Day: April 12, 2021

Categories : CancerTags :

CD40 Agonists Before Therapy Kick Off T Cell Response

On By ModernMedia

Giving a CD40 immune-stimulating drug to early-stage pancreatic cancer patients helped kick off a T cell attack on the tumour’s stubborn microenvironment before surgery and other treatments, according to a new study.

Altering the tumour microenvironment to host more T cells using a CD40 agonist earlier could help slow cancer progression and prevent metastasis.

The data was presented by Katelyn T Byrne, PhD, an instructor of Medicine in the division of Hematology-Oncology in the Perelman School of Medicine at the University of Pennsylvania, during a plenary session at the American Association for Cancer Research annual meeting.

“Many patients with early-stage disease undergo surgery and adjuvant chemotherapy. But it’s often not enough to slow or stop the cancer,” Dr Byrne said. “Our data supports the idea that you can do interventions up front to activate a targeted immune response at the tumor site–which was unheard of five years ago for pancreatic cancer–even before you take it out.”

CD40 is a tumour necrosis factor receptor superfamily member expressed broadly on antigen-presenting cells (APC) such as dendritic cells, B cells, and monocytes as well as many non-immune cells and a range of tumours.

CD40 agonists serve to accelerate the immune system by activating antigen-presenting cells, such as dendritic cells, to “prime” T cells and also through enhancement of destruction of the tumour site through non-immune system means. This has been investigated mostly in combination with other therapies for pancreatic cancer patients. This is the first study showing the drug drove immune response in early-stage patients both at the tumour site and systemically, mirroring mouse study findings.

Prior to surgery, 16 patients were treated with selicrelumab. Of those, 15 underwent surgery and received adjuvant chemotherapy and a CD40 agonist. Data collected from those patients’ tumours and responses were compared to data from controls (CD40 not received before surgery) treated at Oregon Health and Science University and Dana Farber Cancer Institute.

Multiplex imaging of immune responses revealed that in patients who received the CD40 agonist before surgery, 82% of tumours were T cell enriched, compared to 37% of untreated tumors and 23% chemotherapy or chemoradiation-treated tumours.

Selicrelumab tumours also had less tumour-associated fibrosis, which are tissue bundles inhibiting T cell and drug entry, and antigen-presenting cells known as dendritic cells were more mature.

Disease-free survival was 13.8 months in the treatment group, and median overall survival was 23.4 months, with eight patients alive at a median of 20 months after surgery.

“This is a first step in building a backbone for immunotherapy interventions in pancreatic cancer,” Dr Byrne said.

On the strength of these findings, researchers are pursuing combining CD40 with other therapies to help further boost immune response in pre-surgery pancreatic cancer patients.

“We’re starting to turn the tide. This latest study adds to growing evidence that therapies such as CD40 before surgery can trigger an immune response in patients, which is the biggest hurdle we’ve faced,” said senior author Robert H Vonderheide, MD, DPhil, and Director, Abramson Cancer Center (ACC), University of Pennsylvania. “We’re excited to see how the next-generation of CD40 trials will take us even closer to better treatments.”

Source: News-Medical.Net

Categories : COVIDTags : 1 Comment

Blood Clotting Concerns Resulting in Vaccination Delays

On By ModernMedia

Vaccination programmes are facing increasing delays because of concerns over AstraZeneca’s very rare blood clotting incidents.

Australia and Greece are the latest governments deciding to offer young people alternatives to AstraZeneca’s vaccine. This will delay inoculation campaigns by around a month in Australia, France and Britain. Meanwhile, the World Health Organization said most countries lacked vaccines to cover health workers and others at high risk from exposure to the virus.

WHO Director-General Tedros Adhanom Ghebreyesus said high income countries had on average vaccinated one in four people whilst low income countries the figure was one in over 500.

“There remains a shocking imbalance in the distribution of vaccines,” he told a press briefing on Friday.

The WHO and GAVI vaccine alliance’s COVAX mechanism seeks to secure vaccines for poorer nations. GAVI alliance head Seth Berkley said AstraZeneca’s supply chain had in fact “picked up” when asked whether the vaccine was being shunned.

“As countries decide they are going to prioritise one vaccine or another, that may free up doses, and in so doing we will try to make sure those doses are made available without delay, if countries are willing to make that happen,” he said.

Australia doubled its orders for Pfizer after its health body recommended that people under 50 receive an alternative vaccine. Greece followed Britain’s example in recommending that people under 30 seek an alternative jab.

AstraZeneca said it was working with regulators “to understand the individual cases, epidemiology and possible mechanisms that could explain these extremely rare events”.

Sabine Straus, chair of the EMA’s safety committee, said that the European Medicines Agency (EMA) received reports of 169 cases of the rare brain blood clot by early April, after 34 million doses had been administered.

Most of the cases reported had occurred in women under 60.

