Immunotherapeutic drugs are a potent way of transforming the immune system into a ferocious guard dog that can sniff out and destroy tumor cells. But for some therapies, it helps to have a leash. Without one, immunotherapies can do their job too well, stimulating the immune system to overreact, causing systemic toxicity.
A new clinical trial by investigators set out to test the safety and effectiveness of controlling a powerful immunotherapy, known as human interleukin-12 (hIL-12), by using an oral activator -- a drug that can give finer control over when a gene gets turned on -- in patients with recurrent glioblastoma. The protein hIL-12 can stimulate many branches of the immune system, but previous clinical trials that leveraged it were halted because of toxicity.
Results from the new clinical trial, sponsored by Ziopharm Oncology, Inc., are more promising: the drug-inducible gene therapy approach showed anti-tumor effects, with tolerable and reversible side effects. The study lays groundwork for more robust clinical trials of this therapy, with potential applications for glioblastoma and beyond. Results are published in Science Translational Medicine.
"In a phase 1 trial, we're always trying to find a glimmer: Is there any evidence of efficacy? These results give us that glimmer of hope," said corresponding author. "We believe it is now possible to do regulatable immunotherapy via genes. It's well-tolerated in patients with glioblastoma, with some encouraging evidence that the drug is having its intended effect."
Glioblastoma is an aggressive, incurable cancer with a median overall survival of 15 months. Patients with glioblastoma receive surgery, radiation and chemotherapy, but in almost all cases, tumors return within months. When glioblastoma recurs, median overall survival is only a few months. In the current, multi-center study, 31 patients with recurrent glioblastoma received a dose of veledimex, the oral activator, before surgery to remove brain tumors. They received an injection of an hIL-12 vector (Ad-RTS-hIL-12), which delivered an IL-12 drug, at the time of surgery. They then continued taking veledimex for 14 days.
Patients received 10-40 mg of veledimex, and the researchers reported dose-related increases of veledimex, IL-12, and other measures of immune activity in the blood of patients. Frequency and severity of adverse events, including cytokine release syndrome, correlated with the veledimex dose, reversing promptly upon discontinuation. Patients taking the 20 mg dose of veledimex had a median overall survival rate of 12.7 months.
The team found that taking corticosteroids while on the IL-12 gene therapy negatively impacted survival. Corticosteroids are prescribed to relieve brain swelling but are also immunosuppressive, potentially dampening the effectiveness of the therapy. Overall, Patients taking 20 mg of veledimex with minimal corticosteroids had a median overall survival of 17.8 months (6.4 months for those on corticosteroids).
While these median overall survival times are favorable compared to recurrent glioblastoma historical controls (numbers reported in previous studies), more advanced studies with more patients will need to be performed to confirm if the treatment is truly efficacious.
When the researchers had access to tissue from tumors that had been treated with the IL-12 gene therapy, they saw evidence that immune cells had infiltrated the tumor -- a good sign -- but also saw evidence of increased checkpoint signaling, a trick that cancer cells use to stop the immune system. As a next step, the team is combining IL-12 gene therapy with intravenous checkpoint inhibitors.
https://www.brighamandwomens.org/about-bwh/newsroom/press-releases-detail?id=3409
https://stm.sciencemag.org/content/11/505/eaaw5680
Glioblastoma clinical trial with regulatable IL-12 shows promising results
- 980 views
- Added
Edited
Latest News
TB blood test which could d…
By newseditor
Posted 27 Mar
Propionate supplementation…
By newseditor
Posted 27 Mar
Role of human Kallistatin i…
By newseditor
Posted 26 Mar
Addressing both flu and COV…
By newseditor
Posted 26 Mar
How the brain senses body p…
By newseditor
Posted 26 Mar
Other Top Stories
Attention recruits frontal cortex in human infants
Read more
Early life stress in neurons is mediated by epigenetic mechanism
Read more
Negative mood linked to prolonged amygdala activity
Read more
How the brain understands sentences
Read more
Does 'harsh parenting' lead to smaller brains?
Read more
Protocols
All-optical presynaptic pla…
By newseditor
Posted 23 Mar
Epigenomic tomography for p…
By newseditor
Posted 20 Mar
A mouse DRG genetic toolkit…
By newseditor
Posted 17 Mar
An optogenetic method for t…
By newseditor
Posted 13 Mar
Profiling native pulmonary…
By newseditor
Posted 08 Mar
Publications
Balancing neuronal activity…
By newseditor
Posted 28 Mar
OSBP-mediated PI(4)P-choles…
By newseditor
Posted 28 Mar
Integrated plasma proteomic…
By newseditor
Posted 27 Mar
APP antisense oligonucleoti…
By newseditor
Posted 27 Mar
Targeting Erbin-mitochondri…
By newseditor
Posted 27 Mar
Presentations
Hydrogels in Drug Delivery
By newseditor
Posted 12 Apr
Lipids
By newseditor
Posted 31 Dec
Cell biology of carbohydrat…
By newseditor
Posted 29 Nov
RNA interference (RNAi)
By newseditor
Posted 23 Oct
RNA structure and functions
By newseditor
Posted 19 Oct
Posters
A chemical biology/modular…
By newseditor
Posted 22 Aug
Single-molecule covalent ma…
By newseditor
Posted 04 Jul
ASCO-2020-HEALTH SERVICES R…
By newseditor
Posted 23 Mar
ASCO-2020-HEAD AND NECK CANCER
By newseditor
Posted 23 Mar
ASCO-2020-GENITOURINARY CAN…
By newseditor
Posted 23 Mar