Positron Emission Tomography/Computed Tomography (PET/CT) and Radioimmunotherapy of Head and Neck Cancer Patient Derived Xenografts in NRG Mice with Theranostic [64Cu]Cu-DOTA-Panitumumab F(ab')2 and [177Lu]Lu-DOTA-Panitumumab F(ab')2.

Abstract

Head and neck squamous cell carcinoma (HNSCC) expresses epidermal growth factor receptors (EGFR) in 90% of cases. Here we studied PET/CT imaging of three clinically relevant HNSCC patient derived xenografts (PDX) with low (#61531), moderate (#73191) or high (#88955) EGFR expression in NRG mice using anti-EGFR [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂. We further assessed the effectiveness of β-particle-emitting [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ for radioimmunotherapy (RIT) of these PDX. All PDX were visualized by PET/CT at 24 h postinjection (p.i.) of [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂. In addition, in mice with PDX #88955, an axillary lymph node metastasis was imaged by PET and lung metastases were imaged by SPECT/CT at 3 to 12 d p.i. of [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂. Tumor uptake of [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ at 24 h p.i. was directly correlated with EGFR expression (6.7 ± 3.5%, 13.5 ± 2.5% and 16.7 ± 1.0% ID/g for PDX #61531, #73191 and #88955, respectively). Intravenous administration of 5.0 MBq (50 μg) of [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ to healthy NRG mice caused no hematologic, liver or kidney toxicity or decrease in body weight. RIT with 4.0-5.0 MBq (50 μg) of [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ decreased the tumor growth rate vs 0.9% NaCl by 2, 9 and 3.2-fold, respectively in mice with PDX #61531, #73191 and #88955 (P = 0.014, P < 0.001, P = 0.004). Treatment of mice with unlabeled DOTA-panitumumab F(ab')₂ did not decrease the tumor growth rate of PDX#61531 (P = 0.457) but modestly decreased the tumor growth rate of PDX #73191 by 1.3-fold (P = 0.024) and PDX #88955 by 1.4-fold (P = 0.027). RIT was EGFR-specific as irrelevant anti-HER2 [¹⁷⁷Lu]Lu-DOTA-trastuzumab F(ab')₂ was not effective for treatment of PDX #73191 vs 0.9% NaCl (P = 0.282). RIT with [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ was 3-fold more effective for treating moderately EGFR-expressing PDX #73191 than PDX #88955 with high EGFR expression. This may be explained by the human papilloma virus (HPV) positivity of PDX #73191 since HPV-positive HNSCC is more responsive to external radiation beam treatment. We conclude that [⁶⁴Cu]Cu-DOTA-panitumumab F(ab')₂ and [¹⁷⁷Lu]Lu-DOTA-panitumumab F(ab')₂ are a promising theranostic pair for PET/CT imaging and RIT of HNSCC.