Tag Archives: Oncology

Microbiology

First-in-human nanoparticle HIV vaccine induces broad and publicly targeted helper T cell responses

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Reviewed by Lily Ramsey, LLMMay 25 2023

Researchers from Fred Hutchinson Cancer Center in Seattle, Scripps Research in La Jolla, California, IAVI and other collaborating institutions have characterized robust T-cell responses in volunteers participating in the IAVI G001 Phase 1 clinical trial to test the safety and immune response of a self-assembling nanoparticle HIV vaccine.

Their work, published in Science Translational Medicine, signals a major step toward development of a vaccine approach to end the HIV/AIDS epidemic worldwide. The antigen used in this study was jointly developed by IAVI and Scripps Research and has been shown in previous analyses to stimulate VRC01-class B cells, an immune response considered promising enough for boosting in further studies.

We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine. These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV.”

Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division and co-senior author of the study

However, she added, this is the first step, and heterologous booster vaccines will still be needed to eventually produce VRC01-class broadly neutralizing antibodies, which in previous studies have demonstrated the ability to neutralize approximately 90% of HIV strains.

“We showed previously that this vaccine induced the desired B-cell responses from HIV broadly neutralizing antibody precursors. Here we demonstrated strong CD4 T-cell responses, and we went beyond what is normally done by drilling down to identify the T cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” William Schief, PhD, executive director of vaccine design for IAVI’s Neutralizing Antibody Center at Scripps Research and professor, Department of Immunology and Microbiology, at Scripps Research, who is co-senior author of the study.

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The trial is a phase 1, randomized, double-blind and placebo-controlled study to evaluate the safety and effectiveness of a nanoparticle HIV vaccine in healthy adult volunteers without HIV. It was comprised of two groups with 18 vaccine and six placebo recipients per group, with 48 total enrollees. Participants were given two doses of the vaccine or placebo eight weeks apart.

McElrath acknowledged the groundbreaking work of her lab team, the biostatistical team and Fred Hutch’s Vaccine Trials Unit for their invaluable contributions to the study. The Vaccine Trials Unit conducts multiple vaccine trials and was one of only two sites for this study.

Findings from the study include:

  • Vaccine-specific CD4 T cells were induced in almost all vaccine recipients.
  • Lymph node GC T follicular helper cells increased after vaccination compared to placebo.
  • Lumazine synthase protein, needed for self-assembly of the particle, also induced T-cell responses that can provide additional help to ultimately enhance efficacy in a sequential vaccine strategy.
  • Vaccine-specific CD4 T cells were polyfunctional and had diverse phenotypes.
  • LumSyn-specific CD8 T cells were highly polyfunctional and had a predominantly effector memory phenotype.
  • CD4 T-cell responses were driven by immunodominant epitopes with diverse and promiscuous HLA restriction.
  • CD8 T-cell responses to LumSyn were driven by HLA-A*02-restricted immunodominant epitopes B- and T-cell responses correlated within but not between LN and peripheral blood compartments.

This study was funded by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI Neutralizing Antibody Center; National Institute of Allergy and Infectious Diseases; and Ragon Institute of MGH, MIT and Harvard.

Study authors WRS and SM are inventors on a patent filed by Scripps and IAVI on the eOD-GT8 monomer and 60-mer immunogens (patent number 11248027, “Engineered outer domain (eOD) of HIV gp 120 and mutants thereof”). WRS, KWC and MJM are inventors on patents filed by Scripps, IAVI and Fred Hutch on immunodominant peptides from LumSyn (Title: Immunogenic compositions; filing no. 63127975).

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Source:

Fred Hutchinson Cancer Center

Journal reference:

Cohen, K. W., et al. (2023) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Science Translational Medicine. doi.org/10.1126/scitranslmed.adf3309.

Microbiology

Novel computational platform can expand the pool of cancer immunotherapy targets

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Reviewed by Megan Craig, M.Sc.May 17 2023

Researchers at Children’s Hospital of Philadelphia (CHOP) and the University of California, Los Angeles (UCLA) have developed a computational platform capable of discovering tumor antigens derived from alternative RNA splicing, expanding the pool of cancer immunotherapy targets. The tool, called “Isoform peptides from RNA splicing for Immunotherapy target Screening” (IRIS), was described in a paper published today in the Proceedings of the National Academy of Sciences.

Immunotherapy has revolutionized cancer treatment, but for many cancers including pediatric cancers, the repertoire of antigens is incomplete, underscoring a need to expand the inventory of actionable immunotherapy targets. We know that aberrant alternative RNA splicing is widespread in cancer and generates a range of potential immunotherapy targets. In our study, we were able to show that our computational platform was able to identify immunotherapy targets that arise from alternative splicing, introducing a broadly applicable framework for discovering novel cancer immunotherapy targets that arise from this process.”

