These 4 lethal viruses could fuel the next pandemic, new research says. What they are—and how the world can prepare
Northern Border: Agents Arrest Group Of Chinese Trying To Sneak Into Maine From Canada
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By entering your email and pushing continue, you are agreeing to Fox News' Terms of Use and Privacy Policy, which includes our Notice of Financial Incentive. To access the content, check your email and follow the instructions provided. Having trouble? Click here.Immigration agents stationed along the United States' northern border arrested a group of Chinese nationals trying to sneak into Maine from Canada.
"After noticing suspicious activity along the border, vigilant Fort Fairfield Border Patrol agents arrested three Chinese nationals attempting to use the cover of darkness to illegally enter the United States," U.S. Border Patrol Houlton sector said in a statement.
According to the statement, a fourth Chinese national who was suspected of attempting to pick up the group and smuggle them into the country was also arrested nearby.
It added, "A driver from New York, also a Chinese national who is already in immigration proceedings, was also arrested and suspected of attempting to further the illegal entry."
CHINESE MIGRANTS ECLIPSE MEXICAN NATIONALS IN KEY SOUTHERN BORDER SECTOR
Border Patrol agents in Fort Fairfield, Maine, arrested a group of Chinese nationals attempting to cross the U.S.-Canada border. (U.S. Border Patrol Houlton sector)
The arrest comes as counties in New York, Vermont and New Hampshire have seen a record uptick in illegal border crossings in the last quarter, as migrants are reportedly crossing the Canadian border to avoid detection.
U.S. Officials at the northern border have recorded 191,603 encounters with people crossing into the United States last year, a 41% increase from 2022.
While most still use legal ports of entry, more than 12,200 migrants were apprehended crossing illegally from Canada in 2023, a 241% uptick from the 3,578 arrested the previous year.
Chinese nationals crossing through the northern border into Maine is very rare, according to Fox News' Bill Melugin, who regularly covers immigration crossings over the U.S.-Mexico border.
7.2M ENTERED THE US UNDER BIDEN ADMIN, AN AMOUNT GREATER THAN POPULATION OF 36 STATES
The number of Chinese nationals seeking entry into the U.S. Has been increasing since fiscal 2021, when more than 450 were apprehended.
A Chinese migrant speaks to a Border Patrol officer before being processed after crossing the Rio Grande into the U.S. (Brandon Bell)
In fiscal 2022, numbers increased to more than 2,000 in total across the whole of the U.S.-Canadian border.
In fiscal 2023, that number then surged to more than 24,314.
As of the end of January, there have been more than 18,750 encounters so far in fiscal 2024, which began in October. There were nearly 6,000 encounters in December alone.
A fourth Chinese national, a driver from New York who is already in immigration proceedings, was also arrested, authorities said. (U.S. Border Patrol Houlton sector)
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Border Patrol encourages people to report any suspicious activity to Houlton Sector headquarters at 207-532-6512, ext. 5.
Fox News Digital's Danielle Wallace and Adam Shaw contributed to this report.
Long Covid Is Not The Only Chronic Condition Triggered By Infection
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SOME INFECTIONS—HIV/AIDS, for example—are chronic. If you catch one you are stuck with it indefinitely, unless a treatment exists to clear away the guilty pathogen. Many, though, are acute. Unless they kill you, your immune system will do the clearing and you can carry on as before.
For an unlucky few, however, that is not the end of the story. Certain infections have a second act, brought about by some consequence of the pathogen's visit. Sometimes, the physiological chain is clear. One well-known example concerns a variant of Streptococcus that causes rheumatic heart disease when the body's immune response also attacks cardiac tissue. Often, though, the connections are more opaque—particularly with neurological symptoms. Indeed, it may not even be clear which pathogen is involved.
Many researchers suspect, for example, that what is variously labelled chronic-fatigue syndrome or myalgic encephalomyelitis (ME) is such a post-infectious neurological syndrome (PINS). However, a suggestion that Epstein-Barr virus is the trigger has never been nailed down. Much remains mysterious about the condition itself, and, with at least nine different proposed definitions, it may well be that the umbrella term encompasses different conditions with overlapping symptoms and varied causes.
