Virus World

Babies develop risk of cancer in womb, but will not go on to develop it without second ‘hit’ from an infection, scientists believe. Childhood leukaemia is driven by common childhood infections meeting pre-cancerous cells in the blood, scientists believe. Experts at the Institute of Cancer Research (ICR) in London have found babies develop the risk for leukaemia in the womb, but will not go on to develop the disease without a second ‘hit’ from a viral or bacterial infection, such as flu. The research highlights the importance of allowing infants to socialise with other children early in their lives, to prime their immune systems against infections. The discovery came by studying pairs of twins, where only one initially developed acute lymphoblastic leukaemia (ALL) - the most common type of the cancer in children. Identical twins are around 15-25 per cent more likely to go on to develop ALL if their sibling already has the disease, while less than one per cent of non-identical twins or other siblings go on to develop the disease. Researchers followed the twins for up to 15 years and found the high risk only applies if the identical twins shared a single placenta before birth - which only happens in around 60 per cent of identical twin pairs.

Findings 'confirm disease can be traced back to womb'

It confirms that the conditions needed to trigger leukaemia first arise in the womb, and even the healthy twin will carry "pre-leukaemia" cells in the blood, which have occurred through a spontaneous developmental error, and passed between the two. But clinically silent cells will not develop into cancer without a post-birth "hit", probably from common childhood infections. Prof Sir Mel Greaves, the founding director of the Centre for Evolution and Cancer and Professor of Cell Biology at The Institute of Cancer Research, London, said: “Our study provides new insights into the origins of childhood acute lymphoblastic leukaemia. “These new findings confirm that the disease can be traced back to the womb when pre-leukaemia cells spread via the twins’ shared blood supply. "What remained a mystery until now was why sometimes only one twin is diagnosed with leukaemia. “We still do not know for certain what leads to the first ‘hit’ of genetic changes in the womb, but we think that the second ‘hit’ of genetic changes is probably triggered by common childhood infections – opening up the possibility of ‘priming’ the immune system in infancy to avoid the development of the disease later on in life.” Acute lymphoblastic leukaemia is the most common type of childhood cancer, accounting for 80 per cent of leukaemia cases in children. The team are now focussed on finding the the second infection-driven hit after birth.

Boosting the gut could protect children against disease

They believe that the gut microbiome may be playing a key role in protecting children against developing leukaemia even if they have pre-cancerous cells. Although vaccines have little impact on preventing ALL, boosting the gut in early life may help. Prof Greaves added: “Risk of ALL is elevated by C-section birth, lack of breast feeding and paucity of social contacts in infancy. “Conversely, attendance at play groups in infancy is protective. So, to some extent , risk can be modified without medical intervention.” The findings will also allow doctors to assess the risk of ALL for twins,  firstly by determining whether the twins are identical and sharing a placenta and then by regularly tracking the levels of pre-leukaemia cells in their blood. Sarah McDonald, the deputy director of research at Blood Cancer UK, who funded the work said: “Understanding the mechanism as to how the cancer develops in identical twins, and why often only one develops leukaemia is an important question to answer. “It helps us understand both the risk of the other sibling developing leukaemia and provides insight into how leukaemia develops in all children. “This research shows that in cases where one twin develops leukaemia, and both twins both share a placenta during pregnancy, two events are needed to determine whether the other sibling develops the disease - one before birth and the other after.”

Research published (Dec. 20, 2022) in the journal Leukaemia:

https://doi.org/10.1038/s41375-022-01756-1 

Orchard Therapeutics said its gene therapy Strimvelis, approved by European authorities in 2016 to treat the rare inherited condition ADA-SCID, has been linked to a patient’s leukemia. No patients will be treated while Orchard investigates. The potential of gene therapies as cures for some hard-to-treat genetic diseases can be very attractive. But one such product is now suspected of causing a serious safety problem.  Friday, Orchard Therapeutics said its Strimvelis treatment, approved by European authorities in 2016 to treat the rare inherited condition ADA-SCID, has been linked to a patient’s leukemia. “Preliminary findings suggest this diagnosis may be attributable to an insertional event related to treatment with Strimvelis,” the company said. It’s now investigating whether there’s indeed a causal relationship.   Since its 2016 EU approval—when it was owned by original developer GlaxoSmithKline—only 16 patients have been treated with Stimvelis. The patient who developed leukemia had apparently been treated under a GSK compassionate use program in 2016. No more patients will get the therapy before the investigation is complete, Orchard said. The drug was never approved in the U.S. ADA-SCID is a condition marked by a mutation in the gene making the adenosine deaminase (ADA) enzyme, which is essential for maintaining normal white blood cells. ADA-SCID patients, with a dysfunctional immune system, have less than two years to live without effective intervention.

