CAR-NKT cell therapy shows promising results against neuroblastoma in phase 1 clinical trial
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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Anti-GD2 CAR-NKT cells in relapsed or refractory neuroblastoma: updated phase 1 trial interim results
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Flavanols are linked to better memory and heart health – here’s what foods you can eat to get these benefits – Yahoo Canada Sports
There are plenty of good reasons to make sure you’re eating enough fruit and vegetables each day. Not only do fruit and vegetables contain many of the important vitamins and minerals our body needs to function at its best, they also keep our gut healthy and may even help maintain a healthy weight.
But some plant foods may be more beneficial for health than others, thanks to a group of compounds called flavanols.
For instance, a recent study I helped conduct showed that people who eat a diet high in flavanol-rich foods may have better memory compared to those who have a low intake. A previous study also found that people with a low intake of flavanols were at higher risk of heart disease. Overall, there’s convincing evidence that consuming enough flavanols has health benefits.
But while research shows that flavanols have many health benefits, it’s important for consumers to know that not all flavanol-rich foods contain the same amount of flavanols – meaning some may be more beneficial to health than others.
Flavanols are a group of compounds that are found in many plants – including apples, berries, plums and even beverages such as tea.
There are two main groups of flavanols, with many different subgroups. Each plant will contain different combinations of flavanols, as well. These compounds each have different structures and different effects on the body. That means that not all flavanols are created equal.
For example, a portion of blueberries and a cup of tea may contain the same amount of total flavanols – but they are made up of completely different types of flavanols, which may have completely different health effects.
So in order to investigate the health effects of flavanols, it’s therefore important to use a source which includes a wide range of different types. This is why flavanols extracted from cocoa are an ideal model, as they contain the two main types of flavanols. It also allows researchers to calculate which other foods are likely to have benefits based on how similar the compounds they contain are to cocoa flavanols.
Since foods such as cocoa, berries and tea contain a combination of many types of flavanols, it’s currently not clear which individual compounds generate health benefits. But some research has linked the specific flavanol epicatechin with better vascular function. Cocoa and tea both contain epicatechin.
Many different types
Another thing to know is that even if a food contains flavanols, it may contain lower amounts compared to others.
To better understand how flavanol intake affects health, a few years ago we developed a test that uses urine to measure flavanol intake. The test is based on the way the human body processes flavanols and tells us whether someone has eaten large amounts, small amounts or no flavanols at all.
Using this test, we were able to show that people with high flavanol intake had lower blood pressure and better memory than those with lower intake.
When we developed the urine test, we also investigated how it is affected by different types of flavanols and foods. This allowed us to estimate what amount of different flavanol-rich foods a person needs to consume to achieve approximately 500mg of flavanols per day – similar to the amount used in studies, which has been shown to have clinical benefit.
According to our research, only two-and-a-half cups of green tea are needed daily to get the recommended 500mg of flavanols. Just under a cup of millet (sorghum grain) can also provide you with the recommended daily amount.
But if you were to try and get your flavanols from one type of fruit and vegetable, our research shows you’d need to consume large amounts of each to achieve the recommended amount. For example, you’d need to consume nearly 15 cups of raspberries alone to get 500mg of flavanols.
As such, the best way to get enough flavanols daily is by consuming a combination of different fruits and vegetables. For example two apples, a portion of pecan nuts and a large portion of strawberries can achieve the 500mg target – or a salad made with millet and fava beans.
It’s also important to note that while the flavanols used in many studies were extracted from cocoa, unfortunately chocolate (even dark chocolate) is a very poor source of flavanols – despite what some headlines might claim. This is because these flavanols are lost during processing.
Although there’s still much we don’t know about flavanols – such as why they have the effect they do on so many aspects of our health – it’s clear from the research we do have that they are very likely beneficial to both memory and heart health.
This article is republished from The Conversation under a Creative Commons license. Read the original article.
Gunter Kuhnle has received research funding from Mars, Inc., a company engaged in flavanol research and flavanol-related commercial activities.
'Social deprivation' speeds up aging, and death: McMaster study – Hamilton Spectator
We are dying every day, wrote Seneca, a stoic philosopher in ancient Rome.
And if you struggle living alone or have weak familial bonds, you risk speeding up death by as much as one year, according to findings published by McMaster University on Monday.
