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.
Smart virus is efficient at eliminating GBM cells and activating immune response
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
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Some Ontario doctors have started offering a free shot that can protect babies from respiratory syncytial virus while Quebec will begin its immunization program next month.
The new shot called Nirsevimab gives babies antibodies that provide passive immunity to RSV, a major cause of serious lower respiratory tract infections for infants and seniors, which can cause bronchiolitis or pneumonia.
Ontario’s ministry of health says the shot is already available at some doctor’s offices in Ontario with the province’s remaining supply set to arrive by the end of the month.
Quebec will begin administering the shots on Nov. 4 to babies born in hospitals and delivery centers.
Parents in Quebec with babies under six months or those who are older but more vulnerable to infection can also book immunization appointments online.
The injection will be available in Nunavut and Yukon this fall and winter, though administration start dates have not yet been announced.
This report by The Canadian Press was first published Oct. 21, 2024.
-With files from Nicole Ireland
Canadian Press health coverage receives support through a partnership with the Canadian Medical Association. CP is solely responsible for this content.
ISLAMABAD (AP) — Polio cases are rising ahead of a new vaccination campaign in Pakistan, where violence targeting health workers and the police protecting them has hampered years of efforts toward making the country polio-free.
Since January, health officials have confirmed 39 new polio cases in Pakistan, compared to only six last year, said Anwarul Haq of the National Emergency Operation Center for Polio Eradication.
The new nationwide drive starts Oct. 28 with the aim to vaccinate at least 32 million children. “The whole purpose of these campaigns is to achieve the target of making Pakistan a polio-free state,” he said.
Pakistan regularly launches campaigns against polio despite attacks on the workers and police assigned to the inoculation drives. Militants falsely claim the vaccination campaigns are a Western conspiracy to sterilize children.
Most of the new polio cases were reported in the southwestern Balochistan and southern Sindh province, following by Khyber Pakhtunkhwa province and eastern Punjab province.
The locations are worrying authorities since previous cases were from the restive northwest bordering Afghanistan, where the Taliban government in September suddenly stopped a door-to-door vaccination campaign.
Afghanistan and Pakistan are the two countries in which the spread of the potentially fatal, paralyzing disease has never been stopped. Authorities in Pakistan have said that the Taliban’s decision will have major repercussions beyond the Afghan border, as people from both sides frequently travel to each other’s country.
The World Health Organization has confirmed 18 polio cases in Afghanistan this year, all but two in the south of the country. That’s up from six cases in 2023. Afghanistan used a house-to-house vaccination strategy this June for the first time in five years, a tactic that helped to reach the majority of children targeted, according to WHO.
Health officials in Pakistan say they want the both sides to conduct anti-polio drives simultaneously.
WASHINGTON (AP) — Millions of people with private health insurance would be able to pick up over-the-counter methods like condoms, the “morning after” pill and birth control pills for free under a new rule the White House proposed on Monday.
Right now, health insurers must cover the cost of prescribed contraception, including prescription birth control or even condoms that doctors have issued a prescription for. But the new rule would expand that coverage, allowing millions of people on private health insurance to pick up free condoms, birth control pills, or “morning after” pills from local storefronts without a prescription.
The proposal comes days before Election Day, as Vice President Kamala Harris affixes her presidential campaign to a promise of expanding women’s health care access in the wake of the U.S. Supreme Court’s decision to undo nationwide abortion rights two years ago. Harris has sought to craft a distinct contrast from her Republican challenger, Donald Trump, who appointed some of the judges who issued that ruling.
“The proposed rule we announce today would expand access to birth control at no additional cost for millions of consumers,” Health and Human Services Secretary Xavier Becerra said in a statement. “Bottom line: women should have control over their personal health care decisions. And issuers and providers have an obligation to comply with the law.”
The emergency contraceptives that people on private insurance would be able to access without costs include levonorgestrel, a pill that needs to be taken immediately after sex to prevent pregnancy and is more commonly known by the brand name “Plan B.”
Without a doctor’s prescription, women may pay as much as $50 for a pack of the pills. And women who delay buying the medication in order to get a doctor’s prescription could jeopardize the pill’s effectiveness, since it is most likely to prevent a pregnancy within 72 hours after sex.
If implemented, the new rule would also require insurers to fully bear the cost of the once-a-day Opill, a new over-the-counter birth control pill that the U.S. Food and Drug Administration approved last year. A one-month supply of the pills costs $20.
Federal mandates for private health insurance to cover contraceptive care were first introduced with the Affordable Care Act, which required plans to pick up the cost of FDA-approved birth control that had been prescribed by a doctor as a preventative service.
The proposed rule would not impact those on Medicaid, the insurance program for the poorest Americans. States are largely left to design their own rules around Medicaid coverage for contraception, and few cover over-the-counter methods like Plan B or condoms.