Since its 2016 EU approval—when it was owned by original developer GlaxoSmithKline—only 16 patients have been treated with Stimvelis. The patient who developed leukemia had apparently been treated under a GSK compassionate use program in 2016. No more patients will get the therapy before the investigation is complete, Orchard said. The drug was never approved in the U.S. ADA-SCID is a condition marked by a mutation in the gene making the adenosine deaminase (ADA) enzyme, which is essential for maintaining normal white blood cells. ADA-SCID patients, with a dysfunctional immune system, have less than two years to live without effective intervention.  Besides Strimvelis, Orchard is also developing OTL-101, which uses a lentivirus to insert a functional copy of the ADA gene into a patient’s cells. The drug is currently undergoing a registrational trial and has won breakthrough and orphan drug designations from the FDA. All the gene therapy candidates in Orchard’s pipeline use lentiviral vectors that have been “specifically designed to avoid insertional oncogenesis after administration,” Orchard said, adding that no dangerous gene insertion has been reported around lentiviral vector-based stem cell gene therapy in any indication.

Company's Press Release (Oct. 30, 2020):

https://ir.orchard-tx.com/news-releases/news-release-details/orchard-statement-strimvelisr-gammaretroviral-vector-based-gene 

New way of altering DNA is used to engineer an "exciting", experimental therapy for a 13-year-old girl. A teenage girl's incurable cancer has been cleared from her body in the first use of a revolutionary new type of medicine. All other treatments for Alyssa's leukaemia had failed. So doctors at Great Ormond Street Hospital used "base editing" to perform a feat of biological engineering to build her a new living drug. Six months later the cancer is undetectable, but Alyssa is still being monitored in case it comes back. Alyssa, who is 13 and from Leicester, was diagnosed with T-cell acute lymphoblastic leukaemia in May last year. T-cells are supposed to be the body's guardians - seeking out and destroying threats - but for Alyssa they had become the danger and were growing out of control. Her cancer was aggressive. Chemotherapy, and then a bone-marrow transplant, were unable to rid it from her body. Without the experimental medicine, the only option left would have been merely to make Alyssa as comfortable as possible. "Eventually I would have passed away," said Alyssa. Her mum, Kiona, said this time last year she had been dreading Christmas, "thinking this is our last with her". And then she "just cried" through her daughter's 13th birthday in January......

For the first time, a patient got treated for HIV and cancer at the same time, with an infusion of gene-edited stem cells. The results? Mixed. Imagine you’re 27 years old and you start feeling ill. Ill enough that you go to the hospital, and after much poking and prodding and waiting for lab results you learn you’re HIV-positive. Two weeks later you find out that’s not even the worst of it. You’ve got leukemia too.

Under any circumstances it would be a lot to take in. Especially in China, where HIV/AIDSis highly stigmatized. But for one young man living there, who this happened to in the late spring of 2016, there was one small but significant silver lining to this double whammy of a diagnosis. He would be eligible to participate in the first-ever clinical trial to assess the safety of trying to cure both the cancer and the infection in a single procedure using the gene editing tool call Crispr. In July of 2017, doctors in Beijing blasted the patient with chemicals and radiation to wipe out his bone marrow, making space for millions of stem cells they then pumped into his body through an IV. These new stem cells, donated by a healthy fellow countryman, would replace the patient’s unhealthy ones, hopefully resolving his cancer. But unlike any other routine bone marrow transplant, this time researchers edited those stem cells with Crispr to cripple a gene called CCR5, without which HIV can’t infiltrate immune cells.

Now, more than two years later, the patient is in good health, his cancer in full remission, as researchers report today in the New England Journal of Medicine. The edited stem cells survived and are still keeping his body supplied with all the necessary blood and immune cells, and a small percentage of them continue to carry the protective CCR5 mutation. Not enough to have cured him of HIV, though—he remains infected and on antiretroviral drugs to keep the virus in check. Still, experts say the new case study shows this use of Crispr appears to be safe in humans and moves the field one step closer toward creating drug-free HIV treatments.

“The safety profile appears to be acceptable,” pioneering cancer researcher Carl June wrote in an accompanying editorial, noting that the editing appeared to be precise, and that the engineered stem cells didn’t provoke an immune response in the patient. June did offer a caveat that the study’s single patient offered only limited data to draw on. What he found more striking was how quickly the science has moved from the first reports of using Crispr to treat HIV infection in mice to trying it in humans: only two years. At the University of Pennsylvania, June has led work in  a ground-breaking cancer treatment called CAR-T, which involves genetically reprogramming immune cells into a clone army of tumor-targeting assassins. But it took him five years to go from studies in animals to trials involving humans. In this case, China’s more permissive biomedical research regulations might have expedited the work, or it could be that genetic engineering is lending new momentum to the race for an HIV/AIDS cure, he wrote. “In any case, the genie is out of the bottle with genome editing.”

This is the first time an HIV-positive patient has been treated with Crispr-edited cells. But scientists have been trying to find ways to genetically disable CCR5 for more than a decade now. It all started in 2007, when a German doctor took a 41-year-old man with HIV/AIDS and leukemia off of his antiretroviral drugs and hooked a thin tube up to a vein in his chest. Through it, the so-called Berlin Patient received blood cells from a bone marrow donor who had a naturally occurring mutation called CCR5 Δ32. He was missing a chunk of DNA that ultimately allows an HIV virus to enter immune cells. The patient survived his cancer and became the first (though no longer the only) person considered to be fully cured of HIV/AIDS....

The study was published on September 11, 2019 in the New England Journal of Medicine:

https://doi.org/10.1056/NEJMoa1817426