Between the extremes of rheumatic heart disease and ME there are, however, a group of post-infectious illnesses where the original cause is clear, even though the physiology is obscure. The most recently recognised is long covid, which has shone a spotlight on the field. A session at this year's meeting of the American Association for the Advancement of Science (AAAS), in Denver, therefore took a closer look at PINS. In particular, participants discussed the similarities between PINS with different causative agents; how transient infections might, via the immune responses they provoke, cause long-term neurological problems; and whether what is going on is similar to the effects of some cancer therapies. This does not, unfortunately, bring immediate prospects of treatment. But it opens avenues of investigation.
One well-established PINS is post-treatment Lyme disease (PTLD), the province of John Aucott, of Johns Hopkins University. Lyme disease is a tick-borne bacterial infection that causes raised temperature, headaches, muscle and joint pain, and tiredness. For most of those affected, these pass after treatment with antibiotics. But in 10-20% of cases the pain and tiredness, together with difficulty concentrating and difficulty sleeping, become chronic.
Dr Aucott has been studying the matter for 15 years. In 2018 he showed that PTLD can cause a mild but measurable decline in verbal learning ability—something previously contested. He was therefore struck ("shocked", he said), when reading an early paper on long covid, by how similar a chart of its principal symptoms was to one he had published on PTLD.
To understand how PTLD wreaks its havoc, Dr Aucott recruited functional MRI, a scanning technique. He stress-tested people's brains by making them do cognitive tests while lying in the scanner, and compared the responses of those who had PTLD with others who did not.
He predicted that any differences would show up in the brain's grey matter, which, with its high concentration of neuron cell bodies, is where most brain activity occurs. Instead, he got a response in the white matter: the wiring, composed of long protuberances called axons, connecting cell bodies in different parts of the brain. Something odd is thus going on, though what, exactly, is not clear.
As to the cause of the neurological symptoms of PTLD, a clue may lie elsewhere, in a study Dr Aucott cited on synovial fluid, a lubricant and shock absorber found in many skeletal joints. A non-neurological symptom of PTLD is a type of arthritis caused (as with Streptococcus-related heart disease) by the immune system's attack on healthy tissue. Sampling this fluid in people with PTLD revealed molecules called peptidoglycans that form part of the cell wall of the Lyme-disease-causing bacterium. These are known to be antigens—substances that provoke the immune system. The interesting point is that these antigens long outlived the bacteria.
Picking up on the theme of immune response, Christopher Bartley of America's National Institute of Mental Health went on to describe a paradox. He showed that, although covid has some suggestive immune-related consequences, these are seen equally in those with and without neurological symptoms of long covid.
One thing which does seem clear is that SARS-CoV-2, the covid-causing virus, does not get into the central nervous system. When post-mortem samples have been examined for viral genetic material, scarcely any is found in brains—and what little there is comes from blood vessels, not brain cells themselves. Any persistent covid-related brain damage, in other words, is not a consequence of direct infection.
It might, though, be "autoimmune", like rheumatic heart disease. Certain other viruses, including herpes simplex, Japanese encephalitis and varicella zoster virus, are known to provoke autoimmune brain illness. And one early study showed that up to 73% of antibodies produced against SARS-CoV-2 are autoreactive, meaning that they stick to, and potentially harm, at least some human tissue.
Using more sophisticated techniques, Dr Bartley and his colleagues were able to identify a number of antibodies produced in response to covid by immune-system cells inside the brain, and which reacted strongly with brain tissue. But herein lies the paradox. Those who have long covid and those who seem to have recovered completely have similar profiles of these antibodies. Nor is there any difference, six months after infection, in levels of molecules that are signs of the sorts of brain damage that might be expected.
