Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma
Department of Medicine
Amino Acids, Peptides, and Proteins | Cancer Biology | Neoplasms
Many patients with advanced melanoma are resistant to immune checkpoint inhibition. In the ILLUMINATE-204 phase I/II trial, we assessed intratumoral tilsotolimod, an investigational Toll-like receptor 9 agonist, with systemic ipilimumab in patients with anti-PD-1- resistant advanced melanoma. In all patients, 48.4% experienced grade 3/4 treatment-emergent adverse events. The overall response rate at the recommended phase II dose of 8 mg was 22.4%, and an additional 49% of patients had stable disease. Responses in noninjected lesions and in patients expected to be resistant to ipilimumab monotherapy were observed. Rapid induction of a local IFNalpha gene signature, dendritic cell maturation and enhanced markers of antigen presentation, and T-cell clonal expansion correlated with clinical response. A phase III clinical trial with this combination (NCT03445533) is ongoing.
SIGNIFICANCE: Despite recent developments in advanced melanoma therapies, most patients do not experience durable responses. Intratumoral tilsotolimod injection elicits a rapid, local type 1 IFN response and, in combination with ipilimumab, activates T cells to promote clinical activity, including in distant lesions and patients not expected to respond to ipilimumab alone. This article is highlighted in the In This Issue feature, p. 1861.
DOI of Published Version
Haymaker C, Johnson DH, Murthy R, Bentebibel SE, Uemura MI, Hudgens CW, Safa H, James M, Andtbacka RHI, Johnson DB, Shaheen M, Davies MA, Rahimian S, Chunduru SK, Milton DR, Tetzlaff MT, Overwijk WW, Hwu P, Gabrail N, Agrawal S, Doolittle G, Puzanov I, Markowitz J, Bernatchez C, Diab A. Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma. Cancer Discov. 2021 Aug;11(8):1996-2013. doi: 10.1158/2159-8290.CD-20-1546. Epub 2021 Mar 11. PMID: 33707233; PMCID: PMC8544022. Link to article on publisher's site
Haymaker C, Agrawal S, Bernatchez C, Diab A. (2021). Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma. Open Access Publications by UMass Chan Authors. https://doi.org/10.1158/2159-8290.CD-20-1546. Retrieved from https://escholarship.umassmed.edu/oapubs/4875