Targeted Radionuclide Therapy in Patient-Derived Xenografts Using ¹⁷⁷Lu-EB-RGD

Abstract

Currently, most patients with non–small cell lung cancer (NSCLC) are diagnosed in advanced stages with a poor five-year survival rate. Therefore, intensive research aimed at finding novel therapeutic strategies has been ongoing; experimental models that reliably emulate NSCLC disease are greatly needed to predict responses to novel therapeutics. Therefore, we developed patient-derived xenograft (PDX) models of NSCLC, which we then used to evaluate the therapeutic efficacy of ¹⁷⁷Lu-EB-RGD, a peptide-based radiopharmaceutical with improved pharmacokinetics that targets integrin α_vβ₃. In this study, three different groups of NSCLC-PDXs were successfully established, all of which maintained the same IHC and genetic characteristics of the human primary tumor. The two NSCLC-PDX groups with intense and low expression of integrin α_vβ₃ (denoted as PDX_αvβ3+ and PDX_αvβ3-) were chosen as the experimental models to evaluate the in vivo biological behavior of ¹⁷⁷Lu-EB-RGD. In SPECT imaging and biodistribution studies, ¹⁷⁷Lu-EB-RGD showed significantly higher accumulation in PDX_αvβ3+ and PDX_αvβ3- models than its corresponding monomer ¹⁷⁷Lu-RGD. A single dose of 18.5 MBq ¹⁷⁷Lu-EB-RGD was enough to completely eradicate the tumors in PDX_αvβ3+, with no sign of tumor recurrence during the observation period. Such treatment was also efficacious in PDX_αvβ3-: a single dose of 29.6 MBq ¹⁷⁷Lu-EB-RGD led to a significant delay in tumor growth as compared with that in the control or ¹⁷⁷Lu-RGD group. The preclinical data from the use of this model suggest that ¹⁷⁷Lu-EB-RGD may be an effective treatment option for NSCLC and should be further evaluated in human trials.