Results from a clinical trial suggest that local delivery of anti-CTLA-4 immunotherapy drug is safer than systematic delivery.
The study, published in Science Immunology, shared the results of a phase 1 clinical trial. 13 patients with early-stage melanoma received local injections of anti-CTLA-4.
Researchers from the Cancer Centre Amsterdam, who conducted the study, found that the patients avoided the typical toxic and immune-related side effects associated with systemic delivery of this immune checkpoint blockade treatment.
“Although the concept of intratumoral immunomodulation or ablation to achieve in vivo vaccination has long been proposed and pursued, there are very few clinical studies that have explored the effects of local delivery of immune checkpoint inhibitors,” the authors reported.
Immune checkpoint blockades
Systemic immune checkpoint blockades (ICB) display therapeutic efficacy in cancers. They induce robust clinically effective T cell immunity in patients with metastatic melanoma, which is associated with better patient survival. However, they also cause immune-related adverse events. Avoiding these adverse effects is crucial for effective ICB.
While anti-PD1 is the conventional type of immune checkpoint blockade therapy, anti-CTLA-4 is a close second. However, anti-CTLA-4 is used less often because it has more toxic effects and can cause more immune-related adverse events in patients. Both therapies are traditionally delivered systemically rather than locally.
“Preclinical studies indicate that intratumoral administration of CTLA-4 blocking antibody in a low dose is as effective in inducing tumour eradication as systemic delivery, without the risk of immune-related adverse events,” noted the authors.
Localised delivery of anti-CTLA-4 therapy yields less harmful side effects
In this phase I clinical trial, the team tested whether localised delivery of anti-CTLA-4 therapy would yield less harmful side effects. They injected an anti-CTLA-4 drug, tremelimumab, in sites that drained into the same lymph nodes as immune cells from the tumour.
They discovered that this prompted the creation of tumour antigen-specific T cells. They also observed an increased migratory dendritic cell activation and reduced immunosuppressive regulatory T cells.
These responses imply that the drug enhanced tumour fighting activity. Notably, 7 out of the 13 patients had minimal to no side effects.
Although the researchers were primarily focused on establishing safety, the study also provided preliminary evidence that the method could be effective for treating melanoma tumours.
The authors cautioned that this phase 1 trial enrolled only a small numbers of patients but proposed that this study supports the concept of local instead of systemic anti–CTLA-4 blockade for future adjuvant immunotherapeutic strategies in patients.
The authors wrote, “These observations suggest that local administration of anti-CTLA-4 may offer a safe and promising adjuvant treatment strategy for patients with early-stage melanoma.”
Written by Poppy Jayne Morgan, Front Line Genomics
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