PRECIOUS aims at scaling-up biodegradable nanomedicines for multimodal precision cancer immunotherapy. With 3.5 million cancer patients in Europe every year, new cancer medicines are eagerly awaited, notably for prostate and ovarian cancer. Systemically applied new immunotherapies are promising, but their toxicity is a hurdle. Vaccination against cancer is safe but rather the efficacy can be disappointing, i.e. the microenvironment shuts down anti-tumour immunity. PRECIOUS will tackle 2 bottlenecks: 1. Production of non toxic multimodal nanomedicines, which induce vigorous immune responses, and at the same time reverse immunosuppression 2. Large scale GMP production of nanomedicines, and initiate a multimodal immunotherapy Phase I trial. We want to solve these bottlenecks by: Objective 1: Two types of GMP biodegradable nanoparticles: 1) a nanovaccine, containing tumour antigens and immune activators, and 2) a nanoparticle composed of compounds, which reverses the suppression and reactivates immunity in the tumour. Objective 2: Clinical Phase I trial to show efficacy. Nanomedicines will be used by 1) injection of vaccines to evoke immune responses and 2) injection of nanoparticles in the tumour microenvironment, which slowly release compounds that reverse suppression. To achieve this, a platform is formed with 6 leading industrial partners to produce large scale GMP nanomedicines and an excellent immunomodulator track record, together with 5 renowned academic partners to perform clinical studies. Relevance to call: Large scale GMP production, industrial leadership, nanotechnology and advanced manufacturing KET technologies, translation to the clinic, marketing development.

Glioma is a rare brain cancer with one of the highest mortality rates. It is considered an orphan disease due to its low prevalence (less than 0.5 cases per 10,000 inhabitants in the EU) and the lack of plausible therapies. Based on the discovery of the lipid proliferation switch (high membrane PE-to-SM molar ratio that enables recruitment of cell growth transducers to the membrane), the SME Lipopharma (leading this application) defined a novel anticancer drug target, the tumor repressor protein sphingomyelin synthase 1 (SMS1). An innovative SMS1 activator, 2OHOA, was designed and showed safety and efficacy in preclinical GLP and non-GLP studies. A first-in-man clinical trial I/IIa (ClinicalTrials.gov identifier #NCT01792310) further demonstrated its safety and efficacy in humans. The European Medicines Agency (EMA) designated 2OHOA orphan drug for the treatment of glioma and approximately half of the patients with glioma submitted to >2 months of treatment showed positive response. The present project aims to perform a clinical phase IIB study to demonstrate 2OHOA’s efficacy against glioblastoma multiforme, the most aggressive form of glioma. In this context, a written formal report from the EMA after scientific advice and protocol assistance (SA/PA-EMA/CHMP/SAWP773534/2014) indicates that 2OHOA would obtain Conditional Marketing Authorisation if this phase-IIB study further demonstrates statistically significant efficacy. In addition this project will further investigate 2OHOA’s safety, mechanism of action and biomarkers for glioblastoma diagnosis, prognosis and response to 2OHOA treatment. These studies will let us (i) know the molecular basis underlying the response to 2OHOA treatment, (ii) define new biomarkers, (iii) design more efficacious personalized treatments and (iv) investigate therapeutic alternatives in patients who do not respond to treatment.