Yi Xing, PhD, co-senior author, director of the Center for Computational and Genomic Medicine at CHOP

Cancer immunotherapy has ushered in a sea change in the treatment of many hematologic cancers, harnessing the power of a patient’s own immune system to fight the disease. Chimeric antigen receptor T-cell (CAR-T) and T cell receptor-engineered T cell (TCR-T) therapies modify a patient’s own T cells to attack known antigens on the surface of cancer cells and have often led to durable responses for cancers that were once considered incurable. However, the field has encountered challenges in the solid tumor space, in large part due to a lack of known and suitable targets for these cancers, highlighting the need for novel approaches to expand the pool of immunotherapy targets.

Alternative splicing is an essential process that allows for one gene to code for many gene products, based on where the RNA is cut and joined, or spliced, before being translated into proteins. However, the splicing process is dysregulated in cancer cells, which often take advantage of this process to produce proteins that promote growth and survival, allowing them to replicate uncontrollably and metastasize. This happens in many adult and pediatric cancers. Scientists have suggested splicing dysregulation could be a source of novel tumor antigens for immunotherapy, but identifying such antigens has been a challenge.

To address this difficulty, the researchers created IRIS to leverage large-scale tumor and normal RNA sequencing data and incorporate multiple screening approaches to discover tumor antigens that arise due to alternative splicing. Integrating RNA sequencing-based transcriptomics data and mass spectrometry-based proteomics data, the researchers showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules, the part of the human immune system that presents antigens to T cells.

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The researchers then applied IRIS to RNA sequencing data from neuroendocrine prostate cancer (NEPC), a metastatic and highly lethal disease known to involve shifts in RNA splicing, as discovered in a prior study by CHOP and UCLA researchers. From 2,939 alternative splicing events enriched in NEPC, IRIS predicted 1,651 peptides as potential TCR targets. The researchers then applied a more stringent screening test, which prioritized 48 potential targets. Interestingly, the researchers found that these targets were highly enriched for peptides encoded by short sequences of less than 30 nucleotides in length – also known as “microexons” – which may arise from a unique program of splicing dysregulation in this type of cancer.

To validate the immunogenicity of these targets, the researchers isolated T cells reactive to IRIS-predicted targets, and then used single-cell sequencing to identify the TCR sequences. The researchers modified human peripheral blood mononuclear cells with seven TCRs and found they were highly reactive against targets predicted by IRIS to be good immunotherapy candidates. One TCR was particularly efficient at killing tumor cells expressing the target peptide of interest.

“Immunotherapy is a powerful tool that has had a significant impact on the treatment of some cancers, but the benefits have not been fully realized in many lethal cancers that could benefit from this approach,” said Owen N. Witte, MD, University Professor of Microbiology, Immunology, and Molecular Genetics and member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “The discovery of new antigenic targets that may be shared among different patients – and even different tumor types – could be instrumental in expanding the value of cell-based therapies. Analyzing massive amounts of data on tumor and normal tissues, which requires sophisticated computational tools like those developed by the Xing Lab, provides actionable insights on targets that one day could be tested in the clinic.”

“This proof-of-concept study demonstrates that alternatively spliced RNA transcripts are viable targets for cancer immunotherapy and provides a big data and multiomics-powered computational platform for finding these targets,” Dr. Xing added. “We are applying IRIS for target discovery across a wide range of pediatric and adult cancers. We are also developing a next-generation IRIS platform that harnesses newer transcriptomics technologies, such as long read and single cell analysis.”

This research was supported in part by the Immuno-Oncology Translational Network (IOTN) of the National Cancer Institute’s Cancer Moonshot Initiative, other National Institutes of Health funding, the Parker Institute for Cancer Immunotherapy, the Cancer Research Institute, and the Ressler Family Fund.

Source:

Children’s Hospital of Philadelphia

Journal reference:

Pan, Y., et al. (2023) IRIS: Discovery of cancer immunotherapy targets arising from pre-mRNA alternative splicing. PNAS. doi.org/10.1073/pnas.2221116120.

Microbiology

Live attenuated nasal vaccine elicits superior immunity to SARS-CoV-2 variants in hamsters

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Reviewed by Emily Henderson, B.Sc.Apr 4 2023

Since the beginning of the COVID-19 pandemic, researchers have been working on mucosal vaccines that can be administered through the nose. Now, scientists in Berlin have developed a live attenuated vaccine for the nose. In “Nature Microbiology”, they describe the special immune protection it induces.

Coronaviruses spread primarily through the air. When infected people speak, cough, sneeze or laugh, they expel droplets of saliva containing the virus. Other people then breathe in these airborne pathogens and become infected themselves. A research team in Berlin decided to try to fight the virus that causes COVID-19 where it first takes hold: the mucous membranes of the nose, mouth, throat, and lungs. To do so, the scientists developed a live attenuated SARS-CoV-2 vaccine that is administered through the nose. In the latest issue of the journal “Nature Microbiology“, the interdisciplinary team describes how this live attenuated vaccine confers better immunity than vaccines injected into muscle.