The possibility remains that any autoimmune brain damage is inflicted quickly, while the disease is still acute, meaning that a search for relevant molecules months after the event is a wild-goose chase. But, as Dr Bartley wryly observed, "we are still trying to figure this out."
Be that as it may, Michelle Monje, a neuro-oncologist at Stanford School of Medicine, homed in on precisely how covid-induced neurological damage might occur—particularly focusing on glial cells, as brain cells other than neurons are known.
Such cells come in three varieties: microglia, a group of immune-system cells which are also responsible for neurological "gardening"—pruning the connections between neurons to improve neural circuits; astrocytes, which regulate the flow of information across junctions between neurons; and oligodendrocytes, which wrap axons with a fatty substance called myelin that acts like an insulator and stops interference with the passage of signals. (It is myelin which gives white matter its colour.) All three of these have their activity disrupted by anticancer chemotherapy, resulting in a condition known colloquially as "chemo brain fog". Dr Monje's instant reaction when she read about long covid was that the way patients describe its symptoms is often reminiscent of this.
That got her interested. And, together with Akiko Iwasaki of Yale School of Medicine, she assembled a research collaboration to investigate, using a mouse strain engineered by Dr Iwasaki specifically for covid work. This showed that microglia in the white matter were reacting to immune-cell-activating molecules called cytokines released in response to covid infection. Moreover, subsequent post-mortem examinations suggested the same thing was happening in people.
One of these cytokines, CCL11, caught their attention in particular. CCL11 has previously been associated with reduced generation of new nerve cells—and new nerve cells are important to memory formation. Its levels, they found, were elevated in the bloodstreams and brains of their mice, and a subsequent study on people with long covid showed it was elevated in their bloodstreams, too. On top of this, when they injected CCL11 into uninfected mice, it did, indeed, inhibit nerve-cell formation.
Correlation is not causation. But that is an interesting coincidence. As all three presenters made clear, research on both PINS in general and long covid in particular is very much a work in progress. But, to the extent that these disparate conditions do share mechanisms, they might share any eventual treatment, too. ■
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As FDA Filing Approaches For Tab-Cel In EBV+ PTLD, Decades Of Science Bear Fruit
Approved in Europe, tabelecleucel may soon be considered by FDA to treat patients who develop Epstein-Barr virus following a transplant, which then triggers a type of deadly lymphoma that may not respond to traditional therapy. Tab-cel, an allogeneic T-cell therapy, comes 30 years after the discovery that T cells might offer hope, followed by decades of research on how to harness them without the side effects.
Cancer can emerge from many corners. For some patients, it can start with a cure.
Patients may seek an allogeneic hematopoietic stem cell transplant (HSCT) to treat a blood cancer or an immune disorder. They may undergo a solid organ transplant (SOT), such as a new kidney to resolve renal failure. For many patients, these are lifesaving treatments. But for a small number, a transplant sets off Epstein-Barr virus (EBV), which affects up to 90% of the population at some point, many of whom may not show symptoms.1
For those taking immunosuppressive drugs after a transplant, however, it's another story.
Epstein-Barr virusImage: Dr Microbe
EBV can linger in B cells. With immunosuppression dampening a patient's normal T-cell response, the virus can multiply, triggering a potentially fatal complication called EBV-positive (EBV+) posttransplant lymphoproliferative disease (PTLD),2 in which the virus kicks off a type of lymphoma.
