1. Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti–PD-1 Refractory Melanoma
- Author
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Salah-Eddine Bentebibel, Willem W. Overwijk, Montaser Shaheen, Marc Uemura, Courtney W. Hudgens, Marihella James, Ravi Murthy, Gary C. Doolittle, Robert H.I. Andtbacka, Chantale Bernatchez, Michael A. Davies, S. Chunduru, Douglas B. Johnson, Daniel H. Johnson, Igor Puzanov, Patrick Hwu, Shah Rahimian, Cara Haymaker, Adi Diab, Joseph Markowitz, Denái R. Milton, Michael T. Tetzlaff, Sudhir Agrawal, Nashat Gabrail, and Houssein Safa
- Subjects
Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Skin Neoplasms ,Antigen presentation ,Ipilimumab ,Article ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Adverse effect ,Immune Checkpoint Inhibitors ,Melanoma ,Aged ,Aged, 80 and over ,business.industry ,Dendritic cell ,Middle Aged ,Gene signature ,medicine.disease ,United States ,Immune checkpoint ,Clinical trial ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,business ,medicine.drug - Abstract
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 IFNα 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
- Published
- 2021