Already in the fall of last year, two nasal vaccination formulations were approved for use in India and China. These contain modified adenoviruses – which typically cause respiratory or gastrointestinal illnesses – that are self-attenuating, meaning they either replicate poorly or stop replicating altogether, and therefore never trigger disease. Other live nasal vaccines are currently undergoing development and testing around the world.

Protection at the site of infection

The benefits of a nasal vaccine go far beyond just providing an alternative for people afraid of needles. When a vaccine is injected, it infers immunity primarily in the blood and throughout the entire body. However, this means that the immune system only detects and combats coronaviruses relatively late on in an infection, as they enter the body via the mucous membranes of the upper respiratory tract. “It is here, therefore, that we need local immunity if we want to intercept a respiratory virus early on,” explains the study’s co-last author Dr. Jakob Trimpert, a veterinarian and research group leader at the Institute of Virology at Freie Universität Berlin.

“Nasal vaccines are far more effective in this regard than injected vaccines, which fail or struggle to reach the mucous membranes,” emphasizes Dr. Emanuel Wyler, another co-last author. He has been researching COVID-19 since the start of the pandemic as part of the RNA Biology and Posttranscriptional Regulation Lab, which is led by Professor Markus Landthaler at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB).

In an ideal scenario, a live intranasal vaccine stimulates the formation of the antibody immunoglobulin A (IgA) directly on site, thus preventing infection from occurring in the first place. IgA is the most common immunoglobin in the mucous membranes of the airways. It is able to neutralize pathogens by binding to them and preventing them from infecting respiratory tract cells. At the same time, the vaccine stimulates systemic immune responses that help provide effective overall protection from infection.

Memory T cells that reside in lung tissue play a similarly useful role to antibodies in the mucosa. These white blood cells remain in affected tissue long after an infection has passed and remember pathogens they have encountered before. Thanks to their location in the lungs, they can respond quickly to viruses that enter through the airways.” The co-first author draws attention to one of the observations the team made during their study: “We were able to show that prior intranasal vaccination results in the increased reactivation of these local memory cells in the event of a subsequent SARS-CoV-2 infection. Needless to say, we were particularly pleased with this result.”

Dr. Geraldine Nouailles, immunologist and research group leader at the Department of Pneumology, Respiratory Medicine, and Intensive Care Medicine at Charité

Local immunity impedes viral infection

The scientists tested the efficacy of the newly developed intranasal COVID-19 vaccine on hamster models that had been established by Trimpert and his team at Freie Universität Berlin at the beginning of the pandemic. These rodents are currently the most important non-transgenic model organisms for research into the novel coronavirus, as they can be infected with the same virus variants as humans and develop similar symptoms. They found that after two doses of the vaccine, the virus could no longer replicate in the model organism. “We witnessed strong activation of the immunological memory, and the mucous membranes were very well protected by the high concentration of antibodies,” Trimpert explains. The vaccine could therefore also significantly reduce the transmissibility of the virus.

In addition, the scientists compared the efficacy of the live attenuated vaccine with that of vaccines injected into the muscle. To do so, they vaccinated the hamsters either twice with the live vaccine, once with the mRNA and once with the live vaccine, or twice with an mRNA or adenovirus-based vaccine. Then, after the hamsters were infected with SARS-CoV-2, they used tissue samples from the nasal mucosa and lungs to see how strongly the virus was still able to attack the mucosal cells. They also determined the extent of the inflammatory response using single-cell sequencing. “The live attenuated vaccine performed better than the other vaccines in all parameters,” Wyler summarizes. This is probably due to the fact that the nasally administered vaccine builds up immunity directly at the viral entry site. In addition, the live vaccine contains all components of the virus – not just the spike protein, as is the case with the mRNA vaccines. While spike is indeed the virus’s most important antigen, the immune system can also recognize the virus from about 20 other proteins.

Better than conventional vaccines

The best protection against the SARS-CoV-2 was provided by double nasal vaccination, followed by the combination of a muscular injection of the mRNA vaccine and the subsequent nasal administration of the live attenuated vaccine. “This means the live vaccine could be particularly interesting as a booster,” says the study’s co-first author Julia Adler, a veterinarian and doctoral student at the Institute of Virology at Freie Universität Berlin.

The principle of live attenuated vaccines is old and is already used in measles and rubella vaccinations, for example. But in the past, scientists generated the attenuation by chance – sometimes waiting years for mutations to evolve that produced an attenuated virus. The Berlin researchers, on the other hand, were able to specifically alter the genetic code of the coronaviruses. “We wanted to prevent the attenuated viruses from mutating back into a more aggressive variant,” explains Dr. Dusan Kunec, a scientist at the Institute of Virology at Freie Universität Berlin and another co-last author of the study. “This makes our live vaccine entirely safe and means it can be tailored to new virus variants,” stresses Kunec, who was instrumental in developing the vaccine.

