Virus World

Drug hunters are finding that ancient virus-like artifacts in the human genome could offer new avenues to treat neurodegeneration, cancer, autoimmunity and even aging with antibodies, vaccines and antiretroviral agents. A new wave of therapies is taking aim at virus-like elements spread throughout the human genome. These genomic parasites, which have accumulated over the course of human evolution, are embedded in the vast expanse of DNA sequences that dwell in the spaces between our genes — what scientists call the ‘dark genome’. Although they were largely ignored in the past, growing scientific evidence indicates that these normally dormant elements — including retroviruses, transposons and other repetitive sequences — can reactivate, triggering inflammation, cancer and other disease-related cellular damage.

No cervical cancer cases were detected in Scotland in women born between 1988-1996 and fully vaccinated against HPV between ages 12 to 13, study says. A historic new study out of Scotland shows the real-world impact of vaccines against the human papillomavirus: The country has detected no cases of cervical cancer in women born between 1988-1996 who were fully vaccinated against HPV between the ages of 12 and 13. Many previous studies have shown that HPV vaccines are extremely effective in preventing cervical cancer. But the study, published on Monday in the Journal of the National Cancer Institute, is the first to monitor a national cohort of women over such a long time period and find no occurrence of cervical cancer.

“The study is super exciting. It shows that the vaccine is extremely effective,” said Kathleen Schmeler, a professor of gynecologic oncology at the University of Texas MD Anderson Cancer Center, who was not involved in the research. “It’s obviously early. We’re just starting to see the first data of the impact of the vaccine because it takes so long from the time of the vaccine to the effects.” The results underscore the importance of working to increase uptake of the HPV vaccine in the U.S., said Schmeler. Scotland, for example, introduced routine immunization in schools in 2008, and close to 90% of students in their fourth year of secondary school (equivalent to 10th grade in the U.S.) in the 2022-2023 school year had received at least one dose of the vaccine. In the U.S., where HPV vaccines are not administered in school, uptake among adolescents ages 13 to 17 is a little over 60%....

Study available here (jan. 22, 2024):

https://doi.org/10.1093/jnci/djad263

In a recent study published in the journal Scientific Reports, researchers used a nationwide case-control study of Taiwanese residents to investigate the association between human papillomavirus (HPV) and thyroid cancer. Analyses of the 3,062 thyroid cancer patients and 9,186 healthy controls revealed that individuals with a prior HPV infection had more than double the likelihood of developing thyroid cancer than those without the infection (odds ratios 2.199 for HPV patients). This research presents the first concrete evidence of a carcinogen for thyroid cancer, the most common endocrine cancer and a growing concern worldwide.

In new research, scientists have linked increased CT scan exposure to an increased risk of blood cancer in younger people. A team of researchers at Barcelona Institute for Global Health found that childhood exposure to CT scan radiation is linked to an increased risk of blood cancer in the years that follow. The study is published today (9 November) in the scientific journal, Nature Medicine.  "We must keep studying how we can limit radiation exposure in those seeking diagnoses, as this could help prevent cases of blood cancer, potentially saving lives"

Human endogenous retroviruses (HERVs) are ancestral viral relics that constitute nearly 8% of the human genome. Although normally silenced, the most recently integrated provirus HERV-K (HML-2) can be reactivated in certain cancers. Here, we report pathological expression of HML-2 in malignant gliomas in both cerebrospinal fluid and tumor tissue that was associated with a cancer stem cell phenotype and poor outcomes. Using single-cell RNA-Seq, we identified glioblastoma cellular populations with elevated HML-2 transcripts in neural progenitor–like cells (NPC-like) that drive cellular plasticity. Using CRISPR interference, we demonstrate that HML-2 critically maintained glioblastoma stemness and tumorigenesis in both glioblastoma neurospheres and intracranial orthotopic murine models.

Additionally, we demonstrate that HML-2 critically regulated embryonic stem cell programs in NPC-derived astroglia and altered their 3D cellular morphology by activating the nuclear transcription factor OCT4, which binds to an HML-2–specific long-terminal repeat (LTR5Hs). Moreover, we discovered that some glioblastoma cells formed immature retroviral virions, and inhibiting HML-2 expression with antiretroviral drugs reduced reverse transcriptase activity in the extracellular compartment, tumor viability, and pluripotency. Our results suggest that HML-2 fundamentally contributes to the glioblastoma stem cell niche. Because persistence of glioblastoma stem cells is considered responsible for treatment resistance and recurrence, HML-2 may serve as a unique therapeutic target.

Published in JCI (July 3, 2023):

https://doi.org/10.1172/JCI167929 

An experimental mRNA cancer vaccine developed by Moderna Inc and Merck & Co cut the risk of death or recurrence of the most deadly skin cancer by 44% compared with Merck's immunotherapy Keytruda alone, U.S. researchers reported at a medical meeting on Sunday.

