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

Periodic Reporting for period 4 - PRECIOUS (Scaling-up biodegradable nanomedicines for multimodal for multimodal precision cancer immunotherapy)

Okres sprawozdawczy: 2020-05-01 do 2022-04-30

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 9.6 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 micro-environment.

The PRECIOUS project established 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. In PRECIOUS we developed a manufacturing process at industrial scale for immunomodulating nanomedicines. We produced clinical batches nanomedicines and we tested the potential of these nanoparticle-based immunotherapies in the clinic. In addition, we developed a marketing and commercialisation strategy for these novel medicines.

Together, with 6 leading industrial partners and 5 renowned academic partners, we have been able to realize within the PRECIOUS project a major improvement in cancer therapy by building a novel nanomedicine platform and demonstrated proof of concept in the clinic.
The aim of WP 1 was to optimise (A) lead PLGA nanoparticles for Fast Track trials and to further develop (B) next-generation PLGA particles for the Discovery Track. We developed a protocol to generate immunosuppressive cell populations in vitro, selected the drugs that can inhibit the suppression mechanisms, and performed functional assays using both the soluble drug and after encapsulation within PLGA nanoparticles. This assay is now being used by iTEOS to screen for potential novel drugs affecting immunosuppressive MFSC. Furthermore, a systematic titration and comparison of PLGA-P containing antigen and either conventional TLR3 ligand polyI:C or GMP-grade Riboxxim has been performed.

In WP2, toxicity/efficacy of (A) lead and (B) next-generation PLGA was pre-clinically validated. The mice models have been studied extensively by various partners for Pharmacokinetic and Pharmacodynamics (PK/PD) of PLGA- and conjugate particles in vivo. Also, a tox study has been carried out with the PLGA particles produced for the clinical study to determine any adverse effects.

WP3 aimed at optimising manufacturing process for production of PLGA particles. During this project this manufacturing process was further optimised from small laboratory scale towards industrial scale GMP production of complex nanoparticles. A manufacturing protocol for the production of a large scale GMP batch of PLGA nanoparticles was established. Additionally, a series of quality control tests were also performed to assess the functioning of the PLGA molecules. The GMP production pipeline at RUMC was used to produce four clinical batches.

WP4 entailed the development and management of clinical trial files. We have progressed significantly, and approval was obtained by the respective regulatory authorities (see deliverable 4.1). During the project we were hampered by the coronavirus pandemic, which delayed all processes at RUMC.

In WP5, we performed a Phase I clinical trial to demonstrate the potential of this large scale GMP production platform. The start of trial was delayed by the COVID-19 pandemic, was started in Q1 of 2021 and is still ongoing.

The development of a business model and marketing strategy was the aim of WP6. Before the start of PRECIOUS we 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. So far, we have updated our market research plan and our business plan and developed an IP strategy deliverable (see deliverable 6.4 6.7 & 6.9).

The aim of WP7 was to ensure dissemination of results and the day-to-day operational project management. We were managing this project continuously and made sure that all partners disseminate the results when appropriate. Several meetings have been organized so far and recently, we organized a review meeting (virtual) with all partners including the EC and external contact and the final (virtual) consortium and review meeting took place in April 2022.
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-throughput 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.
As such PRECIOUS has with the novel nanomedicine platform a major impact for society, not only within the field of oncology where it results in novel treatment modalities, but potentially in all immune related diseases including autoimmune diseases.