The next step is safety testing: The researchers are collaborating with RocketVax AG, a Swiss start-up based in Basel. The biotech company is developing the live attenuated SARS-CoV-2 vaccine and preparing a phase 1 clinical trial in humans. “We are thrilled to be at the forefront of developing and manufacturing the live attenuated SARS-CoV-2 vaccine as a nasal spray at RocketVax. Our goal is to rapidly scale-up production and advance clinical development towards market access to provide protection against post-COVID symptoms for all. We see great potential in the market for seasonal nasal vaccines”, says Dr. Vladimir Cmiljanovic, CEO of RocketVax.

The future will show which nasal vaccine will ultimately provide better protection. The manufacturers of the nasal adenovirus vaccines developed in India and China have not yet applied for approval in Europe. But one thing is clear to the scientists: since they are administered as nasal sprays or drops, nasal vaccines are a good option for use in places with limited access to trained medical staff. They are also inexpensive to produce and easy to store and transport. Last but not least, live attenuated vaccines such as this one have been proven to provide cross-protection against related viral strains, and thus presumably also against future SARS-CoV-2 variants.

Source:

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Journal reference:

Nouailles, G., et al. (2023). Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters. Nature Microbiology. doi.org/10.1038/s41564-023-01352-8

Microbiology

Moderna’s experimental cancer vaccine treats but doesn’t prevent melanoma – a biochemist explains how it works

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Media outlets have reported the encouraging findings of clinical trials for a new experimental vaccine developed by the biotech company Moderna to treat an aggressive type of skin cancer called melanoma.

Although this is potentially very good news, it occurred to me that the headlines may be unintentionally misleading. The vaccines most people are familiar with prevent disease, whereas this experimental new skin cancer vaccine treats only patients who are already sick. Why is it called a vaccine if it does not prevent cancer?

I am a biochemist and molecular biologist studying the roles that microbes play in health and disease. I also teach cancer genetics to medical students and am interested in how the public understands science. While preventive and therapeutic vaccines are administered for different health care goals, they both train the immune system to recognize and fight off a specific disease agent that causes illness.

Most vaccines are administered to healthy people before they get sick to prevent illnesses caused by viruses or bacteria. These include vaccines that prevent polio, measles, COVID-19 and many other diseases. Researchers have also developed vaccines to prevent some types of cancers that are caused by such viruses as the human papillomaviruses and Epstein-Barr virus.

Your immune system recognizes objects such as certain microbes and allergens that do not belong in your body and initiates a series of cellular events to attack and destroy them. Thus, a virus or bacterium that enters the body is recognized as something foreign and triggers an immune response to fight off the microbial invader. This results in a cellular memory that will elicit an even faster immune response the next time the same microbe intrudes.

The problem is that sometimes the initial infection causes serious illness before the immune system can mount a response against it. While you may be better protected against a second infection, you have suffered the potentially damaging consequences of the first one.

This is where preventive vaccines come in. By introducing a harmless version or a portion of the microbe to the immune system, the body can learn to mount an effective response against it without causing the disease.

For example, the Gardasil-9 vaccine protects against the human papillomavirus, or HPV, which causes cervical cancer. It contains protein components found in the virus that cannot cause disease but do elicit an immune response that protects against future HPV infection, thereby preventing cervical cancer.

Unlike cervical cancer, skin melanoma isn’t caused by a viral infection, according the latest evidence. Nor does Moderna’s experimental vaccine prevent cancer as Gardasil-9 does.

The Moderna vaccine trains the immune system to fight off an invader in the same way preventive vaccines most people are familiar with do. However, in this case the invader is a tumor, a rogue version of normal cells that harbors abnormal proteins that the immune system can recognize as foreign and attack.

What are these abnormal proteins and where do they come from?

All cells are made up of proteins and other biological molecules such as carbohydrates, lipids and nucleic acids. Cancer is caused by mutations in regions of genetic material, or DNA, that encode instructions on what proteins to make. Mutated genes result in abnormal proteins called neoantigens that the body recognizes as foreign. That can trigger an immune response to fight off a nascent tumor. However, sometimes the immune response fails to subdue the cancer cells, either because the immune system is unable to mount a strong enough response or the cancer cells have found a way to circumvent the immune system’s defenses.

Moderna’s experimental melanoma vaccine contains genetic information that encodes for portions of the neoantigens in the tumor. This genetic information is in the form of mRNA, which is the same form used in the Moderna and Pfizer-BioNtech COVID-19 vaccines. Importantly, the vaccine cannot cause cancer, because it encodes for only small, nonfunctional parts of the protein. When the genetic information is translated into those protein pieces in the body, they trigger the immune system to mount an attack against the tumor. Ideally, this immune response will cause the tumor to shrink and disappear.

Notably, the Moderna melanoma vaccine is tailor-made for each patient. Each tumor is unique, and so the vaccine needs to be unique as well. To customize vaccines, researchers first biopsy the patient’s tumor to determine what neoantigens are present. The vaccine manufacturer then designs specific mRNA molecules that encode those neoantigens. When this custom mRNA vaccine is administered, the body translates the genetic material into proteins specific to the patient’s tumor, resulting in an immune response against the tumor.

