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Small Trial of Cancer-Killing Virus With Immunotherapy Shows Positive Results

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Intratumoral delivery of an engineered oncolytic virus (DNX-2401) targeting glioblastoma (GBM) cells combined with subsequent immunotherapy was safe and improved survival outcomes in a subset of patients with recurrent GBM, according to results from a multi-institutional Phase I/II clinical trial co-led by researchers at The University of Texas MD Anderson Cancer Center and the University of Toronto.

The study, published today in Nature Medicine, met its primary safety endpoint and demonstrated the combination was well tolerated overall with no dose-limiting toxicities. The study did not meet its primary efficacy endpoint of objective response rate, but the combination achieved a 12-month overall survival (OS) rate of 52.7%, which is greater than the prespecified efficacy threshold of 20%. Three patients remained alive at 45, 48 and 60 months after treatment.

“This viral therapy is a different approach to the current standard of care,” said co-corresponding author Frederick Lang, M.D., chair of Neurosurgery. “Our previous trial demonstrated that not only does the virus act by killing cancer cells directly, it also effectively activates the innate immune system to convert these immunologically cold tumors into hot tumors. This led us to evaluate a combination with checkpoint inhibitors, which we now see can improve survival outcomes in a subset of patients.”

Glioblastoma is an aggressive brain cancer with a median OS of six months; patients typically experience recurrence with standard radiation and chemotherapy approaches. While immune checkpoint blockade has improved outcomes in other cancer types, the unique immunosuppressive tumor microenvironment in recurrent GBM shields it against immune cell infiltration, making it notoriously difficult to treat with immunotherapy.

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Smart virus is efficient at eliminating GBM cells and activating immune response

Together with Lang, Juan Fueyo, M.D., and Candelaria Gomez-Manzano, M.D., both professors of Neuro-Oncology, are the co-inventors of DNX-2401, a cold virus engineered to selectively target and invade GBM cells while avoiding normal cells.

In previous Phase I trial results, DNX-2401 monotherapy effectively induced cancer cell death and changed the microenvironment to allow for increased T cell infiltration, resulting in an anti-tumor immune response. Twenty percent of patients with recurrent GBM remained alive for at least three years, and tumor reduction in complete responders continued for more than a year.

These results showed an increase in PD-1 checkpoint expression following treatment, suggesting that the immune system may be primed to respond to anti-PD-1 immunotherapy. Preclinical models supported this hypothesis, as treatment with pembrolizumab one week after DNX-2401 treatment improved survival outcomes compared to either treatment alone.

“Injecting a virus into a patient’s brain tumor is disruptive science, because this therapeutic strategy aims to awaken the patient’s immune system and trigger a healing from within,” Fueyo said. “After injection, patients that respond well develop inflammation inside the tumor, triggering an immune response that first kills the virus. Once the virus is wiped out, the continued immune reaction, stimulated by additional immunotherapy, destroys the cancer cells in a tightly regulated way without the side effects common to chemotherapy or radiation therapy.”

Combination therapy prolongs survival and improves quality of life in subset of patients

The current trial was designed to evaluate the combination of intratumoral DNX-2401 followed by intravenous pembrolizumab. The study enrolled 49 patients with recurrent GBM from several institutions between September 28, 2016 to January 17, 2019. The median age of patients was 53 years and 41% were women.

Forty-eight of the 49 patients (98%) were treated with one dose of DNX-2401 after biopsy, followed by pembrolizumab given one week later. The majority of adverse events were grade 1 or 2, with the most common being brain edema (37%), headache (31%) and fatigue (29%).

The combination achieved a clinical benefit, defined as stable disease or better, in more than half (56.2%) of the patients. Five patients had objective responses and two experienced tumor reduction of 80% or more at six months follow-up. By 18 months, these two patients had a complete response without evidence of disease progression.

Exploratory gene expression and immunophenotypic analysis also revealed that objective response occurred in patients with a moderately inflamed tumor microenvironment and modest PD-1 expression, meriting further investigation of which patient characteristics will determine who is more likely to benefit from this treatment.

