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Τετάρτη 27 Ιουνίου 2018

Therapeutic Immune Modulation Against Solid Cancers with Intratumoral Poly-ICLC: A Pilot Trial

Purpose: Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (Poly-ICLC), a synthetic double-stranded RNA complex, is a ligand for toll-like receptor-3 (TLR3) and MDA-5 that can activate immune cells such as dendritic cells and trigger NK cells to kill tumor cells. Experimental Design: In this pilot study, eligible patients included those with recurrent metastatic disease who failed prior systemic therapy (head and neck squamous cell cancer (HNSCC), melanoma). Patients received 2 treatment cycles, each cycle consisting of 1mg Poly-ICLC 3x weekly intratumorally (IT) for 2 weeks followed by intramuscular (IM) boosters biweekly for 7 weeks with a 1-week rest period. Immune response was evaluated by immunohistochemistry (IHC) and RNA Sequencing (RNASeq) in tumor and blood. Results: Two patients completed 2 cycles of IT treatments and one achieved clinical benefit (stable disease, PFS 6 months), while the remainder had progressive disease. Poly-ICLC was well tolerated with principal side effects of fatigue and inflammation at injection site (< grade 2). In the patient with clinical benefit, IHC analysis of tumor showed increased CD4, CD8, PD1 and PDL1 levels compared to patients with progressive disease. RNASeq analysis of the same patient's tumor and PBMC showed dramatic changes in response to Poly-ICLC treatment including upregulation of genes associated with chemokine activity, T cell activation and antigen presentation. Conclusions: Poly-ICLC was well tolerated in solid cancer patients, and generated local and systemic immune responses as evident in the patient achieving clinical benefit. These results warrant further investigation, and are currently being explored in a multicenter phase II clinical trial (NCT02423863).



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