The Epstein-Barr virus (EBV) is easily spread through bodily fluids, primarily saliva, such as kissing, shared drinks or using the same eating utensils. Not surprisingly then, EBV is also among the most ubiquitous of viruses: More than 90% of the world’s population has been infected, usually during childhood. EBV causes infectious mononucleosis and similar ailments, though often there are no symptoms. Most infections are mild and pass, but the virus persists in the body, becoming latent or inactive, sometimes reactivating. Long-term latent infections are associated with several chronic inflammatory conditions and multiple cancers. In a new paper, published April 12, 2023 in the journal Nature, researchers at University of California San Diego, UC San Diego Moores Cancer Center and Ludwig Cancer Research at UC San Diego, describe for the first time how the virus exploits genomic weaknesses to cause cancer while reducing the body’s ability to suppress it.   These findings show “how a virus can induce cleavage of human chromosome 11, initiating a cascade of genomic instability that can potentially activate a leukemia-causing oncogene and inactivate a major tumor suppressor,” said senior study author Don Cleveland, PhD, Distinguished Professor of Medicine, Neurosciences and Cellular and Molecular Medicine at UC San Diego School of Medicine. “It’s the first demonstration of how cleavage of a ‘fragile DNA’ site can be selectively induced.” Throughout every person’s genome or full set of genes are fragile sites, specific chromosomal regions more likely to produce mutations, breaks or gaps when replicating. Some are rare, some are common; all are associated with disorders and disease, sometimes heritable conditions, sometimes not, such as many cancers.    

In the new study, Cleveland and colleagues focus on EBNA1, a viral protein that persists in cells infected with EBV. EBNA1 was previously known to bind at a specific genomic sequence in the EBV genome at the origin of replication. The researchers found that EBNA1 also binds a cluster of EBV-like sequences at a fragile site on human chromosome 11 where increasing abundance of the protein triggers chromosomal breakage.  Other prior research has shown that EBNA1 inhibits p53, a gene that plays a key role in controlling cell division and cell death. It also suppresses tumor formation when normal. Mutations of p53, on the other hand, are linked to cancer cell growth. When the scientists examined whole-genome sequencing data for 2,439 cancers across 38 tumor types from the Pan-Cancer Analysis of Whole Genomes project, they found that cancer tumors with detectable EBV revealed higher levels of chromosome 11 abnormalities, including 100% of the head and neck cancer cases. “For a ubiquitous virus that is harmless for the majority of the human population, identifying at-risk individuals susceptible to the development of latent infection-associated diseases is still an ongoing effort,” said the study’s first author Julia Li, PhD, a postdoctoral fellow in Cleveland’s lab.  “This discovery suggests that susceptibility to EBNA1-induced fragmentation of chromosome 11 depends on the control of EBNA1 levels produced in latent infection, as well as the genetic variability in the number of EBV-like sequences present on chromosome 11 in each individual. Going forward, this knowledge paves the way for screening risk factors for the development of EBV-associated diseases. Moreover, blocking EBNA1 from binding at this cluster of sequences on chromosome 11 can be exploited to prevent the development of EBV-associated diseases.”

Newswise — An enzyme that defends human cells against viruses can help drive cancer evolution towards greater malignancy by causing myriad mutations in cancer cells, according to a study led by investigators at Weill Cornell Medicine. The finding suggests that the enzyme may be a potential target for future cancer treatments. In the new study, published Dec. 8 in Cancer Research, scientists used a preclinical model of bladder cancer to investigate the role of the enzyme called APOBEC3G in promoting the disease and found that it significantly increased the number of mutations in tumor cells, boosting the genetic diversity of bladder tumors and hastening mortality. “Our findings suggest that APOBEC3G is a big contributor to bladder cancer evolution and should be considered as a target for future treatment strategies,” said study senior author Dr. Bishoy M. Faltas, assistant professor of cell and developmental biology at Weill Cornell Medicine, and an oncologist who specializes in urothelial cancers at NewYork-Presbyterian/Weill Cornell Medical Center. The APOBEC3 family of enzymes is capable of mutating RNA or DNA—by chemically modifying a cytosine nucleotide (letter “C” in the genetic code). This can result in an erroneous nucleotide at that position. The normal roles of these enzymes, including APOBEC3G, are to fight retroviruses like HIV—they attempt to hobble viral replication by mutating the cytosines in the viral genome.

The inherent hazardousness of these enzymes suggests that mechanisms must be in place to prevent them from harming cellular DNA. However, starting about a decade ago, researchers using new DNA-sequencing techniques began to find extensive APOBEC3-type mutations in cellular DNA in the context of cancer. In a 2016 study of human bladder tumor samples, Dr. Faltas, who is also director of bladder cancer research at the Englander Institute for Precision Medicine and a member of the Sandra and Edward Meyer Cancer Center, found that a high proportion of the mutations in these tumors were APOBEC3-related—and that these mutations appeared to have a role in helping tumors evade the effects of chemotherapy. Such findings point to the possibility that cancers generally harness APOBEC3s to mutate their genomes. This could help them not only acquire all the mutations needed for cancerous growth but also boost their ability to diversify and “evolve” thereafter—enabling further growth and spread despite immune defenses, drug treatments, and other adverse factors. In the new study, Dr. Faltas and his team, including first author Dr. Weisi Liu, a postdoctoral research associate, addressed the specific role of APOBEC3G in bladder cancer with direct cause-and-effect experiments.

APOBEC3G is a human enzyme not found in mice, so the team knocked out the gene for the sole APOBEC3-type enzyme in mice, replacing it with the gene for human APOBEC3G. The researchers observed that when these APOBEC3G mice were exposed to a bladder cancer-promoting chemical that mimics the carcinogens in cigarette smoke, they became much more likely to develop this form of cancer (76% developed cancer) compared with mice whose APOBEC gene was knocked out and not replaced (53% developed cancer). Moreover, during a 30-week observation period, all the knockout-only mice survived, whereas nearly a third of the APOBEC3G mice succumbed to cancer.