On Friday, the EMA said that if a causal relationship is confirmed or considered likely, regulatory action will be needed to minimise risk. It is also investigating Johnson & Johnson’s (J&J) vaccine over reports of blood clots. US infectious disease expert Anthony Fauci however said there were no red flags reported for the J&J vaccine.

The AstraZeneca vaccine is the cheapest and most high-volume vaccine to date to curb the pandemic and avert damaging lockdowns, but supplies have been beset by delays.

However, new data in the EU, beset by delays, showed that the pace of vaccine deliveries was picking up. Germany said it was accelerating inoculations but needed a new lockdown as well.

“Every day in which we don’t act, we lose lives,” Lothar Wieler, president of the Robert Koch Institute, said.

Hong Kong Health Secretary Sophia Chan said the city would defer its order of the AstraZeneca vaccine this year “so as not to cause a waste when the vaccine is still in short supply globally”, adding that the government was considering buying a new, more effective type of vaccine.

All the countries recommending age limits for the AstraZeneca shot have emphasised that its benefits far outweigh the risks of catching COVID for older people. Even so, some people have been put off; in Madrid half of over 60s meant to receive the AstraZeneca vaccine turned up, a day after Spain’s recommendation that younger people get a different shot.

In France, where vaccine hesitancy is high, the top health body recommended that those over 55 who had received a first dose of the AstraZeneca shot get a new-style messenger-RNA vaccine for the second one: either the Pfizer/BioNTech one or Moderna’s.

Source: Reuters

Categories : COVIDTags :

South African Variant Escapes Pfizer Vaccine More Easily

On By ModernMedia

The South African variant escapes protection of the Pfizer/BioNTech vaccine better than other forms of the virus, Israeli experts said Sunday.

The study by Tel Aviv University and Clalit Health Services, Israel’s largest healthcare provider, compared patients with COVID, 400 unvaccinated patients to 400 partially or fully vaccinated ones.

Less than one percent of COVID cases in Israel were due to the South African variant. However, among the 150 people who were fully vaccinated yet had developed COVID, “the prevalence rate [of the B.1.351 variant] was eight times higher than the rate in the unvaccinated [individuals],” the authors wrote.

“This means that the Pfizer-BioNtech vaccine, though highly protective, probably does not provide the same level of protection against the South African (B.1.351) variant of the coronavirus,” the authors added.

“The South African variant is able, to some extent, to break through the vaccine’s protection,” said professor Adi Stern of Tel Aviv University’s Shmunis School of Biomedicine and Cancer Research, one of the study’s authors.

Prof Stern said that the study did not assess whether the eight people infected with the South African developed severe COVID.
“Since we found a very small number of vaccinees infected with B.1.351, it is statistically meaningless to report disease outcomes,” he said.

The possibility of reduced protection was already hinted at in two studies conducted by principal vaccine manufacturers Pfizer/BioNTech and Moderna, showing that the presence of antibodies after vaccination was less pronounced in people exposed to the B.1.351 variant. This marked the first real-world assessment of B.1.351’s ability to bypass a vaccine.

Israel’s vaccination campaign has seen 5.3 million people receive a first dose, while 4.9 million, or 53 percent of the population, have had two shots. 

Clalit’s earlier study on 1.2 million Israelis found that the Pfizer/BioNTech jab gave 94 percent protection against COVID.

Israel has eased many of its restrictions since its vaccine rollout, but various measures remain in place including mask-wearing and a “green passport” system that allows vaccinated people access to certain locations. With cases down 97% since January, Israel may have achieved “herd immunity”, according to Eran Segal, a computational biologist at the Weizmann Institute of Science.

Ran Balicer of Clalit said inoculations, plus mask-wearing and other safety measures had likely helped contain the B.1.351 variant, despite its apparent ability to break through the Pfizer/BioNTech vaccine.

A combination of all these factors “are most likely… preventing the virus strains, including the South African one, from spreading” significantly in Israel, he said.

“As we taper down the non-pharmaceutical interventions, we must do so gradually to ensure we do not cross a threshold that would enable these variants to spread.”

Source: Medical Xpress

Categories : Neurodegenerative DiseasesTags :

Sleep Apnoea Treatment May Reduce Risk of Dementia

On By ModernMedia

Older adults receiving positive airway pressure therapy for obstructive sleep apnoea (OSA) may have a lower risk of developing Alzheimer’s disease and other kinds of dementia, according to a new study.

In a nationally representative study, Researchers from Michigan Medicine’s Sleep Disorders Centers analysed Medicare claims of over 50 000 Medicare beneficiaries 65 and older with OSA. They sought to find out whether people using positive airway pressure therapy had less risk of receiving a new diagnosis of dementia or mild cognitive impairment over the next 3 years, compared to those not using positive airway pressure therapy.