Although relatively uncommon, especially following HSCT, overall survival with this condition following HSCT remains grim.3 And if patients who develop EBV+ PTLD following SOT fail to respond to the usual treatment of rituximab or rituximab with chemotherapy, 2-year survival rates are around 10%.4
A New Treatment Option
The makers of a novel T-cell therapy to treat EBV+ PTLD are expected to file a biologics license application (BLA) with the FDA before this summer. Tabelecleucel, or tab-cel, is an allogeneic therapy—meaning it is manufactured for use by an unspecified patient. This offers several advantages over treatments such as chimeric antigen receptor (CAR) T-cell therapies that are customized for an individual patient. The treatment, sold as Ebvallo by Atara Biotherapeutics in the European Union and the United Kingdom,5 is given intravenously in 35-day cycles; in each cycle, the therapy is administered once weekly for 3 weeks.6
The ALLELE study (NCT03394365), phase 3 findings of which were published recently in The Lancet Oncology, found that 22 of 43 patients with EBV+ PTLD treated with tab-cel achieved an objective response, and those who responded had longer overall survival (OS) than nonresponders.6 The estimated 1-year OS for responders was 84.4% (95% CI, 58.9%-94.7%) compared with 34.8% for nonresponders (95% CI, 14.6%-56.1%). Interim results had been presented in December 2022 at the American Society of Hematology Annual Meeting and Exposition.6,7
Tab-cel comes after decades of research to understand how to harness T cells to fight EBV-associated lymphoma while sidelining harmful effects. It's work that Susan Prockop, MD, has been doing for years, first at Memorial Sloan Kettering Cancer Center (MSK) before she became the program director for Clinical and Translational Research at Dana-Farber/Boston Children's Cancer Institute.
Prockop is the senior author of the ALLELE study, which the authors said broke new ground as the first publication of phase 3 results for an allogeneic, EBV-specific T-cell therapy in a peer-reviewed journal.
Susan Prockop, MDImage: Dana-Farber Cancer Institute
"The use of viral-specific T cells started over 20 years ago, and it has been shown by a number of different studies in a number of different settings to be effective in patients who fail to respond to rituximab alone or rituximab and chemotherapy," Prockop said in an interview with The American Journal of Managed Care. "This is a demonstration of the efficacy of that in a patient population that, overall, otherwise has a very poor prognosis."
The success of tab-cel comes not just in the responses, but also in the lack of adverse events, which Prockop attributes both to features of the T-cell generation process and to patients' status prior to treatment.
As the ALLELE authors wrote, "These data represent a potentially transformative and accessible treatment advance for patients with relapsed or refractory disease with few treatment options," offering hope for patients "for whom there are no other approved therapies, without evidence of safety concerns seen with other adoptive T-cell therapies."6
ALLELE Phase 3 Results
In ALLELE, investigators enrolled 63 patients from June 27, 2018, to November 5, 2021; those eligible to continue included 43 male and 19 female patients (56% vs 44%). Additional results were as follows6:
Adverse events. The most common adverse events were disease progression; this was seen in 4 of 14 (29%) among the HSCT group and 8 of 29 (28%) in the SOT group. Investigators reported decreased neutrophil count in 4 of 14 (29%) in the HSCT group and 4 of 29 (14%) in the SOT group. Other findings included the following:
A Long Road to Success
The full story of tab-cel goes back to 1994, when an MSK research group showed how T-cell infusions eliminated EBV+ PTLD in 5 patients, but with serious adverse effects.8 Prockop described these findings, in which patients were given T cells from transplant donors.
"It was demonstrated…that those T cells could eradicate EBV+ PTLD, even in the [central nervous system]. However, giving bulk T cells resulted in at least 20% of patients developing significant graft-vs-host disease, meaning those T cells could eradicate EBV but could also recognize other aspects of nonself and cause [graft-vs-host disease].
"And so, the idea was, could you isolate the EBV-specific T cells from those bulk T cells and eradicate PTLD using that approach?"
At MSK, the team pursued this strategy, initially pioneered at Baylor, and generated these T-cell lines in advance. This was more efficient, Prockop explained, because although T-cell generation is a time-consuming process and the number of EBV+ PTLD cases is small, it is well known which patients are at risk of developing it.
A key milestone came when the team showed these pregenerated T cells could eliminate EBV+ PTLD, and another came when it was shown that T cells could be used in a human leukocyte antigen (HLA) mismatch setting. This was important, Prockop said, because T cells might be coming from a transplant donor who wasn't HLA identical. This second step would prove key in the development of tab-cel.
