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CAR-NKT cell therapy shows promising results against neuroblastoma in phase 1 clinical trial

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HOUSTON – (May 15, 2023) – Researchers at Baylor College of Medicine/Texas Children’s Cancer Center and collaborating institutions report interim results from a first-in-human phase 1 clinical trial evaluating the safety, antitumor activity and immunological characteristics of a genetically engineered natural killer T (NKT) cell immunotherapy for neuroblastoma, a childhood tumor that most commonly arises in the adrenal gland. The study published in Nature Medicine shows the treatment was well tolerated, and researchers observed early evidence of strong antitumor activity.

NKT cells were modified to express a GD2-specific chimeric antigen receptor (GD2 CAR), which enables the immune cells to target a molecule found on the surface of neuroblastoma cells, and interleukin-15 (IL-15), a natural protein that supports NKT cell survival. In a previous Nature Medicine publication, the authors reported interim results from the first three children enrolled on this trial.

In the new article, investigators describe the results obtained in 12 patients with stage 4 relapsed neuroblastoma that was resistant to other therapies. They found that the therapy was safe for all 12 patients on four dose levels; there were no reported no dose-limiting toxicities. Three patients showed an objective response to treatment, including one complete response and two partial responses. Two other patients also showed evidence of antitumor activity such as clearance of bone marrow involvement or reduction of metastatic tumor burden not reaching partial response criteria.

“We are encouraged by the evidence of antitumor activity that has been observed in several patients, particularly since this trial is still in the dose escalation phase,” said Dr. Andras Heczey, co-corresponding author and associate professor of pediatrics – hematology and oncology at Baylor. He also is a member of the Center for Advanced Innate Cell Therapy at Texas Children’s Cancer Center, the Center for Cell and Gene Therapy at Baylor and Texas Children’s and the Dan L Duncan Comprehensive Cancer Center at Baylor.

Previous studies from the team have shown that NKT cells can localize to tumor sites in pre-clinical models. This trial has validated those observations in humans. Additionally, researchers found a correlation between higher antitumor activity and in vivo proliferation of infused CAR-NKT cells.

“We cannot always predict the extent of NKT cell expansion in vivo after infusion,” said Dr. Leonid Metelitsa, co-corresponding author and professor of pediatrics – hematology and oncology at Baylor. “In this study, we found the CD62L biomarker expressed on the infused NKT cells, which we identified in our preclinical work, is predictive of both higher NKT cell in vivo expansion and antitumor activity in patients.” Metelitsa is also director of the Center for Advanced Innate Cell Therapy at Texas Children’s Cancer Center and a member of the Center for Cell and Gene Therapy at Baylor and Texas Children’s and the Dan L Duncan Comprehensive Cancer Center at Baylor.

Another important finding revealed a regulatory gene in NKT cells that may impact the efficacy of treatment. Leveraging the multiomic platform of key collaborator Immunai, Inc., Baylor researchers found that upregulation of the BTG anti-proliferation factor 1 (BTG1) gene in infused CAR NKT cells is indicative of cell exhaustion and restricts CAR NKT cell functional activity. Conversely, engineered reduction of BTG1 expression in CAR NKT cells enhanced their therapeutic activity against neuroblastoma in a mouse model.

“This study provides promising initial evidence of antitumor activity of GD2 CAR NKT cells against neuroblastoma. This inspires hope that novel immunotherapeutic strategies, such as the one studied in this trial, will ultimately improve the outcomes for children with neuroblastoma,” Metelitsa said.

Based on the safety profile and promising evidence of antitumor activity, this trial has been expanded to include two higher dose levels for the GD2 CAR NKT cells. Following completions of these additional cohorts, a phase 2 trial to assess the antitumor activity of this novel immunotherapeutic is planned.

Other contributors to this work include Xin Xu, Amy N. Courtney, Gengwen Tian, Gabriel A. Barragan, Linjie Guo, Claudia Martinez Amador, Nisha Ghatwai, Purva Rathi, Michael S. Wood, Yanchuan Li, Chunchao Zhang, Thorsten Demberg, Erica J. Di Pierro, Andrew C. Sher, Huimin Zhang, Birju Mehta, Sachin G. Thakkar, Bambi Grilley, Tao Wang, Brian D. Weiss, Antonino Montalbano, Meena Subramaniam, Chenling Xu, Chirag Sachar, Daniel K. Wells and Gianpietro Dotti. The authors are affiliated with the following institutions: Baylor College of Medicine, Texas Children’s Hospital, Cincinnati Children’s Hospital, Immunai, Inc., and University of North Carolina at Chapel Hill.

This work was supported by Alex’s Lemonade Stand Foundation for Childhood Cancer, St. Baldrick’s Foundation, the American Cancer Society and Athenex, Inc. For a full list of author affiliations and funding for this work, refer to the publication.

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Helping people living with dementia ‘flourish’ through dance

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Dr. Pia Kontos, a Senior Scientist at UHN’s KITE Research Institute, is co-leading an initiative to help people living with dementia flourish. (Photo: Tim Fraser/UHN KITE Studio)

Dr. Pia Kontos believes in the power of the arts to support people to live well with dementia.