To their surprise, the researchers found that APOBEC3G in the mouse cells was present in the nucleus, where cellular DNA is kept using an ‘optical sectioning’ microscopy technique. Previously, this protein had been thought to reside only outside the nucleus. They also found that the bladder tumors of the APOBEC3G mice had about twice the number of mutations compared to the tumors in knockout-only mice. Identifying the specific mutational signature of APOBEC3G and mapping it in the tumor genomes, the team found ample evidence that the enzyme had caused a greater mutational burden and genomic diversity in the tumors, likely accounting for the greater malignancy and mortality in the APOBEC3G mice. “We saw a distinct mutational signature caused by APOBEC3G in these tumors that is different from signatures caused by other members of the APOBEC3 family” said Dr. Liu. Lastly, the researchers looked for APOBEC3G’s mutational signature in a widely used human tumor DNA database, The Cancer Genome Atlas, and found that these mutations appear to be common in bladder cancers and are linked to worse outcomes. “These findings will inform future efforts to restrict or steer tumor evolution by targeting APOBEC3 enzymes with drugs,” said Dr. Faltas.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see profile for Dr. Faltas.

Research Cited  published (Dec. 08, 2022) in Cancer Research:

https://doi.org/10.1158/0008-5472.CAN-22-2912 

An experimental personalized mRNA vaccine in combination with the immunotherapy Keytruda reduced the risk of recurrence or death from melanoma in patients who had already had surgery, Moderna and Merck said Tuesday. The randomized trial included 157 patients with stage 3 or stage 4 melanoma who had already had surgery. Some patients received nine doses of the experimental cancer vaccine made by Moderna and the immunotherapy made by Merck every three weeks for about a year, and some received only the immunotherapy. Treatment with the experimental vaccine in combination with the immunotherapy reduced the risk of cancer recurrence or death by 44% compared with the immunotherapy alone, the companies said. The preliminary results of a Phase 2b trial were shared in a news release and have not been peer-reviewed or published. The companies said they will publish the full data in the future and share results at an upcoming conference. The companies said they will initiate a Phase 3 study in melanoma patients next year, and will study additional tumor types.

“Today’s results are highly encouraging for the field of cancer treatment. mRNA has been transformative for COVID-19, and now, for the first time ever, we have demonstrated the potential for mRNA to have an impact on outcomes in a randomized clinical trial in melanoma,” Stéphane Bancel, chief executive officer for Moderna, said in a news release. Moderna is the maker of one of the mRNA Covid-19 vaccines used in the United States. Moderna and Merck said serious treatment-related adverse events occurred in 14.4% of patients who received the vaccine and immunotherapy in the trial, and in 10% of patients who received only the immunotherapy. Keytruda has some known risks for serious side effects, the companies said. Moderna’s experimental cancer vaccine, mRNA-4157/V940, is designed to prime patients’ immune system to generate a response to their specific tumors. Merck’s Keytruda, which is already used in the treatment of melanoma, stimulates the immune system to attack tumors. According to the American Cancer Society, melanoma accounts for about 1% of all skin cancers, but it causes a majority of skin cancer deaths. It estimates that in 2022, about 100,000 new melanomas will be diagnosed, and more than 7,600 people will die from melanoma.

Press release (Dec. 13, 2022):

https://investors.modernatx.com/news/news-details/2022/Moderna-and-Merck-Announce-mRNA-4157V940-an-Investigational-Personalized-mRNA-Cancer-Vaccine-in-Combination-with-KEYTRUDAR-pembrolizumab-Met-Primary-Efficacy-Endpoint-in-Phase-2b-KEYNOTE-942-Trial/default.aspx 

Clinical study on nasopharyngeal cancer with an unexpected result. Patients with nasopharyngeal cancer are often treated with drugs that activate their immune system against the tumor. Scientists feared that vaccination against COVID-19 could reduce the success of cancer treatment or cause severe  —until now.  A recent study now gives the all-clear in this regard. According to the study, the cancer drugs actually worked better after vaccination with the Chinese vaccine SinoVac than in unvaccinated patients. The results of the study, which was conducted by the Universities of Bonn and Shanxi in the People’s Republic of China, are published as a “Letter to the editor” in the journal Annals of Oncology, but are already available online. Many cancer cells are capable of subverting the body’s immune response. They do this by pushing a kind of button on the immune cells, the PD-1 receptor. In this way, they effectively shut down these endogenous defense forces. Drugs can be used to block PD-1 receptors. This enables the immune system to fight the tumor more effectively. Vaccination against COVID also stimulates the immune response, involving the PD-1 receptor.

“It was feared that the vaccine would not be compatible with anti-PD-1 therapy,” explains Dr. Jian Li of the Institute of Molecular Medicine and Experimental Immunology (IMMEI) at the University Hospital Bonn. “This risk is especially true for nasopharyngeal cancer, which, like the SARS Cov-2 virus, affects the upper respiratory tract.” Together with cooperation partners from the People’s Republic of China, the bioinformatician has now investigated whether this concern is justified. More than 1,500 patients treated in 23 hospitals from all over China participated in the analysis. Such multi-center studies are considered to be particularly informative because the participants are very diverse and, moreover, the results are not distorted by regional characteristics.

