Abstract 4062: Activation of innate and adaptive immunity using intratumoral tilsotolimod (IMO-2125) as monotherapy in patients with refractory solid tumors: a phase Ib study (ILLUMINATE-101)
Authors: Babiker Hani M. , Subbiah Vivek , Maguire Orla , Rahimian Shah , Minderman Hans , Haymaker Cara L. , Bernatchez Chantale , Borazanci Erkut , Geib James , Chunduru Srinivas K. , Anderson Peter M. , Puzanov Igor , Diab Adi 
Published: August 2019

Abstract
While checkpoint inhibitor therapy has transformed treatment of multiple tumor types, many patients remain refractory. Tilsotolimod, a toll-like receptor 9 agonist, has been shown in preclinical models to activate plasmacytoid dendritic cells and increase T cell infiltration to the tumor microenvironment. Preliminary results of a phase 1/2 study suggested that intratumoral injection of tilsotolimod in combination with ipilimumab may revive an immune response in patients with immune checkpoint inhibitor-resistant metastatic melanoma. To further explore the role of tilsotolimod in modulating the tumor immune microenvironment, we conducted a Phase Ib monotherapy trial (ILLUMINATE-101). Adults with histologically or cytologically confirmed diagnosis of cancer not amenable to curative therapies received intratumoral tilsotolimod in doses escalating from 8 mg to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Objectives of the dose evaluation portion included characterizing safety and pharmacokinetics, and evaluating alterations in the tumor microenvironment. Blood samples and tumor biopsies of injected and distal lesions were obtained at baseline and on treatment. Immune analyses included evaluation using Nanostring and/or flow cytometry of activation of the type 1 interferon (IFN) pathway, IFN gamma levels, activation of dendritic cell subsets, and changes in T cell status. As of November 7, 2018, 41 patients have been enrolled, including 38 patients into the dose evaluation portion and 3 patients into a melanoma expansion cohort. No dose-limiting toxicities or treatment-related adverse events have been observed. Within 24 hours, fresh tumor biopsies showed significant increases in IFN gamma levels, activation of the type 1 IFN pathway, induction of an antigen processing gene signature (a measure of the MHC class I antigen presentation pathway), and maturation of dendritic cells as measured by expression of HLA-DR (MHC class II), compared to pretreatment biopsies. Of 25 evaluable patients who received at least 1 dose of tilsotolimod and had at least 1 post-baseline disease assessment, 12 (48%) had a RECIST v1.1 disease assessment of stable disease. For patients with at least one disease assessment following documentation of stable disease (n=8), duration of stable disease ranged from 0.53 to 4.2+ months, with 3 patients ongoing. These results demonstrate that single agent tilsotolimod was well tolerated and induced robust alterations in the tumor microenvironment.
Citation Format: Hani M. Babiker, Vivek Subbiah, Orla Maguire, Shah Rahimian, Hans Minderman, Cara L. Haymaker, Chantale Bernatchez, Erkut Borazanci, James Geib, Srinivas K. Chunduru, Peter M. Anderson, Igor Puzanov, Adi Diab. Activation of innate and adaptive immunity using intratumoral tilsotolimod (IMO-2125) as monotherapy in patients with refractory solid tumors: a phase Ib study (ILLUMINATE-101) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4062.