The Senior Scientist at UHN’s KITE Research Institute focuses on challenging policies and practices that discriminate against those living with dementia and developing and evaluating arts-based and digital knowledge translation initiatives to reduce stigma, improve social inclusion and quality of care for them.

“The predominant assumption is people living with dementia don’t have the capacity to be creative,” says Dr. Kontos, who is also a professor in the Dalla Lana School of Public Health at the University of Toronto. “However, we know through extensive research that dance…powerfully supports people living with dementia to be creative and to flourish.

“And flourishing should be a goal that we all have.”

Dr. Kontos co-produced in 2023 Dancer Not Dementia, a short documentary film. It captured the power of a dance program for seniors – Sharing Dance Older Adults (SDOA) – to challenge the stigma associated with dementia, support social inclusion and enrich lives. It’s told through the eyes of residents and staff at Alexis Lodge Dementia Care Residence and Cedarhurst Dementia Care Home in Toronto.

SDOA was jointly developed by Canada’s National Ballet School (NBS) and Baycrest Centre in 2013 for older adults with a range of physical and cognitive abilities, including dementia.

Typically, dance programs in dementia care settings are provided as a therapeutic intervention for older adults. However, SDOA’s goal is to provide a creative outlet for participants and opportunities for social interaction with other people living with dementia, staff and loved ones.

Now, Dr. Kontos will look to incorporate traditions from marginalized communities into SDOA through a $750,000 Canadian Institutes of Health Research (CIHR) Institute of Aging Implementation Science Team Grant. Dr. Rachel Bar, Director of Research and Health at NBS is co-principal applicant for the grant.

This CIHR funding supports projects that evaluate the effectiveness of existing programs, services and models of care that show promise for those impacted by cognitive impairment and dementia. An important focus is improving equitable and inclusive access to care and support.

The three-year grant to Drs. Kontos and Bar will support SDOA efforts to partner with organizations in Black, Chinese and South Asian communities to integrate their cultural practices into its programming.

Training dancers from these communities to teach the adapted program is central to these partnerships.

“People living with dementia from marginalized communities rarely have their traditions honoured with art and leisure programming,” says Dr. Kontos.

“It’s important to align dance programs with the cultural traditions of these communities. Otherwise, the music and movements wouldn’t reflect the experiences of ethno-culturally diverse populations, and the programs wouldn’t be inclusive.

“We wouldn’t be supporting their capacity to be creative or to be in relationships with others through dance. We would be falling short.”

SDOA has already partnered with Alexis Lodge, Alzheimer Society of Canada, Baycrest, NBS, Indus Community Services, Social Planning Council of Ottawa, and Yee Hong for this initiative.

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CDC: Heat may have contributed to four human cases of bird flu in Colorado

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Credit: Alexas Fotos from Pexels

Heat probably played a role in at least four cases of bird flu in poultry workers confirmed by U.S. health officials Sunday—the first cases in poultry workers in two years.

Sweltering temperatures in Colorado rose to at least 104 degrees, which is suspected to have contributed to the human cases, according to Dr. Nirav Shah, principal deputy director at the Centers for Disease Control and Prevention. The barns where poultry workers were culling chickens were “no doubt even hotter,” Shah said during a press conference on the most recent outbreak of bird flu in humans.

The new cases bring the U.S. total to at least nine cases since the first human case of the current outbreak was detected in 2022, also in a Colorado poultry worker. Eight of the nine were reported this year.

The workers were separating chickens that were going to be killed to stop the spread of the virus. The fans may also have contributed to the human infections because, while helping to keep the environment cooler, they “also spread things like feathers around which are known to carry the virus,” Shah added.

The large and strong fans also make it difficult for protective goggles and face masks to stay in place, he said.

About 60 workers at the poultry farm showed symptoms of illness and were tested for bird flu. Four tested positive for bird flu and one additional presumptive case is awaiting confirmation.

The illnesses were relatively mild, with symptoms including conjunctivitis and common respiratory infection symptoms like fever, chills, coughing, and runny nose, according to the CDC. None were hospitalized, officials said. The other U.S. cases have also been mild.

Officials said they are bracing for more cases.

The CDC says the risk to the general public remains low and the health agency is not recommending livestock workers be vaccinated against bird flu given the “mild symptoms noted thus far,” Shah said.

An initial analysis of virus samples from an infected poultry worker does not show any changes in the virus that would make it easier to spread among people and there is no evidence of person-to-person spread in the U.S.

“It’s important to note that this assessment is based on what we know today and may change,” Shah said. “CDC is constantly looking for key changes that may alter our risk assessment of the virus, such as the severity of illness that it causes, the ease with which it can transmit to humans or changes to its genetic fingerprint.”

At the request of Colorado’s officials, the CDC sent a 10-person team to Colorado to help the state manage the bird flu outbreak in humans and poultry. The team included epidemiologists, veterinarians, clinicians and industrial hygienists.

