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Scaling-up biodegradable nanomedicines for multimodal for multimodal precision cancer immunotherapy

Periodic Reporting for period 1 - PRECIOUS (Scaling-up biodegradable nanomedicines for multimodal for multimodal precision cancer immunotherapy)

Reporting period: 2016-05-01 to 2017-10-31

PRECIOUS (scaling-up immunomodulating nanomedicines for multimodal precision cancer immunotherapy) aims at scaling-up biodegradable nanomedicines for multimodal precision cancer immunotherapy.
Despite the access to different classical treatment strategies such as chemotherapy, radiotherapy and surgery, cancer is still a leading cause of death worldwide accounting for over 8 million deaths per year. Often, tumour cells that have become resistant to chemo- and radiotherapy ultimately lead to the death of a patient. Therefore, radically innovative approaches are highly needed to increase survival rates. In the past 5 years, immunotherapy has completely overhauled the cancer field with several new types of therapies entering the market at a rapid pace. The great benefit of immunotherapy is that it attacks tumour cells via a completely different mechanism than chemo- and radiotherapy, harnessing the power of the body’s own immune system to fight cancer. However, current immunotherapies are challenged by low efficacy, partially due to the immunosuppressive tumour microenvironment.

The PRECIOUS project will establish a platform for the development of new medicines that contain immunomodulating components acting at multiple levels. Nanoparticles offer the optimal platform for a combinational immunotherapy, as they are able to encapsulate immunomodulators in biodegradable particles. Currently, immunomodulating nanomedicines are not used to their full potential due to is challenging manufacturing requirements. PRECIOUS will develop a manufacturing process at industrial scale for immunomodulating nanomedicines and test the potential of these nanoparticle based immunotherapies in the clinic. To ensure that these novel treatment strategies will reach patients, the development of a marketing and commercialisation strategy for these novel medicines is an important part of the project. Together, PRECIOUS will realise a major improvement in cancer therapy to provide cancer patients with enhanced quality of life.

The main objectives in PRECIOUS:
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 trials to show efficacy. Both nanomedicines will be used by 1) local delivery of vaccines in lymphnodes to evoke immune responses and 2) local 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. Local delivery will avoid toxicity, reduce dose, lower costs, and have major impact on the European health care system.
The aim of WP 1 is to optimise (A) lead PLGA nanoparticles for Fast Track trials and to further develop (B) next-generation PLGA particles for the Discovery Track. Through Fast-Tracking the first PLGA generation into a clinical safety trial we will gain initial proof-of-concept of the applicability of this platform already at an early stage of the project. We have worked on the selection of the APIs for the Fast Track, and the initial production of the PLGA particles for the Fast Track. In the Discovery Track we are working on identification of multiple potential next-generation immunomodulators.
In WP2, toxicity/efficacy of (A) lead and (B) next-generation PLGA is preclinically validated. We have several (syngeneic and transgenic) mice models available to exhaustively validate the toxicity/efficacy of both the lead and next gen PLGA particles and their interaction with biological environment. So far, we have optimised mice models and have tested the Fast Track APIs.
WP3 is to optimise manufacturing process for large scale GMP production of PLGA particles. During this project this manufacturing process will be further optimised from small laboratory scale towards industrial scale GMP mass production of complex nanoparticles. In PPR1, we have performed literature search and have compared multiple manufacturing processes.
WP4 entails the development and management of clinical trial files. So far, we have initialised the writing of the clinical trial protocol.
In WP5, we will perform Phase I clinical trials to demonstrate the potential of this large scale GMP production platform. We have not started this wp yet.
The development of a business model and marketing strategy is the aim of WP6. Before the start of PRECIOUS we have already initiated a market analysis and the development of a feasible business case. The PRECIOUS consortium has specifically conceived a sub-objective to develop such plans for the results from the entire PRECIOUS project. Now, we have set a preliminary IP strategy and did a preliminary FTO.
The aim of WP7 is to ensure dissemination of results and the day-to-day operational project management. Progress in any research and development project is largely dependent on correct management, to monitor and subsequently implement results in the next steps of development. We have designed a dissemination strategy, of which the main goal is to ensure that PRECIOUS will achieve the expected impact. We are managing this project continuously and will make sure that all partners disseminate the results when appropriate.
PRECIOUS targets to produce nanomedicines that are the first to aim at both activation of the immune system AND reverse immunosuppression. Also, PRECIOUS will pioneer the development of a high-performing continuous manufacturing process for PLGA-based nanoparticles.

PRECIOUS will deliver:
(1) a novel PLGA-based immunomodulating nanomedicine platform that allows for combinatorial cancer immunotherapy, using different immunomodulating compounds;
(2) protocols to generate GMP-grade clinical trial material of PLGA particles;
(3) clinical safety and tolerability data of the platform;
(4) preclinical data on safety and efficacy of all individual compounds administered locally using the PLGA particles and the combinations thereof.