2. Academic Validation
  3. Tilsotolimod with Ipilimumab Drives Tumor Responses in Anti-PD-1 Refractory Melanoma

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.
Cara Haymaker 1,  Daniel H Johnson 2,  Ravi Murthy 3,  Salah-Eddine Bentebibel 2,  Marc I Uemura 2,  Courtney W Hudgens 1,  Houssein Safa 2,  Marihella James 2,  Robert H I Andtbacka 4,  Douglas B Johnson 5,  Montaser Shaheen 6,  Michael A Davies 2,  Shah Rahimian 7,  Srinivas K Chunduru 7,  Denái R Milton 8,  Michael T Tetzlaff 1 9,  Willem W Overwijk 2,  Patrick Hwu 2,  Nashat Gabrail 10,  Sudhir Agrawal 11,  Gary Doolittle 12,  Igor Puzanov 13,  Joseph Markowitz 14,  Chantale Bernatchez 15,  Adi Diab 15
Affiliations

Affiliations

  • 1 Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 2 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 3 Department of Interventional Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 4 Surgical Oncology Department of Surgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
  • 5 Division of Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
  • 6 Department of Medicine and Cancer Center, University of Arizona, Tucson, Arizona.
  • 7 Idera Pharmaceuticals, Inc., Exton, Pennsylvania.
  • 8 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 9 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
  • 10 Department of Oncology, Gabrail Cancer Center, Canton, Ohio.
  • 11 Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts.
  • 12 Department of Oncology, University of Kansas Medical Center, Kansas City, Kansas.
  • 13 Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
  • 14 Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • 15 Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. [email protected] [email protected].
PMID: 33707233 DOI: 10.1158/2159-8290.CD-20-1546
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.

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