Tilsotolimod Exploits the TLR9 Pathway to Promote Antigen Presentation and Type 1 IFN Signaling in Solid Tumors: A Multicenter International Phase I/II Trial (ILLUMINATE-101)

Authors

Hani Babiker
Erkut Borazanci
Vivek Subbiah
Sanjiv Agarwala
Alain Algazi
Jacob Schachter
Michael Lotem
Corinne Maurice-Dror
Daniel Hendler
Shah Rahimian
Hans Minderman
Cara Haymaker
Daruka Mahadevan
Chantale Bernatchez
Ravi Murthy
Rolf Hultsch
Nadia Kaplan
Gregory Woodhead
Charles Hennemeyer
Srinivas Chunduru
Peter M Anderson
Adi Diab
Igor Puzanov

Publication Date

12-1-2022

Journal

Clinical Cancer Research

Abstract

PURPOSE: Tilsotolimod is an investigational synthetic Toll-like receptor 9 (TLR9) agonist that has demonstrated antitumor activity in preclinical models. The ILLUMINATE-101 phase I study explored the safety, dose, efficacy, and immune effects of intratumoral (it) tilsotolimod monotherapy in multiple solid tumors.

PATIENTS AND METHODS: Patients with a diagnosis of refractory cancer not amenable to curative therapies received tilsotolimod in doses escalating from 8 to 32 mg into a single lesion at weeks 1, 2, 3, 5, 8, and 11. Additional patients with advanced malignant melanoma were enrolled into an expansion cohort at the 8 mg dose. Objectives included characterizing the safety, establishing the dose, efficacy, and immunologic assessment. Blood samples and tumor biopsies of injected and noninjected lesions were obtained at baseline and 24 hours after treatment for immune analyses.

RESULTS: Thirty-eight and 16 patients were enrolled into the dose escalation and melanoma expansion cohorts, respectively. Deep visceral injections were conducted in 91% of patients. No dose-limiting toxicities (DLT) or grade 4 treatment-related adverse events were observed. Biopsies 24 hours after treatment demonstrated an increased IFN pathway signature and dendritic cell maturation. Immunologic profiling revealed upregulation of IFN-signaling genes and modulation of genes for checkpoint proteins. In the dose escalation cohort, 12 (34%) of 35 evaluable patients achieved a best overall response rate (ORR) of stable disease (SD), whereas 3 (19%) of 16 evaluable patients in the melanoma cohort achieved stable disease.

CONCLUSIONS: Overall, tilsotolimod monotherapy was generally well tolerated and induced rapid, robust alterations in the tumor microenvironment. See related commentary by Punekar and Weber, p. 5007.

Keywords

Humans, Toll-Like Receptor 9, Antigen Presentation, Neoplasms, Melanoma, Cohort Studies, Skin Neoplasms, Tumor Microenvironment, TLR9, melanoma, intratumoral, sarcoma

Comments

Supplementary Materials

PMID: 35917516