ABSTRACT
Tumor-targeting oncolytic viruses such as vaccinia virus (VV) are attractive cancer therapeutic agents that act through multiple mechanisms to provoke both tumor lysis and anti-tumor immune responses. However, delivery of these agents remains restricted to intra-tumoral administration, which prevents effective targeting of inaccessible and disseminated tumor cells. In the present study we have identified transient pharmacological inhibition of the leukocyte-enriched phosphoinositide 3-kinase δ (PI3Kδ) as a novel mechanism to potentiate intravenous delivery of oncolytic VV to tumors. Pre-treatment of immunocompetent mice with the PI3Kδ-selective inhibitor IC87114 or the clinically approved idelalisib (CAL-101), prior to intravenous delivery of a tumor-tropic VV, dramatically improved viral delivery to tumors. This occurred via an inhibition of viral attachment to, but not internalization by, systemic macrophages through perturbation of signaling pathways involving RhoA/ROCK, AKT, and Rac. Pre-treatment using PI3Kδ-selective inhibitors prior to intravenous delivery of VV resulted in enhanced anti-tumor efficacy and significantly prolonged survival compared to delivery without PI3Kδ inhibition. These results indicate that effective intravenous delivery of oncolytic VV may be clinically achievable and could be useful in improving anti-tumor efficacy of oncolytic virotherapy.
Subject(s)
Adenine/analogs & derivatives , Administration, Intravenous/methods , Antineoplastic Agents/therapeutic use , Class I Phosphatidylinositol 3-Kinases/antagonists & inhibitors , Immunotherapy/methods , Oncolytic Virotherapy/methods , Oncolytic Viruses/immunology , Purines/therapeutic use , Quinazolines/therapeutic use , Quinazolinones/therapeutic use , Vaccinia virus/immunology , Adenine/pharmacology , Adenine/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival , Combined Modality Therapy/methods , Female , Mice , Mice, Inbred BALB C , Purines/pharmacology , Quinazolines/pharmacology , Quinazolinones/pharmacology , Transplantation, Homologous , Treatment Outcome , Tumor BurdenABSTRACT
We report a rare case of primary laryngeal actinomycosis, which occurred in a 35-year-old woman with end-stage renal failure secondary to systemic lupus erythematosus with membranous glomerulonephritis. The patient, who had been on long-term immunosuppression therapy, presented with hoarseness. Flexible laryngoscopy detected the presence of a granular glottic mass at the anterior commissure of the larynx. Histology revealed actinomycotic organisms associated with an abscess. The patient was treated with a prolonged course of oral penicillin V and speech therapy, and her dysphonia resolved almost completely. Although actinomycotic infection of the larynx is rare, it should be considered in the differential diagnosis of hoarseness in an immunocompromised patient.