TY - JOUR AU - Chettab, Kamel AU - Fitzsimmons, Chantel AU - Novikov, Alexey AU - Denis, Morgane AU - Phelip, Capucine AU - Mathé, Doriane AU - Choffour, Pierre Antoine AU - Beaumel, Sabine AU - Fourmaux, Eric AU - Norca, Patrick AU - Kryza, David AU - Evesque, Anne AU - Jordheim, Lars Petter AU - Perrial, Emeline AU - Matera, Eva-Laure AU - Caroff, Martine AU - Kerzerho, Jerome AU - Dumontet, Charles PY - 2023 M3 - Original Research TI - A systemically administered detoxified TLR4 agonist displays potent antitumor activity and an acceptable tolerance profile in preclinical models JO - Frontiers in Immunology UR - https://www.frontiersin.org/articles/10.3389/fimmu.2023.1066402 VL - 14 SN - 1664-3224 N2 - Bacterial lipopolysaccharides (LPS) are potent innate immunostimulants targeting the Toll-like receptor 4 (TLR4), an attractive and validated target for immunostimulation in cancer therapy. Although LPS possess anti-tumor activity, toxicity issues prevent their systemic administration at effective doses in humans. We first demonstrated that LPS formulated in liposomes preserved a potent antitumor activity per se upon systemic administration in syngeneic models, and significantly enhance the antitumor activity of the anti-CD20 antibody rituximab in mice xenografted with the human RL lymphoma model. Liposomal encapsulation also allowed a 2-fold reduction in the induction of pro-inflammatory cytokines by LPS. Mice receiving an intravenous administration demonstrated a significant increase of neutrophils, monocytes and macrophages at the tumor site as well as an increase of macrophages in spleen. Further, we chemically detoxified LPS to obtain MP-LPS that was associated with a 200-fold decrease in the induction of proinflammatory cytokines. When encapsulated in a clinically approved liposomal formulation, toxicity, notably pyrogenicity (10-fold), was limited while the antitumor activity and immunoadjuvant effect were maintained. This improved tolerance profile of liposomal MP-LPS was associated with the preferential activation of the TLR4-TRIF pathway. Finally, in vitro studies demonstrated that stimulation with encapsulated MP-LPS reversed the polarization of M2 macrophages towards an M1 phenotype, and a phase 1 trial in healthy dogs validated its tolerance upon systemic administration up to very high doses (10µg/kg). Altogether, our results demonstrate the strong therapeutic potential of MPLPS formulated in liposomes as a systemically active anticancer agent, supporting its evaluation in patients with cancer. ER -