Randomised clinical trial in cancer patients shows immune metabolic effects exerted by formulated bioactive phenolic diterpenes with potential clinical benefits

Marta Gómez de Cedrón ^1* Juan Moreno-Rubio ^2,3 Victor de La O Pascual ⁴ Beatriz Alvarez ⁵ Marta Villarino ² María Sereno ^2,3 César Gómez-Raposo ^2,3 Silvia Roa ² Miriam López Gómez ² María Merino-Salvador ² Ana Jiménez-Gordo ^2,3 Sandra Falagán ² Cristina Aguayo ² Francisco Zambrana ² Beatriz Tabarés ² Beatriz Garrido ² Silvia Cruz-Gil ¹ Cristina María Fernández ¹ Lara P Fernández ¹ Susana Molina ¹ María Carmen Crespo ¹ Youness Ouahid ⁶ Juan José Montoya ^7,8 Ricardo Ramos Ruíz ¹ Guillermo Reglero ^10,9 Ana Ramirez De Molina ^1* Enrique Casado ^2,3*

• ¹ Molecular Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, Carretera de Canto Blanco 8, 28702, Madrid, Spain, Madrid, Spain
• ² Medical Oncology Department, Infanta Sofia University Hospital-Henares University Hospital-Foundation for Biomedical Research and Innovation (FIIB HUIS HHEN), Paseo de Europa 34, 28702, Madrid, Spain
• ³ Clinical Oncology Group, IMDEA Food Institute, CEI UAM + CSIC, 28702, Madrid, Spain, Madrid, Spain
• ⁴ Precision Nutrition and Cardiometabolic Health, IMDEA-Food Institute, Campus of International Excellence (CEI) UAM+CSIC, 28049 Madrid, Spain, Madrid, Spain
• ⁵ Centro Nacional de Investigaciones Cardiovasculares Carlos III(CNIC-CarlosIII), Melchor Fernández Almagro, 28029 Madrid, Spain., Madrid, Spain
• ⁶ MiRNAX Biosens Research & Development Unit (MBR&DU). Avda. Industria 4, (Natea Business Park),, Madrid, Asturias, Spain
• ⁷ MiRNAX Biosens Research & Development Unit (MBR&DU). Avda. Industria 4, (Natea Business Park), Madrid, Spain, Madrid, Spain
• ⁸ Faculty of Medicine, School of Sport Medicine, Universidad Complutense de Madrid, 28040 Madrid, Spain, Madrid, Spain
• ⁹ Institute of Food Science Research CIAL CSIC-UAM. Nicolas Cabrera 9, 28049, Madrid, Asturias, Spain
• ¹⁰ Production and Development of Foods for Health, IMDEA Food Institute, CEI UAM + CSIC, Carretera de Canto Blanco 8, 28049, Madrid, Asturias, Spain

Background: Nutrients, including bioactive natural compounds, have been demonstrated to affect key metabolic processes implicated in tumor growth and progression, both in preclinical and clinical trials. Although the application of precision nutrition as a complementary approach to improve cancer treatments is still incipient in clinical practice, the development of powerful "omics" techniques has opened new possibilities for delivering nutritional advice to cancer patients. Precision nutrition may contribute to improving the plasticity and function of antitumor immune responses. Objectives: Herein, we present the results of a randomized, prospective, longitudinal, double-blind, and parallel clinical trial (NCT05080920) in cancer patients to explore the immune-metabolic effects of a bioactive formula based on diterpenic phenols from rosemary, formulated with bioactive alkylglycerols (Lipchronic© WO/2017/187000). The trial involved cancer patients, including those with lung cancer (LC), colorectal cancer (CRC), and breast cancer (BC), undergoing chemotherapy, targeted biological therapy, and/or immunotherapy. The main readouts of the study were the analysis of Lip on systemic inflammation, hemogram profile, anthropometry, lipid and glucose profiles, and tolerability. Additionally, a deep immune phenotyping of peripheral blood mononuclear cells (PBMCs) was performed to identify the functional effects of Lip on key mediators of the immune system. Results: Lip was well tolerated. The lung cancer subgroup of patients showed a reduction in biomarkers of systemic inflammation, including the neutrophil-to-lymphocyte ratio (NLR). Furthermore, modulation of key players in the immune system associated with the experimental treatment Lip compared to the control placebo (Pla) treatment was revealed, with particularities among the distinct subgroups of patients. Our results encourage further research to apply molecular nutrition-based strategies as a complementary tool in the clinical management of cancer patients, particularly in the current era of novel immunotherapies.