Vaccinated patients responded better to cancer therapy

A subset of 373 affected individuals had been vaccinated with the Chinese COVID-19 vaccine SinoVac. “Surprisingly, they responded significantly better to anti-PD-1 therapy than the unvaccinated patients,” explains Prof. Dr. Christian Kurts, Director of IMMEI and member of the Transdisciplinary Research Area “Life & Health” and the Cluster of Excellence ImmunoSensation. “Furthermore, they did not experience severe side effects more often.” The researchers cannot say why the treatment was more successful after vaccination. “We assume that vaccination activates certain immune cells, which then attack the tumor,” says Prof. Dr. Qi Mei of Shanxi University Hospital. “We will now investigate this hypothesis further.” Nasopharyngeal cancer is quite rare in this country. In southern China and other countries in Southeast Asia, however, the disease is widespread. One of the suspected reasons for this is the frequent use of air conditioning in the hot and humid regions. Nutritional factors also appear to play an important role. In Taiwan, nasopharyngeal cancer is now considered one of the leading causes of death among young men.

Study published in Annals of Oncology. (Oct. 6, 2022):

https://doi.org/10.1016/j.annonc.2022.10.002 

The jab could ward off Epstein-Barr virus, which causes glandular fever and is increasingly being linked to multiple sclerosis, lymphoma and stomach cancer.  A vaccine that wards off the common Epstein-Barr virus to potentially prevent glandular fever, multiple sclerosis (MS) and even some cancers has shown promise in mice, ferrets and monkeys. A human trial is expected to start in 2023. Gary Nabel at ModeX Therapeutics in Natick, Massachusetts, and his colleagues developed a vaccine that exposes the body to two proteins that Epstein-Barr virus uses to invade cells, training the immune system to recognise the pathogen if exposed. Initial experiments have shown that mice, ferrets and rhesus macaques developed antibodies against Epstein-Barr virus post-vaccination. To better understand the jab’s potential in people, the researchers engineered mice with human-like immune systems. When exposed to Epstein-Barr virus, only 17 per cent of the mice became infected after receiving antibodies from other vaccinated rodents. In contrast, 100 per cent of the mice without antibodies became infected. “It was a very promising result because we were able to basically block the virus infection almost entirely and stop it from causing even low-level infection,” says Nabel.

None of the mice that received the vaccine-induced antibodies developed lymphomas, cancers of the lymphatic system that are increasingly being linked to Epstein-Barr virus, compared with half of the unprotected rodents. The researchers didn’t look into any other Epstein-Barr-related conditions, such as stomach cancer. More than 95 per cent of adults worldwide are infected with Epstein-Barr virus, a type of herpes that most commonly spreads via saliva. It is known to cause glandular fever, also called “mono”, and is associated with MS. If the vaccine is shown to be safe and effective in people, it could be given to children to prevent Epstein-Barr-related conditions, says Nabel. Moderna, the US company better known for its covid-19 vaccine, recently began a clinical trial for its own Epstein-Barr jab. Moderna’s vaccine differs from the ModeX candidate in that, similarly to its covid-19 jab, it uses mRNA to instruct cells to make several Epstein-Barr virus proteins, rather than administering them directly. Julia Morahan at MS Australia says both vaccines look promising, but MS is a progressive disease and it will be several decades before we can gauge their potential. “If we were able to give every child a vaccine, we would then have to wait a solid 25 years to see if they develop MS,” she says.

Original research published in Science Translational Medicine  (May 4, 2022):

10.1126/scitranslmed.abf3685 

The authorization applies to people who received solid organ transplants and others with similarly compromised immune systems.  The Food and Drug Administration on Thursday authorized third doses of Pfizer-BioNTech’s and Moderna’s coronavirus vaccines for some people with weakened immune systems, giving physicians more leeway to protect those who did not respond enough to an initial series of shots. The authorization, in the form of updates to the existing emergency use authorizations for the two vaccines, applies to people who received solid organ transplants and others with similarly compromised immune systems, the F.D.A. said. The agency’s decision came a day before the Centers for Disease Control and Prevention’s independent advisory committee was set to consider and vote on whether to recommend the move. The committee is likely to give its approval, and the C.D.C. would follow with its own endorsement of the additional doses. “The F.D.A. is especially cognizant that immunocompromised people are particularly at risk for severe disease,” Dr. Janet Woodcock, the acting F.D.A. commissioner, said in a statement. “After a thorough review of the available data, the F.D.A. determined that this small, vulnerable group may benefit from a third dose of the Pfizer-BioNTech or Moderna Vaccines.”

The authorization of the third doses kicks off what promises to be a busy next stretch for federal vaccine regulators — and a new phase of the nation’s inoculation drive. By the start of next month, the agency is expected to grant full approval to Pfizer-BioNTech’s vaccine. That will most likely prompt a wave of vaccination mandates from companies and organizations that waited to require vaccination until the F.D.A. fully cleared a vaccine.  At the same time, government scientists and regulators are grappling with whether more Americans will need booster shots, a hotly debated move that many scientists argue is not yet supported by data. Other countries such as Israel and Germany have implemented booster policies. “Other individuals who are fully vaccinated are adequately protected and do not need an additional dose of Covid-19 vaccine at this time,” Dr. Woodcock said in her statement Thursday, adding that the agency was “actively engaged in a science-based, rigorous process with our federal partners to consider whether an additional dose may be needed in the future.” The United States is the latest country to begin offering third doses to those with weaker immune systems. France has offered additional vaccine doses to certain people with poor immune responses since April, and Germany and Hungary recently followed suit.