Building a Bank of T-Cell Lines
Creating a bank of T-cell lines to treat patients with EBV+ PTLD required studies to determine how best to match donor lines with patients. Investigators had to understand what the T-cell receptors in each line would recognize, and Prockop explained that they were "not in the practice of categorizing what EBV antigen the T cell recognized."
But they were able to categorize the HLA allele that each T cell recognized. "And so, the idea was, you could use a T-cell line in somebody who was very mismatched to the T-cell line as long as you shared the HLA allele through which the T-cell line recognized EBV," she said. In the trials at MSK, donors to the T-cell bank and recipients shared 2 HLA alleles, she said.
Prockop was the lead author of a 2020 paper in the Journal of Clinical Investigation9 that outlined this approach, along with a dose escalation strategy that led to the current 3-dose cycle. In the paper, investigators explain at length their hypotheses and steps that led to the current strategy, which calls for shifting to a different HLA restriction in the subsequent 35-day cycle if patients do not respond to the first one.
The lack of adverse effects. In addition, these experiments also showed how the in vivo expansion approach of the EBV T cells would allow repeat infusions without CRS or other effects seen in CAR T-cell therapy.
Features in the product development contribute to the lack of adverse events, Prockop explained. The process develops an "antigen-presenting cell—essentially a transformed B-cell—that expresses antigens of EBV. And those cells are co-cultured with T cells from the same donor. So, the expansion is happening in an autologous setting," she said. Expansion typically takes up to 4 weeks—much longer than the CAR T-cell process—and there is no artificial activation.
Because the therapy is "off the shelf," patients are treated within 1 to 2 days of the decision; Prockop explained there is no lymphodepleting chemotherapy before infusion. "While patients are immune-incompetent, and they have defects in their EBV-specific immunity, there isn't an acute application of lymphopenia just prior to the infusion of the T cells," she said.
The combination gives patients the best of all worlds in treatment: sustained exposure to T cells without the CRS and other events that have caused clinicians to limit doses with other therapies. Prockop said, "The safety, combined with the efficacy, is what allows these repeat infusions."
Approved in Europe, FDA Filing Next
In December 2022, the European Commission granted tab-cel marketing authorization under orphan drug designation for patients who have received at least 1 prior therapy.5 And at the European Society for Medical Oncology Immuno-oncology Congress in December 2023, Atara Biotherapeutics announced phase 2 results for tab-cel's use in in EBV+ PTLD involving CNS.10
In June 2023, during the American Society of Clinical Oncology (ASCO) annual meeting in Chicago, data were presented for 27 European patients treated with tab-cel through an expanded access program. Of the group, 24 patients with relapsed/refractory EBV+ PTLD received at least 1 dose of tab-cel; this included 16 post-SOT and 8 post-HSCT patients; 4 had primary CNS PTLD. An objective response rate of 66.7% was observed for both the SOT and HSCT groups (95% CI, 44.7%-84.4%); rates were 56.3% (9/16) for the SOT patients and 87.5% (7/8) for the HSCT patients. The best overall response was CR (33.3%; 4 SOT and 4 HSCT) or PR (33.3%; 5 SOT and 3 HSCT). Survival rates at 1 year were 73.7% for both groups.11
"These real-world results affirm the favorable risk-benefit profile seen in the pivotal phase 3 ALLELE study which supported tab-cel as the first-ever allogeneic T-cell immunotherapy approved," said AJ Joshi, MD, chief medical officer, Atara, said in a statement released during the ASCO 2023 meeting. "Tab-cel was well tolerated and delivered a 1-year survival rate of nearly 91% in responders, reinforcing its potential to address an urgent unmet medical need for EBV+ PTLD patients."12
"We are preparing for our tab-cel BLA submission in the second quarter of 2024. We look forward to interacting with the FDA to progress towards approval based on our robust clinical data," Rajani Dinavahi, MD, senior vice president and chief medical officer for Atara Biotherapeutics, Inc., said in an email to The American Journal of Managed Care.
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