Peptide receptor radionuclide therapy targeting the cholecystokinin-2 receptor: Preclinical and first clinical experience in small cell lung cancer

RationalePeptide receptor radionuclide therapy (PRRT) is an established treatment for neuroendocrine tumors (NETs), enabling targeted radiation delivery via radiolabeled peptides. Small cell lung cancer (SCLC) remains a major therapeutic challenge due to its aggressive nature and poor prognosis. Despite advances, relapse rates are high and effective therapies are limited. We previously demonstrated the diagnostic potential of the cholecystokinin-2 receptor-targeting minigastrin analog [68Ga]Ga-DOTA-MGS5 in PET/CT imaging in different NETs. Building on this, we developed and evaluated [177Lu]Lu-DOTA-MGS5 as a therapeutic PRRT agent. MethodsPreclinical studies investigating the cellular internalization and intracellular distribution over time in A431 cells were performed using the fluorescent tracer ATTO-488-MGS5. Short-and long-term cytotoxic effects of [177Lu]Lu-DOTA-MGS5 were evaluated on the same cell line using trypan blue exclusion and clonogenic survival assays. CCK2R expression was assessed by immunohistochemistry in 42 SCLC tissue specimens. In addition, the first PRRT with [177Lu]Lu-DOTA-MGS5 was conducted in a patient with extensive disease SCLC after confirming CCK2R-positive uptake in [68Ga]Ga-DOTA-MGS5 PET/CT. ResultsRapid binding and internalization into A431-CCK2R cells, with progressive accumulation in intracellular compartments, was observed for ATTO-488-MGS5. Short-term irradiation effects of [177Lu]Lu-DOTA-MGS5 were comparable for 4 h and 24 h incubation and lay between the effects obtained with 2 and 4 Gy of EBRT. Clonogenic survival of A431-CCK2R cells incubated with the increasing radioactivity of [177Lu]Lu-DOTA-MGS5 decreased in a dose-dependent manner. Immunohistochemistry on SCLC specimens confirmed moderate to high CCK2R expression in 16 of 42 SCLC samples. In the first patient with SCLC treated with four cycles of [177Lu]Lu-DOTA-MGS5 with a total activity of 17.2 GBq, no signs of toxicity were noticed. ConclusionsThe preclinical and clinical results confirm the feasibility of [177Lu]Lu-DOTA-MGS5 PRRT in patients with SCLC and support further clinical studies investigating the therapeutic value and clinical applicability of this new CCK2R-targeted theranostic approach in larger patient cohorts.