A TCR/anti-CD3 bispecific fusion protein targeting gp100 potently activated anti-tumor immune responses in metastatic melanoma
| Autor: | Middleton, Mark R., McAlpine, Cheryl, Woodcock, Victoria K., Corrie, Pippa, Infante, Jeffry R., Steven, Neil Mathew, Evans, Thomas R Jeffry, Anthoney, Alan, Shoushtari, Alexander Noor, Hamid, Omid, Gupta, Avinash, Vardeu, Antonella, Leach, Emma, Naidoo, Revashnee, Stanhope, Sarah, Lewis, Sion, Hurst, Jacob, O’Kelly, Ita, Sznol, Mario |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Adult
Cytotoxicity Immunologic Male Receptors CXCR3 CD3 Complex Recombinant Fusion Proteins Immunity Receptors Antigen T-Cell Ataxia Telangiectasia Mutated Proteins CD8-Positive T-Lymphocytes Middle Aged Article Disease-Free Survival Neoplasm Proteins Chemokine CXCL10 Gene Expression Regulation Neoplastic Interferon-gamma Tumor Microenvironment Humans Female Melanoma Aged Cell Proliferation gp100 Melanoma Antigen |
| Zdroj: | Clin Cancer Res |
| Popis: | 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 regardless of their intrinsic specificity. Here we report data from a multicentre Phase 1/2 trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp. PATIENTS AND METHODS: 84 patients with advanced melanoma (n=61 cutaneous, n=19 uveal, n=4 other origin) received tebentafusp. Treatment efficacy and treatment-related AEs were assessed and coded, 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 metastatic Uveal melanoma (mUM) and metastatic Uveal melanoma (mCM) patients. A 65% 1-year overall survival rate 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 of gp100-expressing skin melanocytes) showed a positive association with patient survival. CONCLUSIONS: These data suggest that re-directing T cells using a gp100-targeting T cell receptor/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. |
| Databáze: | OpenAIRE |
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