“We found a significant association between positive airway pressure use and lower risk of Alzheimer’s and other types of dementia over three years, suggesting that positive airway pressure may be protective against dementia risk in people with OSA,” said lead author Galit Levi Dunietz, PhD, MPH, an assistant professor of neurology and sleep epidemiologist.

The findings stress the impact of sleep on cognitive function. “If a causal pathway exists between OSA treatment and dementia risk, as our findings suggest, diagnosis and effective treatment of OSA could play a key role in the cognitive health of older adults,” said principal investigator Tiffany J. Braley, MD, MS, associate professor of neurology.

Obstructive sleep apnoea is a condition where there are episodes of complete or partial collapse of the airway with an associated decrease in oxygen saturation or arousal from sleep. This disturbance results in fragmented, nonrestorative sleep, and is associated with a variety of other neurological and cardiovascular conditions. Many older adults are at high risk for OSA. Dementia is prevalent as well, with roughly 5.8 million Americans currently living with it, said Prof Braley.

Source: Medical Xpress

Journal information: G L Dunietz et al, Obstructive Sleep Apnea Treatment and Dementia Risk in Older Adults, Sleep (2021). DOI: 10.1093/sleep/zsab076

Categories : NeurologyTags :

Chronic Sinusitis Linked to Neural Functions

On By ModernMedia

A small proof-of-concept study found that sinonasal inflammation was associated with neural changes that could precede cognitive symptoms in young people.

In comparison to healthy controls, people with chronic rhinosinusitis showed decreased functional connectivity within the frontoparietal network, a major cognition modulating hub, in resting-state functional MRI imaging. The frontoparietal network allows individuals to coordinate behaviour in a rapid, accurate, and flexible goal-driven manner.

These individuals also had greater connectivity of this region to the default mode network (areas that are activated during introspective and self-referential processing) and decreased connectivity to the salience network (areas involved in detection and response to stimuli) on brain imaging, reported Aria Jafari, MD, of University of Washington in Seattle, and colleagues.

Compared to controls, individuals with more severe rhinosinusitis inflammation tended to have greater differences in functional connectivity, Dr Jafari and colleagues stated. 

“Although definitive conclusions are not possible given the limitations inherent in the data set, including lack of rhinosinusitis-specific clinical information, our results present initial evidence for functional connectivity alterations as a potential basis for cognitive impairments seen in patients affected by chronic rhinosinusitis and may help direct future research,” Dr Jafari and colleagues said.

However, in this study, no cognitive deficits accompanied the functional connectivity changes. People with chronic rhinosinusitis and their matched controls shared similar cognitive status and similar sleep quality, with no between-group differences in olfaction, taste, and pain, either.

It was suggested by the researchers that, “given the brain’s ability to adapt and compensate, particularly in young and cognitively healthy individuals, our findings may represent early and subclinical functional brain alterations that may precede or be more sensitive than anticipated behavioral responses.”

“It is possible that a clinical chronic rhinosinusitis cohort with broader age distribution and more significant symptoms may have even greater changes in functional brain connectivity in the regions identified in this study,” they added.

“Overall, I do think that this study gives credence to the large body of evidence that patients with chronic rhinosinusitis, or in this case sinonasal inflammation, do have issues with cognition,” commented Nicholas Rowan, MD, of Johns Hopkins University School of Medicine in Baltimore, who was not part of the study.

Sinonasal inflammation and chronic rhinosinusitis have well established negative impacts on quality of life, according to Rowan. Previous research has found that medical or surgical intervention for chronic rhinosinusitis can alleviate cognitive dysfunction.

“Though unfortunately, the findings here are not actionable from a clinical standpoint, they do provide novel information for further prospective study of patients with chronic rhinosinusitis, as well as laboratory studies that are aimed to better understand the mechanism of why patients with CRS have such substantial quality of life implications,” according to Dr Rowan.

Although comorbid psychiatric disorders and sleep dysfunction are among the proposed mechanisms for cognitive dysfunction, the researchers said their data was supportive of a direct association of immune molecules with brain function.

Using data from The Human Connectome Project, the case-control study included 22 people with radiologic sinonasal inflammation who were matched 1:1 by age and sex to healthy controls. Sinonasal inflammation was classified as moderate in 13 people and severe in nine.

All were young adults age 22 to 35, and 68% were male.

Limitations included the retrospective nature of the study and the small sample size. Since cognitively normal participants identified radiographically from a large database, this limited the generalisability of the results, the authors added.

“Future prospective studies are warranted to determine the applicability of these findings to a clinical chronic rhinosinusitis population,” they said.

Source: MedPage Today

Journal information: Jafari A, et al “Association of sinonasal inflammation with functional brain connectivity” JAMA Otolaryngal Head Neck Surg 2021; DOI: 10.1001/jamaoto.2021.0204.