While this study did not meet its primary efficacy endpoint, it did validate the use of DNX-2401 in combination with immune checkpoint inhibitors as a safe approach that opens the door to exploring other combinations. For instance, the researchers found that specimens from 10 patients showed elevated levels of several immune checkpoints after treatment including LAG3, TIGIT and B7-H3, highlighting these proteins as potential therapeutic targets.

“Our studies using this ‘smart virus’ are ongoing, but we are encouraged that we continue to see a small number of patients who have a very dramatic eradication of the tumor,” Gomez-Manzano said. “These results motivate us to keep searching for the best combination strategy that can optimize the use of this virus to improve patient outcomes.”

Clinical trials currently are underway using mesenchymal stem cells to deliver more of the smart virus to the tumor and more widely through the tumor. Future clinical trials will evaluate alternate treatments, such as checkpoint inhibitors or CAR T cell therapy, in combination with DNX-2401.

Reference: Nassiri F, Patil V, Yefet LS, et al. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial. Nat Med. 2023:1-9. doi: 10.1038/s41591-023-02347-y

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

 

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Common, inexpensive diabetes drug could cut long COVID risk, study finds

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A well-known, inexpensive diabetes drug appears to cut the risk of developing long COVID, hopeful-but-early new research suggests.

The study, published Thursday in the peer-reviewed journal Lancet Infectious Diseases, found outpatient treatment with the drug metformin — a common treatment for Type 2 diabetes — reduced long COVID incidence among infected patients by 41 per cent.

Roughly six per cent of those taking metformin went on to develop the condition, compared to close to 11 per cent of those in the placebo group. Participants on metformin were also less likely to be hospitalized roughly a month after infection by SARS-CoV-2, the virus that causes COVID-19.

“Metformin has clinical benefits when used as outpatient treatment for COVID-19 and is globally available, low-cost and safe,” wrote the research team.

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Lead author Dr. Carolyn Bramante, a physician-scientist with the University of Minnesota in Minneapolis, told CBC News that the effect was even larger when metformin was given quickly �— in less than four days — during someone’s infection. She said metformin may be helping patients fight off the virus, or reducing inflammation, though more research is needed to figure out why the drug appears to work.

“Our data don’t suggest anything about whether metformin would treat long COVID in someone who already has it,” she said, “so that’s an important area of research where trials should be done.”

Two other drugs, ivermectin and fluvoxamine, were also studied, but neither made a difference on the incidence of long COVID.

A new study found metformin — a common treatment for Type 2 diabetes — reduced long COVID incidence among infected patients by 41 per cent. (Francis Dean/Corbis/Getty )

‘Potentially landmark’ findings

The research involved randomized, quadruple-blind trials on roughly 1,400 people at six sites in the U.S., through multiple waves of the pandemic, and looked at both vaccinated and unvaccinated individuals — though only those with first-time infections.

Outside medical experts say it’s one of the more robust studies yet on a potential preventative aimed at long COVID.

“I think it’s a significant start to having a better understanding of the role of metformin in reducing the risk of long COVID,” said Dr. Isaac Bogoch, an infectious diseases specialist with the University Health Network in Toronto. “There’s been hints of data over the last couple of years … this furthers that discussion.”

If confirmed, the findings are “profound and potentially landmark on two distinct counts,” wrote Dr. Jeremy Faust, from Harvard Medical School, in an accompanying commentary in the Lancet.

The paper offers the “first high-quality evidence” showing incidence of long COVID can be reduced through a medical intervention, he wrote, and offers an important medical contribution regarding the very existence of the condition, since “a treatment can only be effective if there is something to treat.”

Most long COVID symptoms clear up within a year, new research suggests

 

New research out of Israel suggests most symptoms of long COVID clear up within a year, but some — like weakness and trouble breathing — are more likely to persist.

In a statement, Dr. Frances Williams, professor of genetic epidemiology at King’s College London, cautioned there would need to be extensive use of metformin to realize the study’s seemingly impressive outcomes.

“In total, 564 people were exposed to the drug metformin to prevent 23 hypothetical cases. This means 24 people would need to take metformin to prevent one case of [long COVID].”

Fatigue, ‘brain fog’

Marked by a variety of lingering symptoms such as fatigue, shortness of breath and feelings of ‘brain fog’, and formally known as post COVID-19 condition, long COVID is thought to be less common by this point in the pandemic, largely thanks to widespread protection from vaccinations.