Vaccines are a form of immunotherapy, because they treat diseases by harnessing the immune system. However, other immunotherapy cancer drugs are not vaccines because, while they also stimulate the immune system, they do not target specific neoantigens.

In fact, the Moderna vaccine is co-administered with the immunotherapy drug pembrolizumab, which is marketed as Keytruda. Why are two drugs needed?

Certain immune cells called T-cells have molecular accelerator and brake components that serve as checkpoints to ensure they are revved up only in the presence of a foreign invader such as a tumor. However, sometimes tumor cells find a way to keep the T-cell brakes on and suppress the immune response. In these cases, the Moderna vaccine correctly identifies the tumor, but T-cells cannot respond to it.

Pembrolizumab, however, can bind directly to a brake component on the T-cell, inactivating the brake system and allowing the immune cells to attack the tumor.

So why can’t the Moderna vaccine be administered to healthy people to prevent melanoma before it arises?

Cancers are highly variable from person to person. Each melanoma harbors a different neoantigen profile that cannot be predicted in advance. Therefore, a vaccine cannot be developed in advance of the illness.

The experimental mRNA melanoma vaccine, currently still in early-phase clinical trials, is an example of the new frontier of personalized medicine. By understanding the molecular basis of diseases, researchers can explore how their underlying causes vary among people, and offer personalized therapeutic options against those diseases.


Mark R. O’Brian

The Conversation

Microbiology

Study reveals subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma

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Reviewed by Emily Henderson, B.Sc.Dec 16 2022

Researchers from the Department of Clinical Oncology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong (HKUMed) discovered a novel subtype of Epstein-Barr Virus (EBV)-positive nasopharyngeal carcinoma (NPC) and EBV-associated immunosuppression in the tumor microenvironment (TME). These findings have provided novel insights into the traditional NPC pathogenesis model and highlights EBV-specific communications in the TME as potential therapeutic target in NPC. The research has been published in eBioMedicine.

Background and research findings

NPC has a high incidence rate in Southeast Asia, in particular Guangdong and Hong Kong. Due to its worldwide rarity, studies on NPC heavily rely on local research teams, and its pathogenesis mechanism remains largely unclear. In Hong Kong, NPC is the commonest cancer type for the men aged 20-44 and ranked 8th highest incidence rate among males. Strikingly, EBV is detected in 95% of the Hong Kong cases. Having thorough understanding of NPC pathogenesis, in particular the role of EBV, is critical for advancing the clinical diagnosis and treatment for this deadly disease and is an active research topic in the field.

The research team used a cutting-edge bioinformatics approach to comprehensively decode the epigenetics of the tumors dissected from NPC patients. EBV+NPC was believed to be massively dysregulated by the global DNA hypermethylation, a phenomenon that denotes a large-scale increase of methyl groups onto the DNA sequences within the cancer cells. These methyl-groups function like an ‘off-switch’ to inactivate tumor-suppressors that safeguard the cells from turning into a tumor, and thereby, promoting tumor development. Moreover, global DNA hypermethylation is rarely observed in non-EBV cancer types proposed to be associated with EBV and is a critical step in NPC pathogenesis.

The research team discovered that, in contrast to what was commonly believed, 20% of NPC cases were characterized by global DNA hypomethylation, which refers to a large-scale decrease of methyl groups onto the DNA sequences in the cancer cells. The study also discovered that EBV may reprogram the cell-cell communications[4]between the cancer cells and the immune cells, and consequently protect the cancer cells from being destroyed by the immune system.

Significance of the study

‘Commonly infected by EBV, the NPC tumours carried distinctive methylation patterns. This finding is not well-recognised by the NPC development model. When global DNA hypomethylation occurs during NPC pathogenesis, whether it occurs as an alternative pathway in a subset of patients and its potential of predicting patients’ survival, clinical features, and response to therapies are critical for understanding NPC and providing personalized treatments for patients.’ commented Dr Dai Wei, Assistant Professor of the Department of Clinical Oncology, School of Clinical Medicine, HKUMed.

Professor Maria Li Lung, Emeritus Professor of the Department of Clinical Oncology, School of Clinical Medicine, HKUMed, added, ‘Since the immunosuppressive cell-cell communications were associated with EBV, these communications are highly-specific to the tumours and could be potential therapeutic targets and biomarkers in NPC.’ ‘We are now designing experiments to explore this feasibility and understand the clinical impacts of NPC subtypes. We hope the work can be beneficial to NPC patients in Hong Kong.’

About the research team

This research was co-supervised by Dr Dai Wei, Assistant Professor, and Professor Maria Li Lung, Emeritus Professor of the Department of Clinical Oncology, School of Clinical Medicine, HKUMed. Dr Larry Chow Ka-yue and Mr Dittman Chung Lai-shun from the Department of Clinical Oncology, School of Clinical Medicine, HKUMed, are the co-first authors, Dr Tao Lihua, Scientific Officer, provided support to the research.

