sleep EEG patterns and psychiatric symptoms, as well as performance in a recall test the next morning. Genetics & Genomics eBook Compilation of the top interviews, articles, and news in the last year. Download a copy today They found that the group with 22q11.2DS had significant alterations in sleep patterns including a greater proportion of N3 NREM sleep (slow-wave sleep) and lower proportions of N1 (the first and lightest sleep stage) and rapid eye movement (REM) sleep, compared with their siblings. Those carrying the chromosome deletion also had increased EEG power for both slow-wave oscillations and spindles. There was also an increase in the frequency and density of spindle patterns and stronger coupling between the spindle and slow-wave EEG features in the 22q112.DS group. These changes may reflect alterations in the connections within and between areas of the brain that generate these oscillations, the cortex and the thalamus. Participants also took part in a 2D object location task before sleep, where they had to remember where matching cards were on a screen. They were tested again on the same task in the morning, and the team found that in those with 22q11.2DS, higher spindle and SW amplitudes were associated with lower accuracy. By contrast, in participants without the chromosome deletion, higher amplitudes were linked to higher accuracy in the morning recall test. Finally, the team estimated the impact of the differences in sleep patterns on psychiatric symptoms in the two groups using a statistical method called mediation. They calculated the total effect of genotype on psychiatric measures and IQ, the indirect (mediated) effect of EEG measures, and then the proportion of the total effect that may be mediated by EEG patterns. They found that the effects on anxiety, ADHD and ASD driven by the 22q11.2 deletion were partially mediated by sleep EEG differences. "Our EEG findings together suggest a complex picture of sleep neurophysiology in 22q11.2DS and highlight differences that could serve as potential biomarkers for 22q11.2DS-associated neurodevelopmental syndromes," concluded co-senior author Matt Jones, Professorial Research Fellow in Neuroscience, University of Bristol, UK. "Further study will now need to clarify the relationship between psychiatric symptoms, sleep EEG measures and neurodevelopment, with a view to pinpointing markers of brain circuit dysfunction that could inform doctors which patients are most at risk, and support treatment decisions."

Genetic screening before pregnancy detects the risk in 44% of couples

Are would-be parents carrying a genetic risk of serious illnesses that they could potentially pass on to their children? In the USA, doctors recommend that couples have genetic screening before trying to conceive. Researchers at the University of Zurich have now shown that a maximal variant of this test detects the risk in 44percent of couples who are related by blood, and in just 5 percent of other couples. Non-hereditary newly acquired mutations are a major reason for the reduced detection rate in the latter. The use of biomarker and genetic tests during pregnancy is now extremely widespread. But what if both parents' genes were broadly analyzed for possible risks prior to conception? Are there any rare hereditary diseases in the genome that the father and/or mother are unknowingly carrying? If both parents have the same genetic defect in their genes and both pass this on to their child, this will often cause the child to have a serious illness. In many parts of the US, broad genetic testing is offered to prospective parents and is usually also recommended in early pregnancy. The screenings predominantly indicate recessively inherited genes that are non-gender specific - in other words, those that have an effect only if both gene copies carry a mutation. Recessive genes on the X chromosome are a special case, whereby healthy mothers can pass this gene onto their children. However, normally only sons suffer from the consequences this mutation as they carry only one X chromosome and therefore do not have a second gene copy to compensate for the defect. More than 3,000 hereditary factors tested Do these genetic tests for inherited risk factors deliver what they promise? Anita Rauch, director of medical genetics at the University of Zurich, and her team in Switzerland have now for the first time addressed this question by extensively studying the potential and pitfalls of such expanded carrier screening (ECS). To this end, the scientists tested sequence data from 700 parents who already had children with neurodevelopmental disorders. Many of the more than 3,000 investigated genes can cause intellectual disabilities, developmental disorders, autism and other disorders. In our study, we were able to show that this type of broad genetic testing can detect the risk of the child having a severe developmental disorder in about 44 percent of cases if the parents are related by blood - for instance as first or second cousins." Anita Rauch, director of medical genetics, University of Zurich Gaps in risk detection for non-consanguineous couples in particular The test still detected about 5 percent of cases in couples who were not blood-related - but only if all known recessive genes were investigated. According to the recommendations in the US, however, non-consanguineous couples should only be tested for common genes that are known to have a certain carrier frequency in the population. "Following the US recommendation would more than halve the risk detection rate, because rarer genes also play a part here," explains Rauch. Genetics & Genomics eBook Compilation of the top interviews, articles, and news in the last year. Download a copy today For children of non-consanguineous couples, a significantly higher proportion of developmental disorders are caused by non-hereditary de novo mutations, whereas in children of parents who are related to each other hereditary gene defects play a distinctly greater role. For this reason, the researchers state that the likelihood of detecting risks by analyzing the parents' genes is limited for non-consanguineous couples. Many pathogenic genes still not detected Further factors also impact the potential of these tests to detect problematic gene variants in known pathogenic genes: in particular, missense gene mutations, in which the genetic blueprint may or may not be altered, and inherited copy-number variants, in which the number of gene copies is incorrect, have been underestimated. Cases that cannot be detected are generally those in which an inherited and a newly acquired genetic defect occur at the same time. In addition, there are likely several thousands of as-yet unidentified genes that probably also cause developmental disorders. For instance, in the investigated study cohort, the cause of the developmental disorder in the respective children remained unexplained in about a 58percent of cases. Conscious decision for or against children Nevertheless, according to the researchers, the study provides data as to how meaningful expanded carrier screening is. Based on the high risk-detection rate for consanguineous parents, the researchers believe that such screening should certainly be offered to these couples. In all other cases, the benefits and disadvantages should be weighed up on a case-by-case basis to avoid creating unrealistic expectations. "If a couple is found to be at risk of having children with neurodevelopmental disorders, they will be fully aware and able to decide whether or not to have children together or to consider prenatal or preimplantation diagnostics," says Rauch. However, the results also show that the potential risk reduction strongly depends on the selected genes and variant classifications in the test. According to Rauch, there is still potential for improvement in the tests offered currently: "To improve the clinical benefit, all couples that want a broad genetic test should be considered for screening all recessive genes irrespective of the population prevalence of a gene variant. Laboratories should also use reasonable thresholds regarding when a genetic defect is considered pathogenic."