SLAMF7-CAR T cells prepared by Sleeping Beauty gene-transfer for immunotherapy of multiple myeloma – a rare hematologic disease | CARAMBA | Project | News & Multimedia | H2020 | CORDIS

Periodic Reporting for period 4 - CARAMBA (SLAMF7-CAR T cells prepared by Sleeping Beauty gene-transfer for immunotherapy of multiple myeloma – a rare hematologic disease)

Berichtszeitraum: 2023-01-01 bis 2023-06-30

The CARAMBA project is using the revolutionary CAR T cell technology, a novel form of personalised cancer therapy, to tackle multiple myeloma (MM) as a rare and incurable hematologic malignancy. MM is associated with a substantial socioeconomic burden and there is a strong demand by patients, their families and caregivers for a curative MM treatment. The CARAMBA investigators are conducting a clinical trial with patient T cells that are gene engineered to express a synthetic designer receptor called chimeric antigen receptor (CAR) specific for the myeloma antigen SLAMF7. SLAMF7 is highly expressed on myeloma cells in every patient (women and men). In the work leading up to this project, the CARAMBA investigators have carefully evaluated and demonstrated the safety and efficacy of SLAMF7 CAR T cells against MM in the preclinical setting. CAR T therapy has been recognised as a ‘breakthrough’ in cancer medicine. Clinical proof-of-concept has been obtained with CD19 CAR T cells in leukemia and lymphoma and with BCMA CAR T cells in MM that are now clinically approved in the EU. CARAMBA is pursuing a novel target molecule – SLAMF7 – to tackle MM, building on cutting-edge CAR technologies including virus-free Sleeping Beauty (SB) CAR gene transfer, which enhances the safety profile and reduces the cost of CAR T cell manufacturing, making it an economically viable and sustainable medicinal product.

Since project start in 2018, the CARAMBA consortium has made rapid progress in implementing the project and clinical trial. The manufacturing authorization for SLAMF7 CAR T was obtained in the 1st project period (PP) and is the first virus-free (i.e. independent from viral gene transfer vectors) CAR T manufacturing process in Europe that uses advanced SB transposon technology with mRNA and minicircle DNA vectors. This unique approach enables high scalable, cost-efficient CAR T manufacturing. The CARAMBA clinical trial received regulatory approval in all 4 intended EU member states - Germany, Spain, Italy, and France and is at present, the only academic investigator-initiated trial with CAR T cells that is active in several EU countries.
During the 4th PP, the site in France was initiated and started patient recruitment. In summary, since 2020, 11 patients have been recruited, of which 9 received SLAMF7 CAR T at increasing doses as foreseen in Phase I of the trial. Considering that several BCMA-directed therapies are concurrently being investigated in MM, patient selection and recruitment has been done prudently, carefully considering the potential benefits and risks of participating in the CARAMBA trial. Of note, CARAMBA is one of the few CAR T trials worldwide that considers MM patients that relapse after prior bone marrow transplantation.
In the CARAMBA trial, SLAMF7 CAR T treatment was well tolerated. The SLAMF7 CAR T cells engrafted after infusion and already show signs of clinical efficacy, even though the administered dose was still low. Of note, patients from all EU-countries are eligible and several patients have been enrolled that have their primary residence outside one of the EU member states represented in the CARAMBA consortium. Myeloma Patients Europe - the largest MM patient advocacy group in Europe is very active in the project and ensures that patient perspectives and concerns are being addressed. In the 3rd and 4th PP, several highly visible and impactful patient information and engagement campaigns were conducted, including videos and information materials in different languages. Significant output from the correlative research (including standardisation and continued quality control of laboratory procedures) and the exploratory research program was delivered. This includes several key note presentations and manuscripts in the world’s leading scientific journals. The CARAMBA consortium was highly active at international societies (EHA, EBMT, ESGCT) and conferences, including the EBMT & EHA European CAR T Cell Meeting as the largest CAR-T event world-wide (Chair 2022 – 2024: M. Hudecek). CARAMBA is also enabling the commercial development and exploitation of CAR T technologies in Europe through the biotech partner T-CURX that scoped the market space, established reimbursement and business development strategies and completed a first financing event in order to create a legacy for the CARAMBA project.
Conclusions: The CARAMBA consortium implemented its set project goals by bringing an innovative virus-free CAR-T product into the clinic. With the regulatory approval in 4 countries, MM patients from across the EU receive access to this new therapeutic approach. Although progress has been made in MM therapy with CAR-T directed against BCMA or GPRC5D both targets have been observed to be subject to antigen loss resulting in relapse of patients. Therefore and due to its much safer genomic insertion profile and reduced manufacturing costs compared to conventional CAR-T products, the interest in SLAMF7 CAR-T alone or as combinatorial target remains unwavering. The project has strengthened the collaboration among the European partners further, gained high visibility in the scientific community and serves with its scalable manufacturing as a platform for development of future CAR-T products in the EU. The aim is to continue the clinical trial after the project end to the product development towards the market and to enable commercial exploitation.
Key metrics: Trial approval in 4/4 EU member states. SLAMF7 CAR T product delivered to 9/9 patients. >100 CARAMBA project presentations at national, European and international conferences. >5 original papers published in excellent scientific journals. >4.000 followers on CARAMBA social media and website. >2.500 patients engaged at patient stakeholder events, conferences and outreach activities. >10 Mio EUR raised in additional public grant funding and private financing by CARAMBA partners during the project.

In summary, CARAMBA has made several critical advances beyond the state of the art, and already made significant, positive impact on the field of cell & gene therapy in Europe:
-Regulatory acceptance and approval for virus-free transposon-based gene-transfer
-Continuous refinement of virus-free gene-transfer to foster adoption by additional academic and industry stakeholders and to enable commercial exploitation
-Implementation of the first multi-national academic CAR T trial in Europe
-Access of MM patients from across the EU to participate in the CARAMBA trial
-Investigation of an innovative immunotherapy in MM not directed against BCMA and suitable for treating MM patients when they relapse after BCMA directed therapy
-Engagement of MM patients in the conception, design and conduct of the CARAMBA trial, intense patient information and HCP engagement activities
-Standardization of CAR-T GMP manufacturing to enable the development of standard product profiles and customize GMP in the EU (link & interaction to T2EVOLVE EU IMI consortium)
-Delivery of an innovation ecosystem around advanced CAR technologies and CAR T therapy comprising academic, industry, patient HCP, regulatory and public stakeholders (link & interaction to imSAVAR &T2EVOLVE EU IMI, AIDPATH EU H2020)
-Intense dissemination and engagement of patient and lay audiences through CARAMBA social media channels, stakeholder events, information material to increase awareness and acceptance of cell- & gene-therapy.

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SLAMF7-CAR T cells prepared by Sleeping Beauty gene-transfer for immunotherapy of multiple myeloma – a rare hematologic disease

Periodic Reporting for period 4 - CARAMBA (SLAMF7-CAR T cells prepared by Sleeping Beauty gene-transfer for immunotherapy of multiple myeloma – a rare hematologic disease)

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