The collaborators included Dr Chan Kui-fat and Dr Stewart Tung Yuk from Department of Clinical Oncology and Department of Clinical Pathology from the Tuen Mun Hospital, Hong Kong; Professor Roger Ngan Kai-cheong, Professor Ng Wai-tong, Professor Anne Lee Wing-mui, Professor Dora Kwong Lai-wan, Dr Victor Lee Ho-fun and Dr Lam Ka-on from the Department of the Clinical Oncology, School of Clinical Medicine, HKUMed; Dr Yau Chun-chung from Department of Oncology from Princess Margaret Hospital, Hong Kong; Professor Chen Honglin and Dr Liu Jiayan from Department of Microbiology, School of Biomedical Sciences, HKUMed.

Source:

The University of Hong Kong

Journal reference:

Chow, L. K-Y., et al. (2022) Epigenomic landscape study reveals molecular subtypes and EBV-associated regulatory epigenome reprogramming in nasopharyngeal carcinoma. eBioMedicine. doi.org/10.1016/j.ebiom.2022.104357.

Microbiology

WashU’s nasal COVID-19 vaccine authorized for emergency use in India as a booster

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Reviewed by Emily Henderson, B.Sc.Dec 9 2022

A nasal COVID-19 vaccine based on technology licensed from Washington University in St. Louis has been approved for emergency use in India as a booster for people who have already received two doses of other COVID-19 vaccines. The approval follows the Indian government’s emergency use authorization in September of the vaccine as a primary series of two doses, and makes the intranasal vaccine the world’s first to receive approval as both a primary vaccine for COVID-19 and a booster.

The expanded authorization means that the vaccine, delivered via drops into the nose, can be received by almost any adult in India. People who have never been vaccinated for COVID-19 are eligible, as well as those who already have received other COVID-19 vaccines. An estimated 900 million people in India have already received two doses of a COVID-19 vaccine.

We are excited by the authorization of the nasal vaccine booster, which enables this intranasal vaccine to be used by many more people and hopefully will curtail transmission.”

Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and Professor of Molecular Microbiology and of Pathology & Immunology

Diamond co-developed the vaccine.

The main advantage of the nasal vaccine — other than that it doesn’t require a needle — is that it triggers an immune response in the nose and upper airway, right where the virus enters the body. In doing so, it has the potential to block infection and break the cycle of transmission. The technology underlying this nasal vaccine is also adaptable, so the vaccine can be quickly and easily modified to match emerging variants of concern.

“A lot of people seem to be unconcerned by the pandemic, but the virus is still here, and people will continue to need to be vaccinated for the foreseeable future,” said David T. Curiel, MD, PhD, the Distinguished Professor of Radiation Oncology, who worked with Diamond to develop the vaccine. “The ability to get a nasal vaccine as a COVID-19 booster – several months after an initial series of injectable vaccines – is a new step in vaccine science. Further developing vaccination strategies that involve a sequence of different types of vaccines each aimed at the same virus could help us better prepare for the next pandemic.”

Diamond and Curiel, along with members of their laboratories, created the nasal vaccine at Washington University in the early months of the COVID-19 pandemic. In summer 2020, Washington University licensed the rights to develop, manufacture and commercialize the technology in India to Bharat Biotech International Limited, a global leader in vaccine innovation and a developer of vaccines for infectious diseases. This October, the university also licensed the technology to Ocugen Inc., a U.S.-based biotechnology company focused on developing and commercializing novel gene and cell therapies and vaccines, for development in the U.S., Europe and Japan.

The vaccine was authorized for use in India based on data from clinical trials conducted by Bharat Biotech. About 3,100 people participated in studies of the two-dose primary vaccination sequence at sites across India. Another 875 people who had already received two doses of either of the two other COVID-19 vaccines used in India — COVAXIN and COVIDSHIELD — participated in booster studies.

Source:

Washington University School of Medicine

Microbiology

Miracles Start in the Lab: the quest to find a vaccine to cure AIDS

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Danielle Ellis, B.Sc.Interview conducted by Danielle Ellis, B.Sc.Nov 30 2022
Thought LeadersDr. Larry CoreyProfessor and President and Director EmeritusFred Hutch Cancer Center

To commemorate World AIDS Day, News Medical spoke to Dr. Larry Corey, an internationally renowned expert in virology, immunology, and vaccine development, and the former president and director of Fred Hutch, about his work within the field of HIV/AIDS research and vaccine development. 

Please can you introduce yourself and tell us about your background in virology, immunology, and vaccine development?  

I’m Dr. Larry Corey. I am a Professor at the University of Washington and Fred Hutchinson Cancer Center. I am a virologist by training. I have worked in the field of HIV since the inception of the recognition of the virus. Initially, I was the leader of the US government’s AIDS Clinical Trials Group, which was devoted to antiviral chemotherapy. I was lucky early in my career to be involved in developing the first effective antiviral drug called Acyclovir, which was for herpes virus infections, especially genital herpes.

