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EURopean Endeavour for Chimeric Antigen Receptor Therapies

Periodic Reporting for period 2 - EURE-CART (EURopean Endeavour for Chimeric Antigen Receptor Therapies)

Reporting period: 2018-07-01 to 2019-12-31

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 improve CAR T cells therapy.
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 successfully performed in tumour models of AML and MM. Moreover, to measure CD44v6 expression in AML and MM tumor samples, a reproducible method was developed, which is currently used for clinical screening of enrolled patients.

WP02 Production of clinical-grade EURE-CART Cells
The manufacturing process and the related analytical methods, to produce clinical-grade EURE-CART cells for patient treatment, were successfully developed. 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, together with the Clinical Protocol, was submitted to the Regulatory Authorities of the countries involved in the clinical trial (Italy, Germany, Spain and Czech Republic). Approval of the clinical trial applications was obtained in Italy and Czech Republic. EURE-CART cells were produced and released for the treatment of the first patient.

WP03 Regulatory approval of the EURE-CART cell product
The involved participants are working towards the harmonized 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 1st RAC workshop was held in October, 2018 in Rome, and gave an important input on the strategy to be followed for the EURE-CART clinical trial application as well as for the strategy to follow for approaching regulatory issues.

WP04 Phase I/Iia clinical study with EURE-CART cells
Drafting and finalization of the clinical protocol was achieved, based on suggestions from EURE-CART members. After its final endorsement by the Consortium, the clinical protocol was submitted to the National Regulatory Authorities (Italy, Germany, Spain and Czech Republic). Approval was obtained in Italy and Czech Republic and three clinical centers were enabled to recruit patients in the EURE-CART-1 study (EudraCT number 2018-000813-19; Clinical NCT 04097301). Three patients were enrolled and one was treated with the EURE-CART cell product, in December 2019.

WP05 Follow-up of EURE-CART Phase I/IIa and correlative studies
The assays for patient’s follow-up including FACS analysis, Real Time PCR and cytokine analysis were set up to harmonize the procedures between local and central laboratories. In particular, all the procedures to reduce the possible variation between pharmacokinetics performed in different centres have been validated.

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 antitumor activity in vivo led to the conclusion that SLAMF7 is a suitable target for CAR T cell therapy of MM. Moreover, in vitro studies targeting multiple antigens, demonstrated that bi-specific CAR T cells are able to eradicate tumor cells that had lost the expression of one target antigen but retain the expression of the second.

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. Three General Assembly and Steering Committee meetings were organised. In October 2019, a teleconference with the Project Officer was held to discuss the proposal for a non-cost extension of the project, which would allow to treat enough patients to assess the clinical outcome of the EURE-CART-1 study.

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. A Twitter account has been set up and used. Workshops were organised and press releases were published by several partners.

WP09 Ethics Requirements
All the required relevant authorisations were collected and submitted as deliverables to the European Commission.
The extraordinaire anti-tumor efficacy of the CAR T cell strategy demonstrated in the treatment of B cell malignancies with CD19 CAR T cells, has led to the approval of Kymriah and Yescarta by FDA and EMA, respectively. Indeed, a single infusion of CD19 CAR T cells confers tumor remission with long-lasting complete responses even in patients in which conventional treatments had failed. These results strongly reinforce the expected impact that the EURE-CART project will have on the life and wellbeing of cancer patients, their families and health care providers. In addition, the CD44v6 antigen fulfils the requirements for a full clinical exploitation of the CAR T approach, being expressed not only in haematological diseases (AML and MM), but also by some of the most frequent solid tumors (breast, colorectal, pancreatic, head and neck cancer). Of note, preclinical studies have recently demonstrated that CD44v6 CAR T cells are highly effective also in xenogenic models of solid human cancers (Porcellini et al Front Immunol, 2020). Moreover, additional CAR targets (i.e. SLAMF7) for combinatorial strategies were identified. Thus, in the long run, the outcome of the 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.