Researchers report two cases of pediatric lung cancer that have resulted from the vaginal transmission of uterine cervical cancer cells from mother to infant, either during, or just prior to, birth. The study is published in the New England Journal of Medicine.  Maternal–fetal transfer of cancer cells is exceptionally rare – ~ 1 per 500,000 mothers with cancer, whereas ~ 1 in 1000 live births involve a mother with a diagnosis of cancer. Eighteen cases of maternal–fetal transfer have previously been reported – all of which are believed to have occurred via transplacental mother-to-fetus transmission. However, transmission via the birth canal during vaginal delivery is also theoretically possible. For example, if the mother has cervical cancer, transformed cells residing in the fluids within the birth canal could enter the lungs of the infant during delivery.

The discovery of the two cases (both male) was made during routine sequencing of paired samples of cancerous and normal tissue, which was part of a prospective clinical trial. The first boy received a diagnosis of lung cancer at 23-months and the second was diagnosed at six years of age. Both mothers were diagnosed with cervical cancer shortly after the birth of the children (within three months). The authors were able to confirm mother-to-infant transmission based on various findings. The tumors in both boys lacked the Y chromosome. Tumor cells from the infants also shared multiple somatic mutations and single nucleotide polymorphism alleles with the cervical tumor cells of each mother. In addition, the human papillomavirus (HPV) genome was detected in the boys’ tumor cells. This was a notable finding, as HPV infection is linked to cancer; Types 16 and 18 are responsible for ~ 70% of cervical cancers. Tumor growth in both cases was localized to the bronchi, the main airways leading from the trachea to the lungs, suggesting that the tumors arose from aspiration of tumor-contaminated fluids during vaginal delivery. In the publication, the authors note that next generation sequencing “may be a useful tool to diagnose cancer that is transmitted from mothers to infants and to understand the prevalence of this transmission.”

Original findings published in NEJM (Jan. 7, 2021):

https://doi.org/10.1056/NEJMoa2030391 

Highlights

Summary

The Zika virus could shrink tumors in a childhood cancer that makes up one in seven cancer deaths, a study from researchers at Nemours Children's Health in Florida suggests. Scientists are hoping to turn a deadly African virus into a therapy for a deadly childhood cancer. The Zika virus is a mosquito-borne infection that reduces levels of a protein which forms in excess levels in patients with certain cancers. A team of researchers in Florida has shown that, in mice at least, it can can wipe out  tumors known as neuroblastomas, which make up one in seven childhood cancer deaths and form in the nerve cells as children develop.

An international team of scientists led by geneticists and disease biologists from the University of Oxford and LMU Munich have used ancient DNA to trace the evolution of Marek's Disease Virus (MDV). This global pathogen causes fatal infections in unvaccinated chickens and costs the poultry industry over $1 billion per year. The findings, published today in the journal Science. The team, which includes archaeologists and biologists, recovered and reconstructed ancient MDV sequences from archaeological chickens spanning the past 1,000 years. By comparing viral genomes derived from both modern and ancient birds, they were able to pinpoint the genetic alterations responsible for the increased virulence of the modern virus.  Based on the ancient genetic sequences, they were also able to resurrect ancient biological processes using cellular assays, demonstrating that ancient strains were significantly milder than their modern counterparts. This breakthrough not only sheds light on the evolutionary history of MDV, but also holds promise for the development of more effective therapies against this devastating poultry disease.

This new study is based on DNA isolated from chicken bones that were excavated from 140 archaeological sites in Europe and the Near East. These ancient genomes revealed that MDV was widespread in European chickens at least 1,000 years before the disease was first described in 1907. This highlights the importance of preserving archaeological remains, especially given their power to reveal valuable insights into the evolution of virulence. When first described, this disease only led to mild symptoms in older chickens. As chicken consumption dramatically increased in the 1950s and 1960s, MDV has continued to evolve and has become increasingly aggressive despite the development of several vaccines. Professor Greger Larson (School of Archaeology, University of Oxford) co-senior author commented: 'We have seen how mitigating diseases often creates a selection pressure that increases the virulence of the virus. Being able to watch this process take place by sequencing ancient virus genomes shows just how dramatically the virulence of MDV has increased in the past century.' Professor Adrian Smith (Department of Biology, University of Oxford), co-senior author said: 'Ancient DNA has provided us with a unique perspective on the emergence of MDV as a deadly chicken virus and may teach us lessons that are applicable to the control of other viral infections of medical and veterinary importance.'

The development of cancer neoantigen vaccines that prime the anti-tumor immune responses has been hindered in part by challenges in delivery of neoantigens to the tumor. Here, using the model antigen ovalbumin (OVA) in a melanoma model, we demonstrate a chimeric antigenic peptide influenza virus (CAP-Flu) system for delivery of antigenic peptides bound to influenza A virus (IAV) to the lung. We conjugated attenuated IAVs with the innate immunostimulatory agent CpG and, after intranasal administration to the mouse lung, observed increased immune cell infiltration to the tumor.

OVA was then covalently displayed on IAV-CPG using click chemistry. Vaccination with this construct yielded robust antigen uptake by dendritic cells, a specific immune cell response and a significant increase in tumor-infiltrating lymphocytes compared to peptides alone. Lastly, we engineered the IAV to express anti-PD1-L1 nanobodies that further enhanced regression of lung metastases and prolonged mouse survival after rechallenge. Engineered IAVs can be equipped with any tumor neoantigen of interest to generate lung cancer vaccines. A cancer vaccine is delivered to the lung by an engineered attenuated influenza virus.

