Dynamic systemic immune modulation in metastatic neuroendocrine tumor (NET) patients treated with targeted alpha-emitter 212 Pb-DOTAMTATE AlphaMedix

Peptide receptor radionuclide therapy (PRRT) has been increasingly explored as a therapeutic strategy for multiple solid tumors, such as prostate cancer and somatostatin receptor-expressing GEP-NETs. While Lutathera (¹⁷⁷Lu-DOTATATE), a beta-emitting PRRT, represents the current GEP-NETs standard of care. alpha-emitting PRRTs such as AlphaMedix (²¹²Pb-DOTAMTATE) are emerging as promising alternatives with distinct radiobiological characteristics. Ionizing radiation from PRRT not only induces DNA damage but also modulate the immune system, contributing to therapeutic response.We sought to identify evidence of systemic immunomodulation associated with alpha-emitter AlphaMedix treatment and to compare it with that elicited by Lutathera. Whole-blood immunotranscriptomes were analyzed using the LITOSeek platform to characterize immune signatures and pathways differentially activated by alpha- and beta-emitting PRRTs. This approach elucidates the immunological mechanisms underlying alpha-particle therapy and uncovers potential biomarkers of treatment response. Methods: Whole blood samples were collected with PAXgene Blood RNA tubes from GEP-NET patients before and throughout AlphaMedix or Lutathera treatment. Differential expression, over-representation analysis, digital cytometry, and trajectory identification were used to characterize treatment-induced regulation of peripheral immunotranscriptomes, immune cell composition, and heterogenous responses within the patient population. Results: AlphaMedix therapy induced strong peripheral transcriptomic changes in patients achieving complete or partial response, detectable from 8 weeks after first infusion, and up to 6 months after end of treatment. AlphaMedix triggers similar transcriptomic changes throughout the treatment among patients responding to the therapy, which is stronger and different from patients treated with Lutathera. The 212 Pb radioligand therapy triggers early generation of ROS, DNA damage, apoptotic responses, inflammation and monocyte recruitment. The results reveal two waves of immunotranscriptome modulation, likely reflecting kinetics heterogeneity of immune activation between early and late responders. Lymphopenia, particularly affecting B cells, was observed in patients treated with either AlphaMedix or Luthatera, with more pronounced lymphopenia among patients treated with Lutathera. Conclusions: Data-driven characterization of treatment-associated transcriptional changes in peripheral immune cells underscores immune modulation associated with clinical response to radioligand therapy. The translational potential of whole-blood RNA liquid biopsy is demonstrated with Immuno-Pharmacodynamic profiling of patient response to radioligand therapy, and identification of immune-related biomarkers of clinical response.