I switched my interests in the late 1990s from therapy to try and develop an HIV vaccine and founded the HIV Vaccine Trials Network with my friend and colleague Tony Fauci. We’ve worked together to develop an HIV vaccine and set up a network within the US of investigators to tackle the immunology of HIV, which has been very formidable. The network has been where probably 80 or 90% of the HIV vaccine clinical trials have been conducted worldwide over the last 20 years.

How have you seen the field of HIV/AIDS research change in this time? How have patient outcomes changed?

HIV is still a pandemic illness. We still have 1.4 million new infections each year. We have a growing number of people living with AIDS, and it is still a perfect storm. You acquire it subclinically, transmit it subclinically, and get it from people you don’t suspect have it. We still need better prevention methods.

Antiretrovirals have saved more lives than any other medical procedure or medical group of therapies in the last 50 or 60 years. We went from a disease that killed everybody to now a disease that, if you take the pills, you can live a normal lifespan essentially. That’s an amazing feat that occurred in the decade from the virus’s isolation.

Image Credit: PENpics Studio/Shutterstock.com

Image Credit: PENpics Studio/Shutterstock.com

HIV research has markedly changed and become markedly more sophisticated. We’re cloning B-cells in the germ lines. We’re doing things you couldn’t conceive 40 years ago. Certainly, a vaccine will be needed to end AIDS and have my granddaughters grow up like I grew up, not worrying about AIDS.

Patient outcomes for treatment have markedly changed. You can live normal lives. But we haven’t made as many inroads in prevention. The reason is that we don’t have a vaccine. When you look at how to prevent disease acquisition on a population basis, it’s only been with a vaccine. So, as hard as it is, the vaccine effort must continue.

In your lab, you study genetically modified T cells to treat HIV-1. How have recent advancements in cancer treatment influenced the treating HIV/AIDS? How can immunological approaches treat chronic viral infections?

In oncology, using the cell as an anti-tumor drug in CAR T-cell therapy is the biggest advance. The lab is trying to take those approaches used in cancer and employ them against HIV through these adopted transfer experiments. We think we’ve had some successes, so that’s our area of interest at the moment.

You are also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network. How has the COVID-19 pandemic impacted HIV/AIDS research?

People working in HIV and the infrastructure from HIV helped the effort against COVID-19. RNA, used in the COVID-19 mRNA vaccines, can allow experiments to be conducted more quickly because it’s synthetic, and you can make a vaccine and get it into humans by doing an early clinical trial. From the idea to putting a jab in your arm, that’s still not happening as quickly with HIV as it did for COVID-19. Still, it is quicker, and we’re optimistic that this RNA technology will help us develop an HIV vaccine quicker.

The HVTN’s goal is to develop a safe, effective vaccine to prevent HIV globally. How close are we to actualizing this goal? From a global perspective, what would it mean to have an effective vaccine?

We make these vaccines that elicit broadly neutralizing antibodies. If we do, we’ll get there because we’ve already proven that broadly neutralizing antibodies can prevent HIV acquisition. Now the issue is how do we get to that target now that we know what the target is? You need to be optimistic. Miracles start in the lab.

The theme of this year’s World AIDS Day is “Equalize.” What does this theme mean to you personally? What needs to be done to address inequalities and help end AIDS?

Everybody wants to be healthy. I think equalize is a great word for World AIDS Day. I think HIV has always been a disease of the underdog.

Image Credit: fizkes/Shutterstock.com

Image Credit: fizkes/Shutterstock.com

But words have meaning and should be actionable. I think the word equalize is just another call to how we actualize the tools and maximize the use of the tools we have. COVID-19 has taught us that even if research invents a remarkably good vaccine, the process of implementing this on a population basis is complicated and needs to be equalized between the haves and the have-nots. The sociology and economics of health need to be equalized globally.

What is next for yourself and your research?

I’ve got my hands full trying to make an HIV vaccine.

Where can readers find more information?

About Dr. Larry Corey

Dr. Larry Corey is an internationally renowned expert in virology, immunology and vaccine development, and the former president and director of the Fred Hutchinson Cancer Research Center. His research focuses on herpes viruses, HIV, the novel coronavirus and other viral infections, including those associated with cancer. He is principal investigator of the HIV Vaccine Trials Network (HVTN), which conducts studies of HIV vaccines at over 80 clinical trials sites in 16 countries on five continents. Under his leadership, the HVTN has become the model for global, collaborative research. Dr. Corey is also the principal investigator of the Fred Hutch-based operations center of the COVID-19 Prevention Network (CoVPN) and co-leads the Network’s COVID-19 vaccine testing pipeline. The CoVPN is carrying out the large Operation Warp Speed portfolio of COVID-19 vaccines and monoclonal antibodies intended to protect people from COVID-19. 

Dr. Corey is a member of the US National Academy of Medicine and the American Academy of Arts and Sciences, and was the recipient of the Parran Award for his work in HSV-2, the American Society of Microbiology Cubist Award for his work on antivirals, and the University of Michigan Medical School Distinguished Alumnus Award. He is one of the most highly cited biomedical researchers in the last 20 years and is the author, coauthor or editor of over 1000 scientific publications. 