Published in Nature Biotechnology:

https://doi.org/10.1038/s41587-023-01796-7 

Using mRNA tailored to each patient’s tumor, the vaccine may have staved off the return of one of the deadliest forms of cancer in half of those who received it. Five years ago, a small group of cancer scientists meeting at a restaurant in a deconsecrated church hospital in Mainz, Germany, drew up an audacious plan: They would test their novel cancer vaccine against one of the most virulent forms of the disease, a cancer notorious for roaring back even in patients whose tumors had been removed. The vaccine might not stop those relapses, some of the scientists figured. But patients were desperate. And the speed with which the disease, pancreatic cancer, often recurred could work to the scientists’ advantage: For better or worse, they would find out soon whether the vaccine helped. On Wednesday, the scientists reported results that defied the long odds. The vaccine provoked an immune response in half of the patients treated, and those people showed no relapse of their cancer during the course of the study, a finding that outside experts described as extremely promising. The study, published in Nature, was a landmark in the yearslong movement to make cancer vaccines tailored to the tumors of individual patients. Researchers at Memorial Sloan Kettering Cancer Center in New York, led by Dr. Vinod Balachandran, extracted patients’ tumors and shipped samples of them to Germany. There, scientists at BioNTech, the company that made a highly successful Covid vaccine with Pfizer, analyzed the genetic makeup of certain proteins on the surface of the cancer cells.

A discovery gives experts new ideas for developing vaccines to treat or even prevent cancer.

Led by the Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, the University of Hong Kong (HKUMed), an international group of the world's top clinicians in managing nasopharyngeal carcinoma (NPC) has recently published recommendations on measuring plasma EBV DNA in managing NPC in an acute setting of serious resource and personnel constraints during the COVID-19 pandemic. The international recommendations serve as important guidelines on future management of NPC when severe disasters or disruptions arise in future. The consensus statements of these recommendations were published in the oncology research journal The Lancet Oncology. NPC is endemic in Southern China, Southeast Asia, and North and East Africa, which is highly associated with prior Epstein-Barr virus (EBV) infection. It is also common in Hong Kong, closely related to genetic predisposition and dietary factors such as consumption of Chinese-style salted fish, with an age-standardized incidence rate of 5.8 per 100,000 population in 2020, ranked 8th and 17th for males and females respectively.

While histological proof is the gold standard in NPC diagnosis, plasma EBV DNA, the secretory DNA fragments of EBV, easily extracted in routine blood taking, has been regarded as the most sensitive and accurate tumor marker that has gained wide popularity and acceptance in NPC screening, diagnosis, stage segregation, treatment response monitoring, and prognostication.

Currently, standard investigations in clinical management of NPC include clinical examinations, imaging scans and nasoendoscopy, a high-risk procedure of aerosol generation. However, the essential personnel, facilities and resources could be exceedingly scarce and constrained during the raging COVID-19 pandemic. Therefore, it is sensible to consider whether plasma EBV DNA could replace nasoendoscopy, imaging scans, and even face-to-face clinical consultations during the COVID-19 pandemic and in the future when similar or even more devastating pandemics occur, leading to insufficiency of personnel and personal protective equipment. The Department of Clinical Oncology invited 33 top international clinicians from a broad range of clinical disciplines (head and neck surgery or otorhinolaryngology, medical oncology, radiation oncology and clinical oncology), representing 51 international professional societies and national clinical trial groups across four continents (Asia, Africa, Europe, and North America) during the COVID-19 pandemic to complete a modified Delphi consensus process of three rounds with 22 questions on whether plasma EBV DNA can replace the aforesaid routine clinical procedures and consultations in various clinical settings of NPC management when they are substantially restrained.

In particular, all experts (100%) disagreed that the use of plasma EBV DNA and IgA viral capsid antigen, without imaging tools, could replace nasoendoscopy and biopsy as the only staging investigations for NPC in the resource-constrained setting. Even with the availability of imaging tools, 73% of the experts disagreed that the use of plasma EBV DNA should replace nasoendoscopy and biopsy as the only staging investigation for NPC. The findings revealed that although plasma EBV DNA (supplemented, when possible, by imaging scans) can be used in most clinical circumstances in the context of resource limitations, it cannot entirely replace nasoendoscopy and tumor biopsy. All experts who rejected the use of plasma EBV DNA as the only tool in NPC management maintained that these procedures are essential, and that the patients' right to receive these standard investigations should not be suppressed, insofar as the health-care system allows. These recommendations have taken into consideration various clinical scenarios from the joint perspectives of surgeons and non-surgeons, unlike previous recommendations published by individual clinical disciplines separately. 

