Details

Autor(en) / Beteiligte

• Ingargiola, M.
• Runge, R.
• Heldt, J.‐M.
• Freudenberg, R.
• Steinbach, J.
• Cordes, N.
• Baumann, M.
• Kotzerke, J.
• Brockhoff, G.
• Kunz‐Schughart, L.A.

Titel

Potential of a Cetuximab‐based radioimmunotherapy combined with external irradiation manifests in a 3‐D cell assay

Ist Teil von

• International journal of cancer, 2014-08, Vol.135 (4), p.968-980

Ort / Verlag

Hoboken, NJ: Wiley-Blackwell

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• Targeting epidermal growth factor receptor (EGFR)‐overexpressing tumors with radiolabeled anti‐EGFR antibodies is a promising strategy for combination with external radiotherapy. In this study, we evaluated the potential of external plus internal irradiation by [90Y]Y‐CHX‐A″‐DTPA‐C225 (Y‐90‐C225) in a 3‐D environment using FaDu and SAS head and neck squamous cell carcinoma (HNSCC) spheroid models and clinically relevant endpoints such as spheroid control probability (SCP) and spheroid control dose 50% (SCD50, external irradiation dose inducing 50% loss of spheroid regrowth). Spheroids were cultured using a standardized platform. Therapy response after treatment with C225, CHX‐A″‐DTPA‐C225 (DTPA‐C225), [90Y]Y‐CHX‐A″‐DTPA (Y‐90‐DTPA) and Y‐90‐C225 alone or in combination with X‐ray was evaluated by long‐term monitoring (60 days) of spheroid integrity and volume growth. Penetration kinetics into spheroids and EGFR binding capacities on spheroid cells were identical for unconjugated C225 and Y‐90‐C225. Spheroid‐associated radioactivity upon exposure to the antibody‐free control conjugate Y‐90‐DTPA was negligible. Determination of the SCD50 demonstrated higher intrinsic radiosensitivity of FaDu as compared with SAS spheroids. Treatment with unconjugated C225 alone did not affect spheroid growth and cell viability. Also, C225 treatment after external irradiation showed no additive effect. However, the combination of external irradiation with Y‐90‐C225 (1 µg/ml, 24 hr) resulted in a considerable benefit as reflected by a pronounced reduction of the SCD50 from 16 Gy to 9 Gy for SAS spheroids and a complete loss of regrowth for FaDu spheroids due to the pronounced accumulation of internal dose caused by the continuous exposure to cell‐bound radionuclide upon Y‐90‐C225‐EGFR interaction. What's new? Patients whose tumors overexpress epidermal growth factor receptor (EGFR) may benefit from the combination of external irradiation with internal radioimmunotherapy using Cetuximab (C225). To investigate the combination, a newly established Y‐90‐C225 conjugate was applied in a long‐term 3‐D assay using two EGFR‐overexpressing head and neck squamous cell carcinoma (HNSCC) spheroid models with different intrinsic radiosensitivity. Spheroids treated with both Y‐90‐C225 and external radiation in the form of X‐rays experienced massive internal dose accumulation, which allowed for a significant reduction in effective external dose. The results are promising and warrant further exploration of the combined treatment strategy.