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

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.

• Authors: Mark R Middleton, Cheryl McAlpine, Victoria K Woodcock, Pippa Corrie, Jeffrey R Infante, Neil M Steven, Thomas R Jeffry Evans, Alan Anthoney, Alexander N Shoushtari, Omid Hamid, Avinash Gupta, Antonella Vardeu, Emma Leach, Revashnee Naidoo, Sarah Stanhope, Sion Lewis, Jacob Hurst, Ita O'Kelly, Mario Sznol
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 26 Issue 22 Pg. 5869-5878 (11 15 2020) ISSN: 1557-3265 [Electronic] United States
• PMID: 32816891 (Publication Type: Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• CD3 Complex
• CXCL10 protein, human
• CXCR3 protein, human
• Chemokine CXCL10
• IFNG protein, human
• Neoplasm Proteins
• Receptors, Antigen, T-Cell
• Receptors, CXCR3
• Recombinant Fusion Proteins
• gp100 Melanoma Antigen
• Interferon-gamma
• Ataxia Telangiectasia Mutated Proteins
• tebentafusp

Topics

• Adult
• Aged
• Ataxia Telangiectasia Mutated Proteins (genetics)
• CD3 Complex (genetics)
• CD8-Positive T-Lymphocytes (drug effects)
• Cell Proliferation (drug effects)
• Chemokine CXCL10 (blood)
• Cytotoxicity, Immunologic (drug effects)
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunity (drug effects)
• Interferon-gamma (blood)
• Male
• Melanoma (blood, drug therapy, genetics, pathology)
• Middle Aged
• Neoplasm Proteins (genetics)
• Receptors, Antigen, T-Cell (genetics)
• Receptors, CXCR3 (blood)
• Recombinant Fusion Proteins (administration & dosage, adverse effects)
• Tumor Microenvironment (drug effects)
• gp100 Melanoma Antigen (genetics)