Significance of the consensus

In contrast to previous recommendations that endoscopic examinations should be exclusive to patients who are deemed to be at high risk of cancer recurrence and mortality from head and neck cancers and only when adequate personal protective equipment is available, this latest consensus concludes that merely measuring plasma EBV DNA should not replace the conventional but essential nasoendoscopic examinations, even when imaging services are very limited. Plasma EBV DNA combined with imaging scans can be considered an acceptable alternative in a very restricted clinical setting, but cannot replace face-to-face consultations and nasoendoscopy, and it cannot be used alone without imaging in NPC management. Dr. Victor Lee Ho-fun, chairperson and clinical associate professor, Department of Clinical Oncology, School of Clinical Medicine, HKUMed, who spearheaded and designed the survey, commented, "These recommendations, which are the results of concerted efforts of international collaboration and cooperation, can serve as references and be used in other acute settings or during natural disasters, where there is an unexpectedly high risk of health hazards to patients and health care workers and a severe paucity of health personnel and resources." Dr. Lee also hopes that "these recommendations can further stimulate international harmonization of plasma EBV DNA leading to more affordable use at institutions and hospitals in low-income and middle-income countries, and foster future researches in devising more sensitive and accurate tumor markers for NPC and other cancers when the pandemic is much contained."

Published December 2022 in The Lancet Oncology:

https://doi.org/10.1016/S1470-2045(22)00505-8 

Babies develop risk of cancer in womb, but will not go on to develop it without second ‘hit’ from an infection, scientists believe. Childhood leukaemia is driven by common childhood infections meeting pre-cancerous cells in the blood, scientists believe. Experts at the Institute of Cancer Research (ICR) in London have found babies develop the risk for leukaemia in the womb, but will not go on to develop the disease without a second ‘hit’ from a viral or bacterial infection, such as flu. The research highlights the importance of allowing infants to socialise with other children early in their lives, to prime their immune systems against infections. The discovery came by studying pairs of twins, where only one initially developed acute lymphoblastic leukaemia (ALL) - the most common type of the cancer in children. Identical twins are around 15-25 per cent more likely to go on to develop ALL if their sibling already has the disease, while less than one per cent of non-identical twins or other siblings go on to develop the disease. Researchers followed the twins for up to 15 years and found the high risk only applies if the identical twins shared a single placenta before birth - which only happens in around 60 per cent of identical twin pairs.

Findings 'confirm disease can be traced back to womb'

It confirms that the conditions needed to trigger leukaemia first arise in the womb, and even the healthy twin will carry "pre-leukaemia" cells in the blood, which have occurred through a spontaneous developmental error, and passed between the two. But clinically silent cells will not develop into cancer without a post-birth "hit", probably from common childhood infections. Prof Sir Mel Greaves, the founding director of the Centre for Evolution and Cancer and Professor of Cell Biology at The Institute of Cancer Research, London, said: “Our study provides new insights into the origins of childhood acute lymphoblastic leukaemia. “These new findings confirm that the disease can be traced back to the womb when pre-leukaemia cells spread via the twins’ shared blood supply. "What remained a mystery until now was why sometimes only one twin is diagnosed with leukaemia. “We still do not know for certain what leads to the first ‘hit’ of genetic changes in the womb, but we think that the second ‘hit’ of genetic changes is probably triggered by common childhood infections – opening up the possibility of ‘priming’ the immune system in infancy to avoid the development of the disease later on in life.” Acute lymphoblastic leukaemia is the most common type of childhood cancer, accounting for 80 per cent of leukaemia cases in children. The team are now focussed on finding the the second infection-driven hit after birth.

Boosting the gut could protect children against disease

They believe that the gut microbiome may be playing a key role in protecting children against developing leukaemia even if they have pre-cancerous cells. Although vaccines have little impact on preventing ALL, boosting the gut in early life may help. Prof Greaves added: “Risk of ALL is elevated by C-section birth, lack of breast feeding and paucity of social contacts in infancy. “Conversely, attendance at play groups in infancy is protective. So, to some extent , risk can be modified without medical intervention.” The findings will also allow doctors to assess the risk of ALL for twins,  firstly by determining whether the twins are identical and sharing a placenta and then by regularly tracking the levels of pre-leukaemia cells in their blood. Sarah McDonald, the deputy director of research at Blood Cancer UK, who funded the work said: “Understanding the mechanism as to how the cancer develops in identical twins, and why often only one develops leukaemia is an important question to answer. “It helps us understand both the risk of the other sibling developing leukaemia and provides insight into how leukaemia develops in all children. “This research shows that in cases where one twin develops leukaemia, and both twins both share a placenta during pregnancy, two events are needed to determine whether the other sibling develops the disease - one before birth and the other after.”

Research published (Dec. 20, 2022) in the journal Leukaemia:

https://doi.org/10.1038/s41375-022-01756-1 

New way of altering DNA is used to engineer an "exciting", experimental therapy for a 13-year-old girl. A teenage girl's incurable cancer has been cleared from her body in the first use of a revolutionary new type of medicine. All other treatments for Alyssa's leukaemia had failed. So doctors at Great Ormond Street Hospital used "base editing" to perform a feat of biological engineering to build her a new living drug. Six months later the cancer is undetectable, but Alyssa is still being monitored in case it comes back. Alyssa, who is 13 and from Leicester, was diagnosed with T-cell acute lymphoblastic leukaemia in May last year. T-cells are supposed to be the body's guardians - seeking out and destroying threats - but for Alyssa they had become the danger and were growing out of control. Her cancer was aggressive. Chemotherapy, and then a bone-marrow transplant, were unable to rid it from her body. Without the experimental medicine, the only option left would have been merely to make Alyssa as comfortable as possible. "Eventually I would have passed away," said Alyssa. Her mum, Kiona, said this time last year she had been dreading Christmas, "thinking this is our last with her". And then she "just cried" through her daughter's 13th birthday in January......