The new study shows that biological clocks tick faster for those dwelling in an environment of social deprivation (a dearth of family or community network resources) or material poverty, such as lacking access to quality housing, healthy food and recreation.
McMaster’s Divya Joshi, the study’s first author, said the findings indicate that living in a “deprived urban neighbourhood” marked by either form of deprivation is associated with “premature biological aging.”
Joshi is a research associate in the university’s Department of Health Research Methods, Evidence and Impact.
“If your (biological) systems are aging faster than your chronological age, then you will have more poor health outcomes, or quicker health outcomes, than someone who is aging slower biologically,” she told The Spectator.
The study analyzed DNA from the blood samples of 1,445 participants across Canada, who are part of the Canadian Longitudinal Study on Aging that is following 50,000 people between age 45 to 85.
“Epigenetic clocks” studied in the samples — also called “DNA methylation-based estimators” — indicated aging at the cellular level, she said.
“To be able to see that living in a socially or materially deprived neighbourhood impacts your healthy aging; that it increases your risk of epigenetic age acceleration by almost a year, beyond your individual health status — I think that is just remarkable,” she said.
When your biological age outpaces your calendar age, she said you have a greater risk of cardiovascular disease, respiratory conditions and neurological disorders that present a “greater risk of premature mortality.”
The findings fit their research hypothesis, she said, but what didn’t fit was the assumption that depression in the test subjects would further “amplify” the rapid aging effect.
In fact, while depression symptoms also contributed to epigenetic aging, environmental factors impacted aging acceleration regardless of depression symptoms.
The findings were published June 5 in “The Journals of Gerontology, Series A: Biological Sciences and Medical Sciences.”
McMaster professor Parminder Raina led the research team, which included investigators from the Netherlands, Norway and Switzerland, according to a news release.
While the presentation of the findings focused on the connection to disadvantaged neighbourhoods, Joshi agreed that an individual will age more rapidly when deprived of familial or social bonds, regardless of where they live.
“That is true, there is evidence that those people who have poor social networks or broken family units have a greater risk of higher epigenetic age acceleration … It is aging you, and that is so relevant coming out of the pandemic, and the isolation many people experienced, especially the toll it had on our older populations.”
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Sudbury health unit offers advice about West Nile Virus – Sudbury.com
The Sudbury health unit is warning area residents to be wary of the possibility of being infected with West Nile Virus.
“Whether you are spending time in your backyard, exploring local trails, or vacationing in Ontario, getting bitten by mosquitos puts you at risk of being infected with West Nile virus,” said the release from Public Health Sudbury and Districts.
The release also said the risk is low, but it is still possible.
“Although the overall risk of becoming infected with West Nile virus is low, everyone is at risk and preventing bites is important to protect yourself and your family,” said Ashley DeRocchis, an environmental support officer with Public Health Sudbury & Districts.
Citizens are advised to use an insect repellent approved by Health Canada and follow the application recommendations on the package.
Also, during the times of day when mosquitoes are most active — during dusk and dawn — people might choose to stay indoors if possible.
The health unit also advised that people can wear light-coloured clothing, including long sleeves, long pants, socks, and a hat whenever they are outdoors. Consider the use of mesh “bug jackets” or “bug hats,” the news release said.
At home, people can check their window and door screens to ensure that there are no tears or holes for mosquitoes to get through. Also, don’t give the bugs a place to lay eggs.
Mosquitoes need only a small amount of calm, standing water to lay their eggs and for larvae to hatch, said PHSD.
Reduce mosquito breeding areas by changing or removing standing water at least once a week from areas such as bird baths. old tires, containers, barrels, flower pot saucers, swimming pool covers, wading pools, clogged gutters and eavestroughs, clogged drainage ditches, small containers like cans or bottle tops and unused children’s toys, said the release.
The health unit said symptoms of West Nile virus can range from mild to severe, from flu-like symptoms to severe nausea and even loss of consciousness.
Public Health Sudbury & Districts will be trapping and testing mosquitoes again this year starting in mid-June and continuing into the fall of 2023, said the release. For more information on West Nile virus, visit the website at phsd.ca or call Public Health Sudbury & Districts at 705-522-9200, ext. 464 (toll-free 1-866-522-9200).
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