Background: Patients with advanced melanoma who progress after treatment with immune checkpoint-inhibitors (ICI) and BRAF-/MEK-inhibitors (if mutated) have no remaining effective treatment options. The presence of CD1c (BDCA-1) and CD141 (BDCA-3) myeloid dendritic cells (myDC) in the tumor microenvironment correlates with pre-existing immune recognition and responsiveness to immune checkpoint blockade. The synthetic saponin-based immune adjuvant AS01 enhances adaptive immunity through the involvement of myDC.
Methods: In this first-in-human phase I clinical trial, patients with metastatic melanoma refractory to ICI and BRAF-/MEK inhibitors (when indicated) were recruited. Patients received an intravenous administration of low-dose nivolumab (10 mg, every 2 weeks) plus an intratumoral (IT) administration of 10 mg ipilimumab and 50 µg (0.5 mL) AS01 (every 2 weeks). All myDC, isolated from blood, were injected on day 2 into the same metastatic lesion. Tumor biopsies and blood samples were collected at baseline and repeatedly on treatment. Multiplex immunohistochemistry (mIHC) was performed on biopsy sections to characterize and quantify the IT and peritumoral immune cell composition.
Results: Study treatment was feasible and well tolerated without the occurrence of unexpected adverse events in all eight patients. Four patients (50%) obtained a complete response (CR) in the injected lesions. Of these, two patients obtained an overall CR, and one patient a partial response. All responses are ongoing after more than 1 year of follow-up. One additional patient had a stable disease as best response. The disease control rate was 50%. Median progression-free survival and overall survival were 24.1 and 41.9 weeks, respectively. Baseline tumor biopsies from patients who responded to treatment had features of T-cell exclusion. During treatment, there was an increased T-cell infiltration, with a reduced mean distance between T cells and tumor cells. Peripheral blood immune cell composition did not significantly change during study treatment.
Conclusions: Combining an intratumoral injection of CD1c (BDCA-1) and CD141 (BDCA-3) myDC with repeated IT administration of ipilimumab and AS01 and systemic low-dose nivolumab is safe, feasible with promising early results, worthy of further clinical investigation.
Trial Registration Number: ClinicalTrials.gov identifier NCT03707808.
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http://dx.doi.org/10.1136/jitc-2023-008148 | DOI Listing |
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December 2024
Department of Radiotherapy, UZ Brussel, Vrije Universiteit Brussel, 1090 Brussels, Belgium. Electronic address:
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Center for Interventional Oncology, Clinical Center, National Institutes of Health, Bethesda, MD, United States of America.
Intratumoral injections often lack visibility, leading to unpredictable outcomes such as incomplete tumor coverage, off-target drug delivery and systemic toxicities. This study investigated an ultrasound (US) and x-ray imageable thermosensitive hydrogel based on poloxamer 407 (POL) percutaneously delivered in a healthy swine model. The primary objective was to assess the 2D and 3D distribution of the hydrogel within tissue across three different needle devices and injection sites: liver, kidney, and intercostal muscle region.
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Oncolytic viruses have emerged as a highly promising modality for cancer treatment due to their ability to replicate specifically within tumors, carry therapeutic genes, and modulate the immunosuppressive tumor microenvironment through various mechanisms. Additionally, they show potential synergy with immune checkpoint inhibitors. A study report indicates that from 2000 to 2020, 49.
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