Abstract
Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related death in both men and women in industrialized countries, resulting in 1.8 million deaths in 2020. Chemotherapy combined with immunotherapy, mainly immune checkpoint inhibitors (ICI) of the Programmed Death-1 (PD-1) axis, is the primary treatment option for advanced stages of NSCLC (stage III and IV), where surgical removal of tumor mass is not feasible. However, especially in later stages, the 5-year survival rate ranges from 0% to 10% for stages IVA-IVB. Recent research in NSCLC has revealed the presence of sympathetic and parasympathetic nerve fibers within the tumor microenvironment (TME). However, the role of this innervation is still controversial, since it is highly tumor- and nerve-specific. It has been shown in lung cancer biopsies that increased sympathetic fibers mainly infiltrated the paratumoral area, while increased parasympathetic fibers were largely restricted to the tumor. Moreover, elevated intratumoral nerve fiber density is correlated with poor tumor prognosis, underscoring its influence on tumor growth and patient survival. CAMELOT aims (i) to study
the process of lung tumor innervation and to reveal its role in influencing tumor growth, immunosurveillance, and metastasis and (ii) to exploit it, by validating an innovative technology for cancer treatment. Our approach involves modulating TME innervation to hinder NSCLC growth and metastasis using a ground-breaking bioelectronic medicine approach. Our strategy entails designing an implantable system composed of a fully polymeric neural interface controlled by an implantable stimulator. Upon revealing the tumor innervation path, we will implant our device and develop selective neuromodulation protocols based on the nature of the innervation (i.e. sympathetic, parasympathetic), and study their effect on TME components alone and in combination with standard ICI on several orthotopic murine models of NSCLC. Therefore, CAMELOT proposes to develop a completely novel cancer therapy against NSCLC exploiting bioelectronic medicine paradigm that could potentially lead to remarkable advancements in enhancing patients' quality of life and driving groundbreaking innovations in the field of oncology.
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