Using a next generation sequencing analysis to examine human endogenous retrovirus (HERV) integration sites, researchers from Kumamoto University, the National Institute of Genetics (Japan), and the University of Michigan (U.S.) have discovered that these ancient retroviruses can undergo retrotransposition (DNA sequence insertion with RNA mediation) into iPS cells. The team believes that their discovery places a spotlight on a possible risk that HERVs pose when using iPS cells in regenerative medicine. The study of ancient retroviruses embedded in our genome requires knowledge about our coexistence with viral threats throughout history. We know that HERVs occupy approximately 8% of the human genome and obtain mutations and deletions over long periods. HERVs are also expressed in early embryos and play several physiological roles in human development. For example, HERV-W and HERV-FRD Env proteins are important for placental formation, and HERV-K is thought to protect host cells from exogenous retrovirus infection. However, uncontrollable HERV-K expression is also thought to be associated with various diseases, including various cancers and neurological diseases, but the details of this association is not well known in humans.

Since no one has yet discovered replication competent HERVs in our genome, it is thought that they are from an extinct (fossil) virus. In their current work, the research team from Japan and the US discovered that HERV-K is expressed in SOX2-expressing cells, such as those in early embryos, cancer stem cells and iPS cells. They also found that some HERV-K are newly integrated into the host genome in the absence of Env, the viral envelope glycoprotein. This integration was dependent on reverse transcriptase, integrase and protease, thus the researchers hypothesized that the HERV-K embedded in our genome is actually not from a fossil virus, but moves on the genome through the synthesis of proviral DNA reverse transcription. Interestingly, when the researchers compared the HERV-K integration sites between iPS and fibroblast cells from the same donor, they found new HERV-K integration sites in iPS cells.

However, the new integration sites were rarely preserved and disappeared during long-term culturing. HERV-K is likely to be randomly integrated into genome, thus the possibility remains that HERV-K retrotransposed-cells predominantly survive depending on their integration site. The movement of HERV-K on the genome might cause cancer and neurological diseases by altering the gene expression profile. The researchers believe that the risk of HERV-K transposition is low in iPS cells but suggest that monitoring HERV-K integration sites should be seriously considered to improve the safety of regenerative medicine using iPS cells. This research was published online on 14 April 2022 in the Journal of Virology.

Research cited published in J. Virology (April 14, 2022):

https://doi.org/10.1128/jvi.00356-22 

Background: Relatively little is known about the long-term impacts of SARS-CoV-2 biology, including whether it increases the risk of cancer. This study aims to identify the molecular interactions between COVID-19 infections and cancer processes.

Materials and Methods: We integrated recent data on SARS-CoV-2-host protein interactions, risk factors for critical illness, known oncogenes, tumor suppressor genes and cancer drivers in EpiGraphDB, a database of disease biology and epidemiology. We used these data to reconstruct the network of molecular links between SARS-CoV-2 infections and cancer processes in various tissues expressing the angiotensin-converting enzyme 2 (ACE2) receptor. We applied community detection algorithms and Gene Set Enrichment Analysis (GSEA) to identify cancer-relevant pathways that may be perturbed by SARS-CoV-2 infection.

Results: In lung tissue, the results showed that 4 oncogenes are potentially targeted by SARS-CoV-2, and 92 oncogenes interact with other human genes targeted by SARS-CoV-2. We found evidence of potential SARS-CoV-2 interactions with Wnt and hippo signaling pathways, telomere maintenance, DNA replication, protein ubiquitination and mRNA splicing. Some of these pathways were potentially affected in multiple tissues.

Conclusions: The long-term implications of SARS-CoV-2 infection are still unknown, but our results point to the potential impact of infection on pathways relevant to cancer affecting cell proliferation, development and survival, favoring DNA degradation, preventing the repair of damaging events and impeding the translation of RNA into working proteins. This highlights the need for further research to investigate whether such effects are transient or longer lasting. Our results are openly available in the EpiGraphDB platform at https://epigraphdb.org/covid-cancer and the repository https://github.com/MRCIEU/covid-cancer (https://doi.org/10.5281/zenodo.6391588).

Preprint available at bioRxiv (April 5, 2022):

https://doi.org/10.1101/2022.04.04.487020 

Antibody treatment for COVID-19 seems to have spurred mutations in the SARS-CoV-2 that infected a man with a compromised immune system.In mid-2020, a man was admitted to hospital with COVID-19. He had been diagnosed with cancer in 2012; the illness and his treatment had probably weakened his immune system. The man’s COVID-19 was treated with two courses of the antiviral drug remdesivir and, later, two courses of convalescent plasma — antibody-laden blood from people who had recovered from COVID-19. He died 102 days after admission. Ravindra Gupta at the University of Cambridge, UK, and his colleagues analysed viral genomes obtained from the man during his illness (S. A. Kemp et al. Nature https://doi.org/10.1038/s41586-021-03291-y; 2021). The viral populations in his blood changed little after remdesivir treatment. But after each course of convalescent plasma, the samples were dominated by viruses with a particular pair of mutations in the SARS-CoV-2 spike protein, the main target of the immune system. Experiments showed that one of the mutations weakened the potency of the antibodies in the convalescent plasma, yet also reduced the virus’s infectivity. The second mutation restored infectivity. The potential for viral evolution means that convalescent plasma should be used cautiously when treating people with compromised immunity, the authors say.

Research published in Nature (Feb. 5, 2021):

https://doi.org/10.1038/s41586-021-03291-y