First-in-human clinical trial with intratumoral BO-112 in solid malignancies: A novel immunotherapy based in double-stranded RNA (dsRNA).
Marquez Rodas I., Rodriguez-Ruiz ME., Lopez-Tarruella S., Perez-Gracia JL., de Miguel E., Calvo A., Blanco-Codesido M., Martin-Algarra S., Martin M., Melero I.
3082 Background: BO-112 is a double stranded synthetic RNA, formulated with the cationic carrier polyethyleneimine that preclinically improves its intracellular delivery and resistance towards nuclease degradation. In melanoma mouse models, systemic administration activates MDA-5 and NOXA, leading to anti-tumoral activity connected to a sustained and extended expression of IFN-response genes. Intratumoral (IT) delivery, seeking a safer and more focused enhancement of local and systemic antitumor effects has been tested in transplanted mouse models. The potential of its IT use as an immune-modulatory treatment, as well as its toxicity profile, is being analyzed in this first in human, proof of concept, clinical trial (NCT02828098). Methods: Four patients with malignant solid tumors and palpable cutaneous/subcutaneous or lymph node metastases >1 cm were treated with a single BO-112 dose of 0.6 mg/ml IT. Pre and post treatment biopsies from the injected metastatic lesion were obtained. Pharmacokinetics, serum cytokines and circulating immune cells were sequentially studied in pre and post treatment samples. Results: Patients did not experience relevant toxicity with the exception of a single episode of completely reversible grade 4 thrombocytopenia in one patient, attributed to the drug. BO-112 was not detectable in bloodstream following IT delivery. No changes in circulating cytokines were detected. Main immunobiological effects are summarized in the table. Conclusions: BO-112 has shown changes in tumoral immune cells in 1/4 patients, while in 3/4 induced both necrosis and changes in circulating immune cells. This ongoing trial will compile more safety data with repeated sequential administrations, escalated to higher doses of BO-112, and will thoroughly characterize its biological effects in humans with solid malignancies amenable to IT injection. Clinical trial information: NCT02828098. [Table: see text]