Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti–PD-1 for patients with anti–PD-1–refractory tumors
Iván Márquez‐Rodas, Federico Longo, María E. Rodríguez-Ruiz, Antonio Calles, Santiago Ponce, Maria Jové, Belén Rubio‐Viqueira, José Luis Perez‐Gracia, Ana Gómez‐Rueda, Sara López‐Tarruella, Mariano Ponz‐Sarvisé, Rosa Álvarez, Ainara Soria-Rivas, Enrique de Miguel, Rocío Ramos‐Medina, Eduardo Castañón, Pablo Gajate, Cayetano Sempere Ortega, Elisabeth Jiménez-Aguilar, M. Ángela Aznar, Aitana Calvo, Pedro P. López‐Casas, Salvador Martín‐Algarra, Miguel Martín, Dominique Tersago, Marisol Quintero, Ignacio Melero
Abstract
Intratumoral therapies, especially Toll-like receptor agonists, can trigger both the innate and adaptive immune systems. BO-112 is a nanoplexed form of polyinosinic:polycytidylic acid (poly I:C) that induces local and systemic immunotherapeutic effects in mouse models. In a multicenter phase 1 clinical trial, repeated intratumoral administrations of BO-112 induced an increase in tumor cell necrosis and apoptosis, as well as augmented immune reactivity according to gene expression profiling. The first three cohorts receiving BO-112 as a monotherapy resulted in a recommended dose of 1 mg that could be safely repeated. Two grade 3 to 4 adverse reactions in the form of reversible thrombocytopenia were reported. In a fourth cohort of 28 patients with tumors that had primary resistance to anti-programmed cell death protein-1 (PD-1), the combination of intratumoral BO-112 with nivolumab or pembrolizumab was also well tolerated, and 3 patients (2 with melanoma and 1 with renal cell carcinoma) achieved partial responses, with 10 more patients having stable disease at 8 to 12 weeks. Thus, local BO-112 combined with a systemic anti-PD-1 agent might be a strategy to revert anti-PD-1 resistance.