#	Pagina
attuale pagina	/open-h2020/projects/216603/results.html

Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - CARAMBA (SLAMF7-CAR T cells prepared by Sleeping Beauty gene-transfer for immunotherapy of multiple myeloma â€“ a rare hematologic disease)

Teaser

Summary

The CARAMBA project is proposing to use the revolutionary CAR T cell technology, a novel form of personalised immune based cancer therapy to tackle multiple myeloma, a rare and incurable hematologic malignancy. Myeloma is associated with a substantial socioeconomic burden and there is a strong demand by patients, their families and caregivers for a curative myeloma treatment. The CARAMBA investigators are striving to conduct a first-in-man phase I / II a clinical trial of immunotherapy with patient derived 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 uniformly expressed on all myeloma cells in every patient and thus SLAMF7 CAR T cells are anticipated to be equally effective in 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 multiple myeloma in preclinical test systems.
CAR T cell therapy has been recognised as a â€˜Breakthroughâ€™ in cancer medicine. Clinical proof-of-concept has been obtained with CD19 CAR T cells in leukemia and lymphoma, and CD19 CAR T cells are now clinically approved in the EU. CARAMBA is pursuing a novel target molecule â€“ SLAMF7 â€“ and a novel indication â€“ multiple myeloma, building on cutting-edge CAR technologies including virus-free Sleeping Beauty 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.

Work performed

Since the project initiation in January 2018, the CARAMBA investigators have made rapid progress in preparing the clinical trial. A first critical step was to establish manufacturing of SLAMF7 CAR T cells in clinical grade quality. In order to obtain this quality grade, manufacturing is done in the clean-room facility of partner DRK-BSD in Frankfurt, Germany. The CARAMBA investigators were successful in transferring the manufacturing process to this facility. And in validation runs they demonstrated their ability to produce SLAMF7 CAR T in clinical grade quality.
The CARAMBA investigators have also submitted the comprehensive documentation packages required by European and national regulators to approve manufacturing and the clinical trial protocol, as well as the conduct of the clinical trial by the competent ethics committees at the clinical trial sites in WÃ¼rzburg (Germany), Milano (Italy), Pamplona (Spain) and Lille (France). Notably however, once the clinical trial is open, citizens from all EU-countries will be able to contact these trial sites and inquire whether they are eligible for enrolment onto this trial. To engage with myeloma patients as the key stakeholders in SLAMF7 CAR T was important from the very beginning of this project. Thus, partner MPE, the largest patient advocacy group in Europe and a full consortium partner has been involved in all steps of the CARAMBA project. The contributions of MPE make sure that patientsâ€™ perspectives and concerns were addressed at all development stages of SLAMF7 CAR-T, e.g. to the design of the clinical trial, patient information and informed consent material, but also the continuous education of myeloma patients, their families and caregivers on the new and exciting treatment opportunity with CAR T cell immunotherapy.
The CARAMBA investigators are hopeful that the first patients will be treated with SLAMF7 CAR T in 2020 and anticipate that the clinical experience, indicating safe and effective treatment, will be confirmed.
At the same time, the CARAMBA investigators were spending a significant effort on continuing the â€˜revolutionâ€™ and innovation in CAR T cell immunotherapy. They were pursuing a dedicated work package to develop even more refined virus-free Sleeping Beauty gene transfer reagents, even more refined CAR T cell products that target novel and combinations of myeloma antigens, and even more refined cell product compositions to further enhance the therapeutic index. At the same time, the CARAMBA investigators are looking ahead into the future of SLAMF7 CAR-T cells and partner T-CURX is preparing strategies for the development of this cell product to clinical approval and market authorisation. Part of the progress that has been made in this work package is a survey and assessment on the medical field, and global market in CAR T cell therapy to treat multiple myeloma.
In conclusion, this first part of the grant period has been very productive for the CARAMBA project. For the first time in Europe, a virus-free CAR T cell manufacturing process has been established and validated in a clean-room facility, and applications for clinical trial authorisation have been submitted to launch this first-in-man clinical trial. The consortium is actively engaging with myeloma patients, their families and caregivers as well as with the medical and scientific community and with regulators to harmonise and facilitate the approval process for CAR T, and with biotech and big-pharma to foster avenues to market approval.

Final results

There is preliminary experience with CAR T cells targeting the BCMA antigen in multiple myeloma. However, even though BCMA CAR T cells induce high rates of initial responses, their longevity and the overall outcome are considered â€˜encouraginglyâ€™ disappointing. The CARAMBA investigators demonstrate in their comprehensive pre-clinical data set, that targeting SLAMF7 may overcome several challenges inherent to BCMA. The preclinical data obtained by the CARAMBA investigators suggest they will observe superior anti-myeloma efficacy in comparison to BCMA CAR T cells. Therefore, the SLAMF7 CAR T products is anticipated to have a significant and transformative impact on multiple myeloma treatment.
Notably, SLAMF7 CAR T will be the first CAR T cell product in Europe that is produced with virus-free Sleeping Beauty gene-transfer technology, and will be the first worldwide to use mRNA and minicircle DNA reagents to accomplish this virus-free gene transfer. This is a critical technological innovation that makes this cell product distinct from all conventional CAR T cell products. The impact of using virus-free SB gene transfer is that the SLAMF7 CAR T has a superior safety profile, can be produced in an easier and more cost-effective way, and will be more accessible compared to conventional CAR T products that are made with viral vectors.
Novel anti-myeloma drugs, such as SLAMF7 CAR T cells, have significant market potential, and the opportunity to move into early lines (or even first line) of therapy. Thus, once the clinical development of SLAMF7 CAR T has been completed, this cell product has a realistic and positive socioeconomic perspective. In particular, to become the first CAR T product in multiple myeloma that has been conceived, developed and brought to market in Europe.
To implement CAR T therapy into translational research and routine clinical medicine, efficient regulatory processes will be required in Europe. All CARAMBA partners are highly engaged to continuously contribute to the improvement of regulatory processes. Especially since the consortiumâ€™s experience has highlighted the urgent need to facilitate and harmonise the approval process for Advanced Therapy Medicinal Products in Europe. CARAMBA will continue its effort as this will be critical for this and future generations of CAR T products.