Shah also noted it was a bilingual team. Overall in the U.S., it is estimated about half of farm workers are Latino.

An analysis of the virus from an infected worker indicates that the infections at the chicken farm are “largely the same” as the strain detected in dairy herds in Colorado and other states, according to Shah. But an investigation is ongoing to determine exactly how the outbreak is spreading between wild birds, chicken and cattle.

Since 2022, a highly contagious strain of bird flu has spread across the U.S. at an unprecedented rate.

Georgia’s powerhouse poultry industry, which produces more broiler chickens than any other in the country, has mostly dodged the kinds of major outbreaks that have resulted in the deaths of more 90 million birds in commercial and backyard poultry flocks in the U.S.

About 1.8 million chickens will be killed at the Colorado poultry farm after these latest bird flu cases were detected.

In late 2023, ducks at a commercial breeding farm in Sumter County, Georgia, tested positive for H5N1. This year, in March, the virus made a jump to a mammal species that surprised many scientists: cows.

With a significant dairy industry, plus even larger beef and poultry interests, the potential arrival of the virus here threatens Georgia’s economy and the health of residents.

As of Monday, the H5N1 virus has been confirmed in 158 dairy herds in 13 states, according U.S. Agriculture Department.

So far in Georgia, there have been no bird flu cases in cattle, and there have been no human cases.

Since the unprecedented spread of H5N1 in poultry in 2022, the Georgia Department of Public Health has quietly monitored 132 people for signs of the virus, according to DPH spokeswoman Nancy Nydam. Those tracked were either first responders to one of the state’s few virus outbreaks in backyard and commercial poultry flocks or farmworkers where the infections occurred. Of those monitored, fewer than 10 people were tested for H5N1 and none came back positive.

Since the virus was discovered in cattle, a small number of first responders from Georgia who went to other states to help with investigations—fewer than 15—have also been monitored for signs of illness.

Federal officials said Tuesday they still believe they can eliminate the bird flu virus from , even as the number of herds infected continues to grow. The latest state to recently report infected dairy cattle was Oklahoma. North Carolina is the only state adjacent to Georgia to report an infected dairy herd.

Eric Deeble, acting senior adviser for the H5N1 response at the USDA, said investigations show the is spreading among cattle through cattle moved from one herd to another and the shared use of milking equipment. It can be contained through enhanced biosecurity measures such as thoroughly cleaning milking “parlors” and equipment, separating sick cows, and having dairy workers wear protective equipment.

Deeble also noted USDA scientists are also working with partners to develop a cattle-specific H5N1 vaccine—a process requires many steps and will take time.

The USDA is also exploring the possibility of developing a poultry vaccine as the number of cases soar, and outbreaks lead to the slaughter of millions of farmed birds. But USDA and industry stakeholders point to challenges that would hinder a vaccination program.

The biggest sticking point is around trade.

Mike Giles, president of the Georgia Poultry Federation, said mass vaccination would be impractical for several reasons, including the fact that the industry would lose its lucrative export market: The United States and many of its trade partners restrict the import of products or eggs from countries affected by the highly pathogenic strain or flocks that have been vaccinated against it.

“(Bird flu) has been, from an animal health standpoint, our top concern,” Giles said. “The challenge, and I think the industry has responded to it well, has been maintaining the state of preparedness and urgency and focus on biosecurity, and I think that has been accomplished.”

2024 The Atlanta Journal-Constitution. Distributed by Tribune Content Agency, LLC.

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CDC: Heat may have contributed to four human cases of bird flu in Colorado (2024, July 17)
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Here is the new guidance for RSV vaccines

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Health officials recently changed the guidelines for respiratory syncytial virus vaccines. Here’s what Canadians need to know about the guidance and the virus itself.

New guidance on vaccines

As of July 12, the National Advisory Committee on Immunization (NACI) now recommends RSV vaccines for individuals who are 75 years old and older, especially those who have a greater risk of developing severe RSV.

Based on current evidence and expert opinion, NACI said in a news release, it also strongly recommends vaccines for those aged 60 and older who live in nursing homes and other chronic care facilities.

What is RSV?

RSV is a common contagious virus that often causes bronchiolitis, a lung infection, and pneumonia.

Infants face the highest risk of developing severe RSV disease, however, this risk also increases with age and with certain medical conditions, according to the Public Health Agency of Canada (PHAC). It can lead to serious complications for older people, including hospitalization and death.

What are the symptoms?

RSV typically causes mild, cold-like symptoms that usually begin two to eight days after exposure to the virus, according to PHAC.

Those with RSV may experience a runny nose, coughing, sneezing, wheezing, fever and less appetite and energy. Infants may be irritable, have trouble breathing and have less appetite and energy.

What is the treatment?

RSV infections are usually mild and last about one to two weeks. If you are infected, health officials recommend you stay home and limit contact with others.

They also recommend lots of rest and drinking plenty of fluids. Take over-the-counter products, such as acetaminophen or ibuprofen, if you have a fever. Seek immediate care or go to the hospital if you’re having trouble breathing or become dehydrated, PHAC adds.

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