Abstract CT134: Tilsotolimod engages the TLR9 pathway to promote antigen presentation and Type-I IFN signaling in solid tumors
Authors: Babiker Hani M. , Subbiah Vivek , Ali Asim , Algazi Alain , Schachter Jacob , Lotem Michal , Maurice-Dror Corinne , Hendler Daniel , Rahimian Shah , Minderman Hans , Haymaker Cara , Bernatchez Chantale , Murthy Ravi , Hultsch Rolf , Caplan Nadia , Woodhead Gregory , Hennemeyer Charles , Chunduru Sri , Anderson Peter , Diab Adi , Borazanci Erkut , Puzanov Igor 
Published: September 2020

Abstract
Background: Tilsotolimod, an investigational Toll-like receptor 9 (TLR9) agonist, modulates the tumor immune microenvironment and has single-agent antitumor activity in preclinical models. The ILLUMINATE-101 phase 1b study (NCT03052205) explored the safety, efficacy, and immune effects of intratumoral tilsotolimod in multiple solid tumors.
Methods: Adults with a histologically- or cytologically-confirmed diagnosis of cancer not amenable to curative therapies received intratumoral tilsotolimod 8, 16, 23, or 32 mg into a single lesion on Days 1, 8, and 15 of Cycle 1 and Day 1 of each subsequent 3-week cycle, for up to 17 cycles. Additionally, patients with advanced melanoma were enrolled into an expansion cohort at the recommended phase 2 dose of 8 mg. The primary objective was to characterize safety (dose escalation cohort) and efficacy (expansion cohort). Secondary objectives included pharmacokinetics of tilsotolimod. Immunological assessment of injected and non-injected tumors was an exploratory objective. Blood samples and tumor biopsies of injected lesions were obtained at baseline and 24 hours post treatment for immune analyses.
Results: A total of 54 patients were enrolled. Of the 38 patients in the dose escalation cohort, 35 had metastatic disease. Patients in this cohort had a median of 7 prior lines of treatment, and the most common cancer types were pancreatic (12 patients) and colorectal (7 patients). All 16 patients in the melanoma cohort had metastatic disease with a median of 3 lines of prior therapy, and 10 patients had elevated LDH. Injected lesions were deep and required interventional radiology in 52 of 54 patients. No dose-limiting toxicities were observed. The most common treatment-related adverse events were pyrexia, fatigue, chills, nausea, and vomiting. Compared to pretreatment, biopsies of injected tumors at 24 hours showed increased activation of the Type-I IFN pathway, upregulation of MHC class I/II, IFNγ expression, and expression of multiple immune checkpoints (i.e. PD-1, LAG3). Of the 35 evaluable patients in the dose escalation cohort, 12 (34%) achieved a best overall response of stable disease (SD). Of the 16 evaluable patients in the melanoma cohort, 3 had SD, 1 who had a 35% tumor reduction with no confirmatory scan.
Conclusions: Tilsotolimod was generally well tolerated and induced alterations in the tumor microenvironment, including immune checkpoint upregulation, activation of dendritic cells, and induction of Type-I IFN signaling. Additional clinical studies of tilsotolimod in combination with checkpoint inhibitors are underway (NCT03445533, NCT03865082, and NCT02644967).
Citation Format: Hani M. Babiker, Vivek Subbiah, Asim Ali, Alain Algazi, Jacob Schachter, Michal Lotem, Corinne Maurice-Dror, Daniel Hendler, Shah Rahimian, Hans Minderman, Cara Haymaker, Chantale Bernatchez, Ravi Murthy, Rolf Hultsch, Nadia Caplan, Gregory Woodhead, Charles Hennemeyer, Sri Chunduru, Peter Anderson, Adi Diab, Erkut Borazanci, Igor Puzanov. Tilsotolimod engages the TLR9 pathway to promote antigen presentation and Type-I IFN signaling in solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT134.