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Preclinical Evaluation of an Anchored Immunotherapy Strategy with Aluminum Hydroxide-Tethered IL-12 in Dogs with Advanced Malignant Melanoma
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DOI：10.1158/1535-7163.MCT-24-0317.png)
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Abstract
En 中文
Melanoma is an aggressive cancer in dogs involving skin and mucosa similar to humans. Anchored immunotherapeutics offer a novel approach to increase intratumoral retention of therapeutic payloads while decreasing systemic exposure, and this strategy can be critically evaluated through a comparative oncology approach. JEN-101 is an anchored canine IL-12 tethered to aluminum hydroxide administered by local injection. A phase I study was conducted to determine the tolerability, activity, and immune responses of JEN-101 in dogs with advanced melanoma. A 3 + 3 dose-escalation design was used to evaluate intratumoral injection of JEN-101 at 1, 3, 10, or 20 mu g/kg every 3 weeks for four cycles. A second course was allowable in the absence of disease progression or toxicity. Peripheral blood, serum, and tumor biopsies were collected at baseline and at prespecified timepoints for pharmacokinetic and immune analyses, which included serum cytokine assay, IHC, and gene expression assessment. JEN-101 was well tolerated with adverse events being fever, lethargy, and isolated elevated liver enzymes. Five dogs experienced grade 3 events, and no grade 4 events were observed. Pharmacokinetic analysis showed a trend toward dose-related maximum serum concentration within 8 hours of injection. Responding dogs demonstrated increased systemic IFN-gamma and IL-10 AUC levels and local recruitment of CD3+ T cells. Increased proinflammatory and antigen-processing gene expression was identified in responding lesions. JEN-101 was well tolerated with evidence of biological and therapeutic activities. Anchored IL-12 immunotherapy merits further investigation in dogs with melanoma, and our approach represents an immunocompetent model to inform human clinical trials.
Keywords:
IFN-GAMMA
INJECTION
PROFILE
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