2. Academic Validation
  3. Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma

Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma

  • Clin Cancer Res. 2020 Nov 15;26(22):5869-5878. doi: 10.1158/1078-0432.CCR-20-1247.
Mark R Middleton 1,  Cheryl McAlpine 2,  Victoria K Woodcock 3,  Pippa Corrie 4,  Jeffrey R Infante 5,  Neil M Steven 6,  Thomas R Jeffry Evans 7,  Alan Anthoney 8,  Alexander N Shoushtari 9,  Omid Hamid 10,  Avinash Gupta 3,  Antonella Vardeu 2,  Emma Leach 2,  Revashnee Naidoo 2,  Sarah Stanhope 2,  Sion Lewis 2,  Jacob Hurst 2,  Ita O'Kelly 2,  Mario Sznol 11
Affiliations

Affiliations

  • 1 Department of Oncology, Medical Sciences Division, University of Oxford, Headington, Oxford, United Kingdom. mark.middleton@oncology.ox.ac.uk.
  • 2 Immunocore Ltd, Abingdon, Oxford, United Kingdom.
  • 3 Department of Oncology, Medical Sciences Division, University of Oxford, Headington, Oxford, United Kingdom.
  • 4 Cambridge University Hospitals, NHS Foundation Trust, Cambridge, United Kingdom.
  • 5 Janssen, Philadelphia, Pennsylvania.
  • 6 Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
  • 7 Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom.
  • 8 Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.
  • 9 Memorial Sloan Kettering Cancer Center, New York, New York.
  • 10 Immunooncology, The Angeles Clinic and Research Institute, Los Angeles, California.
  • 11 Yale Cancer Center, Yale School of Medicine, Yale, Connecticut.
PMID: 32816891 DOI: 10.1158/1078-0432.CCR-20-1247
Abstract

Purpose: Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T-cell receptor (TCR) binding domain and an anti-CD3 T-cell engaging domain, which redirects T cells to kill gp100-expressing tumor cells. Here, we report a multicenter phase I/II trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp.

Patients and methods: Eighty-four patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related adverse events, and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment.

Results: Tebentafusp was generally well-tolerated and active in both patients with metastatic uveal melanoma and patients with metastatic cutaneous melanoma. A 1-year overall survival rate of 65% was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNγ pathway-related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T-cell attractant) and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash (likely due to cytotoxic T cells targeting gp100-expressing skin melanocytes) showed a positive association with patient survival.

Conclusions: These data suggest that redirecting T cells using a gp100-targeting TCR/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.

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