But the condition can still be debilitating for some, including millions of people around the world — including many in Canada — who became infected with earlier SARS-CoV-2 variants before the arrival of vaccines.

While physicians are hopeful the new research may fuel additional study and potentially help bring down long COVID rates even further, there were some key limitations.

For one thing, it only focused on adults between age 30 and 85 who were overweight or had obesity — so the drug’s impact on individuals of other body weights isn’t yet known.

“It’s not entirely clear how generalizable this will be,” Bogoch said.

In his comment for the Lancet, Faust also noted that since the participants were given a diabetes drug, there may be reduced symptoms linked to undiagnosed diabetes among the patients. “Furthermore, the mechanism of action by which metformin might reduce the incidence of long COVID remains unclear,” he wrote.

Dr. Lynora Saxinger, a professor in the division of infectious diseases at the University of Alberta, noted the study didn’t follow long COVID patients using any “standardized criteria.”

But, she said in an email to CBC News, “it still is really positive and encouraging that a treatment in early COVID could reduce risk of prolonged symptoms: additional studies in other patient groups and with more specific long COVID symptom followup will be really helpful.”

Bogoch stressed that, while the drug shows potential, it wouldn’t “solve all of our issues with long COVID.” However, it could become an important tool given its decades-old safety profile, he said.

“If this is something that, indeed, pans out, and if metformin truly has some properties that reduce the risk of developing long COVID, that’s wonderful because it’s a cheap, widely available [drug].”

 

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Hair loss can be difficult, cancer patients say — and some want better access to options – CBC.ca

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White Coat Black Art26:30Hair Loss Part I: The trouble with wigs

Cairo Gregory doesn’t think about her hair too often — anymore.

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For much of her life, she says she didn’t have the “greatest” relationship with her hair. Gregory, a 16-year-old student in Toronto, had at one point straightened her hair so much, it ended up damaged. So she cut it short — “I hated it,” she said.

But eventually, as she learned to style her hair, she grew to love it. So last year, when her hair started falling out in her second week of chemotherapy for ovarian cancer, she says she found the loss difficult. Like many of those going through chemotherapy, she made the decision to completely shave her head as she started shedding.

“I think that was probably the most upsetting part for me,” she told White Coat, Black Art host Dr. Brian Goldman.

“When it fell out, it was like my entire Instagram [timeline] was just hair videos, like new hairstyles because I’d gotten really into that at that point. So it really sucked when it was like something that actually really, really became important to me at that period of time.”

When she began losing her hair during chemotherapy, Gregory enlisted a friend to help shave it off. (Submitted by Cairo Gregory)

Despite advances in cancer treatment, little has changed with respect to its effects on hair. Chemotherapy attacks fast-growing cells in the body — including hair. For many patients, that means losing their locks during treatment.

That can have an impact on a person’s self-confidence and how they feel about themselves during treatment. But alternatives, like wigs and cold-capping procedures that can protect a patient’s hair, are out of reach for many patients due to price and availability.

For Gregory, the problem was compounded by a lack of hospital resources and alternative hair options for people of colour, she said.

“There isn’t a pamphlet that they hand out for people with curly hair to go find wigs. There should be one,” she said.

Wigs can be pricey, but free alternatives exist

Losing hair during cancer treatment can be a shocking experience. Some patients say losing hair can make the psychological burden of chemotherapy feel heavier, given they don’t look like themselves.

“Obviously nobody wants to feel sick, but I didn’t want to look sick,” said Tammy Wegener, who was treated for breast cancer in 2022. “I wanted to feel that I had some peace of mind, that my kids had some peace of mind going through all this.”

That’s something Mona Rozdale says she hears often.

“At the end of the day, everybody wants to feel like themselves, and when you strip something that you’re so used to having, you don’t know life without it,” she said.

Rozdale is responsible for the Canadian Cancer Society’s wig and breast prosthetics bank lending program, which is free.

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She says wigs can be a helpful solution to those facing hair loss. But they can also be pricey. On average, a good quality wig made from human hair can cost around $2,500, according to Rozdale. But cheaper synthetic wigs are starting to look more realistic.

When Gregory couldn’t find a wig that fit her style — or budget of around $500 — at a hospital boutique, she opted to have her mother’s hairdresser make her one at a discount.

