Research ArticleCancer

Intratumoral nanoplexed poly I:C BO-112 in combination with systemic anti–PD-1 for patients with anti–PD-1–refractory tumors

See allHide authors and affiliations

Science Translational Medicine  14 Oct 2020:
Vol. 12, Issue 565, eabb0391
DOI: 10.1126/scitranslmed.abb0391

Interfering with cancer

Many immunotherapies for cancer have emerged in recent years, but none are universally effective. One potential problem is the loss of interferon signaling in tumors, which impairs the effectiveness of both immune checkpoint blockade and cell-based therapies. Kalbasi et al. determined that both JAK1 and JAK2 signaling were essential for the success of immune checkpoint blockade, whereas cell-based therapy only required JAK1 function, which maintained sufficient interferon signaling. The authors showed that defective interferon signaling in tumors could be bypassed with the immunostimulatory compound BO-112. In a companion clinical trial, Márquez-Rodas et al. tested BO-112 in human patients with cancer, with or without immune checkpoint blockade.

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.

View Full Text

Stay Connected to Science Translational Medicine