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EURE-CART Report Summary

Project ID: 733297
Funded under: H2020-EU.3.1.3.

Periodic Reporting for period 1 - EURE-CART (EURopean Endeavour for Chimeric Antigen Receptor Therapies)

Reporting period: 2017-01-01 to 2018-06-30

Summary of the context and overall objectives of the project

EURE-CART is proposing to investigate adoptive immunotherapy with autologous T cells genetically modified with a tumour-reactive chimeric antigen receptor (CAR). CAR T cells specific for CD19, have been shown to eradicate B cell leukemias and lymphomas. On this ground, EURE-CART is dealing with a new CAR directed against CD44v6, which is expressed in multiple haematological tumours, including acute myeloid leukemias (AML) and multiple myelomas (MM), as well as in the majority of carcinomas. Main objective of EURE-CART is to conduct a multicentre, first-in-man Phase I/IIa clinical trial in different EU member countries, to demonstrate safety and efficacy of CD44v6 CAR T cells in AML and MM. Moreover, a key objective of EURE-CART is to obtain regulatory approval for a single, harmonised CAR T cell product in four EU member countries. This is a challenging aim due to the considerable difference in regulatory requirements among EU member countries. In addition, EURE-CART has designed a preclinical program aimed at identifying and validating new target antigens and receptors, to be used in combination to achieve synergistic effects.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

WP01 Efficacy and Safety Studies
Efficacy and safety studies of lymphocytes expressing the CD44v6 CAR and the HSV-TK suicide gene (EURE-CART cells) were performed. Antitumor efficacy of EURE-CART cells was demonstrated in tumour models of AML and MM. Moreover, the observed correlation between antitumor activity and antigen expression levels suggests that EURE-CART cells are highly specific, further supporting a low toxic profile towards healthy tissues expressing low CD44v6 levels. The functionality of the suicide gene, which in case of adverse events allows the elimination of EURE-CART cells by ganciclovir administration, was successfully assessed in mice.

WP02 Production of clinical-grade EURE-CART Cells
The manufacturing process and the related analytical methods, to produce clinical-grade EURE-CART cells for the clinical study, were successfully developed. This will allow the production of the EURE-CART cells for patient treatment. The Investigational Medicinal Product Dossier (IMPD), which includes all the information on EURE-CART cells production, and on the non-clinical toxicology and pharmacology studies, is under final revision for submission to the Regulatory Authorities.

WP03 Regulatory approval of the EURE-CART cell product
The involved participants are working towards the regulatory approval of the EURE-CART cell product for use in the Phase I/IIa clinical study. Top level experts with a solid scientific background were appointed as members of the Regulatory Advisory Committee (RAC). The RAC has started its activities and will meet in its 1st workshop on October 2, 2018 in Rome.

WP04 Phase I/IIa clinical study with EURE-CART cells
Although this WP hasn´t started yet, drafting and finalization of the clinical protocol was achieved, based on suggestions from EURE-CART members. Its final endorsement by the Consortium was obtained during the 2nd General Assembly, and the following Steering Committee.

WP05 Follow-up of EURE-CART Phase I/IIa and correlative studies
Although this WP hasn´t started yet, several assays for patient’s follow-up including FACS analysis, Real Time PCR and cytokine analysis, were set up and validated to harmonize the procedures between local and central laboratories.

WP06 Validation of next-generation EURE-CART cells
SLAMF7 was identified as new target for CAR therapy of MM. Antigen expression profile, in vitro effector function of SLAMF7 CAR T-cells and their potential to eradicate MM cells in vivo led to the conclusion that SLAMF7 is a suitable target for CAR-T cell therapy of MM [Gogishvili T, Blood, 2017]. Studies to identify additional CAR targets in AML and MM are proceeding. Studies with CARs that target multiple antigens on AML and MM, to identify the combination with the best synergistic effect, have commenced. Experiments evaluating EURE-CART cells in personalised xenograft models are currently in preparation.

WP07 EURE-CART Management
Procedures, management methods and tools, to facilitate the fulfilment of contractual duties were set up. Online submission of deliverables has been carried out and rules for decision making processes have been made fully operational. A regular update of the WPs activities was ensured by teleconference, and face to face meeting. Two General Assembly (February 2017 and March 2018) and Steering Committee (every three months) meetings were organised.

WP08 Dissemination and exploitation of EURE-CART results
A detailed plan of the dissemination and communication has been developed. The public website was set up providing all relevant information about the project, including the flyer and the newsletter. Twitter and Linkedin accounts have been set up. Workshops were organised by several partners. In March 2017, a press release has been distributed at national level.

WP09 Ethics Requirements
All the required relevant authorisations for animal experiments, project authorizations, and training certificates/personal l

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Cancer immunotherapy is facing an accelerated phase of development. Indeed, CD19-targeted CAR T cells have successfully been used to treat B cell leukemias and lymphomas. Based on the remarkable clinical results, Kymriah and Yescarta were the first two CAR T cell products approved in the US by the FDA and recently, recommended for marketing authorizations in the EU by EMA.
Until now, the successful application of the CAR T strategy was limited to the treatment of B cell tumours. Therefore, new target antigens are urgently needed to assure the full clinical exploitation of this approach. The CD44v6 antigen fulfils these requirements being expressed by a large variety of cancers, including solid tumours. While two haematological diseases, AML and MM, have been selected for the first-in-man clinical application of CD44v6 CAR T cells within the EURE-CART project, CD44v6 CAR T cells are expected to be potentially applicable to other human cancers, including squamous cell carcinomas and adenocarcinomas. Moreover, additional CAR targets (i.e. SLAMF7) to be used alone or in combinatorial strategies were identified. Thus, in the long run, the outcome of EURE-CART project should benefit the EU population by improving its health and increasing at the same time the competitiveness of the EU biomedical and pharmaceutical industry through the generation of new scientific knowledge.

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