Microbiology

Research findings could bolster the effectiveness of immune-checkpoint therapy

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Reviewed by Emily Henderson, B.Sc.Nov 16 2022

Immune checkpoint inhibitors such as Keytruda and Opdivo work by unleashing the immune system’s T cells to attack tumor cells. Their introduction a decade ago marked a major advance in cancer therapy, but only 10% to 30% of treated patients experience long-term improvement. In a paper published online today in The Journal of Clinical Investigation (JCI), scientists at Albert Einstein College of Medicine describe findings that could bolster the effectiveness of immune-checkpoint therapy.

Rather than rally T cells against cancer, the Einstein research team used different human immune cells known as natural killer (NK) cells-;with dramatic results.

We believe the novel immunotherapy we’ve developed has great potential to move into clinical trials involving various types of cancer.”

Xingxing Zang, M.Med., Ph.D., Study Leader

Xingxing Zang is the the Louis Goldstein Swan Chair in Cancer Research and professor of microbiology & immunology, of oncology, of urology, and of medicine at Einstein and a member of the Cancer Therapeutics Program of the Montefiore Einstein Cancer Center.

Telling friend from foe

The surfaces of immune cells are studded with receptors known as “checkpoint” proteins, which prevent immune cells from straying beyond their usual targets (pathogen-infected cells and cancer cells). When checkpoint receptors on immune cells bind with proteins expressed by the body’s own normal cells, the interaction puts the brakes on a possible immune-cell attack. Diabolically, most types of cancer cells express proteins that bind with checkpoint proteins, tricking immune cells into standing down and not attacking the tumor.

Immune checkpoint inhibitors are monoclonal antibodies designed to short-circuit immune-cell/cancer-cell interactions by blocking either the tumor proteins or the immune-cell receptors that bind with tumor proteins. With no brakes to impede them, immune cells can attack and destroy cancer cells.

New focus on natural killer cells

The limited effectiveness of checkpoint inhibitors prompted Dr. Zang and other scientists to look at checkpoint pathways involving NK cells, which-;like T cells-;play major roles in eliminating unwanted cells. A cancer-cell protein called PVR soon captured their attention. “We realized that PVR may be a very important protein that human cancers use to hobble the immune system’s attack,” said Dr. Zang.

PVR protein is usually absent or very scarce in normal tissues but is found in abundance in many types of tumors including colorectal, ovarian, lung, esophageal, head and neck, stomach, and pancreatic cancer as well as myeloid leukemia and melanoma. Moreover, PVRs appeared to inhibit T cell and NK cell activity by binding to a checkpoint protein called TIGIT-;prompting efforts to interrupt the TIGIT/PVR pathway by using monoclonal antibodies made against TIGIT. More than 100 clinical trials targeting TIGIT are now in progress worldwide. However, several clinical studies including two large phase 3 clinical trials have recently failed to improve cancer outcomes.

Recognizing the role of a new receptor

Meanwhile, the cancer-cell protein PVR was found to have another “binding partner” on NK cells: KIR2DL5. “We hypothesized that PVR suppresses NK cell activity not by binding with TIGIT but by binding with the recently recognized KIR2DL5,” said Dr. Zang. To find out, he and his colleagues synthesized a monoclonal antibody targeting KIR2DL5 and carried out in vitro and in vivo experiments using the antibody.

In their JCI paper, Dr. Zang and colleagues demonstrated that KIR2DL5 is a commonly occurring checkpoint receptor on the surface of human NK cells, which PVR cancer proteins use to suppress immune attack. In studies involving humanized animal models of several types of human cancers, the researchers showed that their monoclonal antibody against KIR2DL5-;by blocking the KIR2DL5/PVR pathway-;allowed NK cells to vigorously attack and shrink human tumors and prolong animal survival (see accompanying illustration). “These preclinical findings raise our hopes that targeting the KIR2DL5/PVR pathway was a good idea and that the monoclonal antibody we’ve developed may be an effective immunotherapy,” said Dr. Zang.

Einstein has filed a patent application for KIR2DL5/PVR immune checkpoint including antibody drugs and is interested in a partnership to further develop and commercialize the technology.

Dr. Zang has previously developed and patented more than 10 immune checkpoint inhibitors. One of those inhibitors is now being tested in China in phase 2 clinical trials involving several hundred patients with advanced solid cancers (non-small cell lung cancer, small cell lung cancer, nasopharyngeal cancer, head and neck cancer, melanoma, lymphoma) or recurrent/refractory blood cancers (acute myeloid leukemia, myelodysplastic syndromes). Another of Dr. Zang’s immune checkpoint inhibitors will be evaluated starting next year in cancer clinical trials in the United States.

Source:

Albert Einstein College of Medicine

Journal reference:

Ren, X., et al. (2022) Blockade of the immunosuppressive KIR2DL5/PVR pathway elicits potent human NK cell-mediated antitumor immunity. Journal of Clinical Investigation. doi.org/10.1172/JCI163620.