The overall goal of CARAT is to deliver a comprehensive platform that will revolutionize cancer therapy for the benefit of all patients and the European community. This intention has led us to our CARAT approach that is outlined in Fig. 2.
One important technological solution for CARAT may already be achieved with the CliniMACS Prodigy system that globally is the only device for fully automated GMP-compliant cell manufacture. Genetic engineering, however, requires more than an innovative device. Hence, we have designed four innovative work packages contributing key technologies to enhance the envisaged CAR T-cell product itself (WP1-4).
WP1 aims to improve the biological features of the starting cell fraction and culture conditions. Current cell culture protocols are still suboptimal in terms of T-cell function. Hence, WP1 will be responsible for the selection of the most efficient starting cell subset and development of enhanced cell culture protocols that lead to CAR T-cell products with improved efficacy and better safety. Importantly, WP1 will integrate results from WP2 and 3 for preclinical in vitro and in vivo validation. Partner 2, OSR will be responsible for WP1 due to their particular expertise in development and translation of innovative gene therapy concepts and especially GMP-compliant manufacture of CAR T-cell products.
WP2 will design improved CARs enabling better functional control. A CAR sharing platform will serve to establish joint reference CARs targeting hematologic and solid tumours. Partner 5 (UCL) has a proven, internationally renowned track record for design of innovative CAR constructs and will thus be in charge of leading WP2. Generated CAR constructs will be transferred to WP1 for further preclinical validation.
WP3 will facilitate targeted viral and non-viral gene-delivery. Two main strategies will be followed to improve gene-delivery: a) innovative viral vectors will be designed for targeted transduction of selected T-cell subsets and/or minimally activated T-cells. b) designer nucleases (Crispr/Cas9 and TALENs) will be used to knock-out the endogenous TCR loci and subsequent integration of the CAR constructs into a safe harbour locus. These tasks will be fulfilled by partner 3 (PEI) who has made outstanding world-wide recognized contributions to the surface engineering and receptor-targeting of viral vectors and partner 7 (UKL-FR) who advanced significantly the field of safe genome editing tools (including TALENS, Crispr/Cas9). New technologies from WP3 will also be transferred to WP1 to generated improved small-scale research manufacturing processes.
WP4 aims to investigate and subsequently improve characteristics and mode of action of CAR T-cell products. WP4 will pick up improved cell products from WP1 to investigate their functionalities in novel analytical assays: The tumour slice assay was established by partner 4 (INSERM) who has accumulated a thorough expertise in analysing T-cell activities in lymphoid tissue and tumours. MICS Technology from partner 1 (Miltenyi) will deliver complementary information on the characteristics of CAR T-cells.
WP5 represents the central work package of CARAT. Here, tools and technologies from the other research WPs will be integrated towards an optimized, simplified and cost-efficient GMP-compliant process for clinical use. Miltenyi will coordinate this WP as the company’s core competence is clinical cell separation technology. Complementary logistic tools will be contributed by TrakCel that has developed a unique system for the monitoring of complex supply chains for high-value or high-risk products.
WP6, 7 and 8 are providing the framework for successful execution of the more research-oriented WPs 1 to 5. WP6 will ensure that the CARAT process effectively meets all requirements related to regulatory issues. Hence, this WP will be led by partner 3 (PEI) who naturally has a specific expertise on regulatory issues of gene therapy medicinal products. WP7 will ensure efficient project management and consequently is led by Eurice, an experienced consultancy with a longstanding history in management of EU projects. WP8, finally, will facilitate effective communication, broad dissemination and structured exploitation of project results. The coordinator, Miltenyi (with support of Eurice) will take over the responsibility for WP8 as the company already has powerful channels to manage all these tasks.
Importantly, the CARAT platform will be designed in a modular way. This will allow for the development of flexible manufacturing protocols that can be easily adopted towards different requirements, other disease entities or further target cells. New technological features may be integrated rapidly into the process and it will be possible to fulfil the demands of various consumers from research, clinics and pharmaceutical industry. The modular approach also serves as risk minimization: If one of the work packages fails, the entire approach will not be endangered as alternative solutions from the other WPs could be integrated as substitutes into the CARAT process.
Consequently, as CARAT focuses on a broadly applicable technical solution, and related platform, we do not limit our approach to a single given disease or definite CAR. Instead, CARAT will offer general solutions to cure hematologic and solid tumours. In WP5 and 6, however, we will define an exemplary indication to translate our optimized and simplified process and develop supporting documents that are relevant for regulatory approval of clinical trials and can be used as blueprints for other investigators.