Scalp cooling is resource-intensive

Some people being treated for cancer have kept their natural hair with a process known as scalp cooling or cold capping.

Patients wear an intensely cold helmet before, during and after chemotherapy that constricts blood vessels in the scalp. It involves chilled caps that are swapped out regularly, or a machine that pumps cold liquid through an attached cap. In doing so, chemotherapy is less likely to reach and damage hair follicles, potentially reducing hair loss.

Woman in a chair, wrapped in a knitted blanket, wears a helmet like cap at a hospital.
Tammy Wegener decided to try scalp cooling during her treatment for breast cancer, for both herself and her family. (Submitted by Tammy Wegener)

With limited data on its efficacy and a high price tag, however, cold capping is not widely available across Canada.

“The greatest limitation is chair time. It is a resource-rich type of use of the machine,” said Dr. Shannon Salvador, gynecologic oncologist at the Jewish General Hospital in Montreal and an associate professor at McGill University.

“When you have a patient who has to come for chemo every single week, that’s a great deal of time for them and a lot of time in the hospital to be able to come and use the machine.” 

But Salvador, who has studied the effectiveness of scalp cooling, says there is evidence it does work for some patients.

In a 2021 study she co-authored, published in the journal Gynecologic Oncology Reports, over half of patients who were on a smaller weekly dose of a chemotherapy drug retained about 50 per cent of their hair when using a cold cap. The cold cap treatment didn’t work for those on a larger dose. 

Cold caps limited at Canadian hospitals

Cold capping is not available to people with certain types of cancer, such as blood cancers, and those being treated with certain types of chemotherapy.

White Coat, Black Art reached out to several cancer centres in Canada, and found scalp cooling offered at just a handful of hospitals, often at the patient’s expense.

Wegener, 49, was able to access the treatment for free at Saint John Regional Hospital after a scalp cooling machine was donated by a nurse at the institution. 

LISTEN | Why advocates want scalp cooling available at more hospitals:

26:30Hair Loss Part II: Cold Capping

Salvador says she expects hospitals will still rely on donations and external support for scalp cooling technology, rather than funding them directly.

“We need to acknowledge that, in Canada, we are in a socialized health-care system where we need to place the money where it’s going to do the most benefit,” she said. 

“Unfortunately that does mean turning away things that are of great emotional benefit to patients, but may not play a great deal in their actual clinical care.”

Woman poses for a selfie
Wegener says she was able to keep most of her hair thanks to the cold cap, noticing only some thinning. (Submitted by Tammy Wegener)

Cold capping was a success for Wegener, who says during her chemotherapy treatment she noticed only some thinning of her hair and eyebrows. Based on her own experience, she hopes to see it in more places.

“Not that it’s for everybody and not everybody sees the results I saw with mine,” Wegener said. “But I think it still should be an option for everyone.”

Growing back

Gregory, the Toronto student who is still anxious about her cancer potentially returning, has become more comfortable with — and without — her wig. 

She went to class bald for the first three months of the school year, in part because she also lost hair on and around her face, making the wig look unnatural. But she has since confidently worn wigs to school, and now has enough of her natural hair to add in braids.

“That took a year. It’s almost been a year since my hair started going back,” she said.

“I think by next summer I could probably wear a ponytail wig and then hopefully, like maybe a few summers after that, I won’t wear wigs anymore at all.”

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Addictions counselling services expanded for Vancouver Islanders

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People struggling with mental health and substance abuse can access up to 12 free counselling sessions per year in a new Island Health program.

Leah Hollins, Island Health Board Chair, says “This represents a significant expansion and investment in community-based counselling services to improve access to these services on Vancouver Island.”

Virtual Island-wide services will be available through Cognito Health, and Trafalgar Addiction Treatment Centre. Services are also available in Port Hardy through North Island Crisis and Counselling Services and in Nanaimo through EHN Outpatient Services and Tillicum Lelum Aboriginal Society.

The publicly-funded, community-based counselling is intended for people with moderate challenges. The new partnership with Island health will meet the counselling needs of at least 1,500 people per year.

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Access to the counselling services is via referral or self-referral through Island Health Mental Health and Substance Use locations.

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