Bench-to-Bedside ATMP Development Platform
Good Manufacturing Practice (GMP) Good Clinical Practice (GCP)
Within the CRC/TRR, several gene-engineered T cell products (advanced therapy medicinal products, ATMPs in ‘regulatory’ terminology) are being developed. The ambition is to advance some of them into first-in-human (FIH) clinical trials within the CRC/TRR lifetime, even though funding for such clinical trials will have to procured from other funding schemes. Project Z02 serves as a gateway infrastructure and service project to enable and facilitate the clinical translation of selected ATMPs from the CRC/TRR portfolio.
The conduct of a FIH clinical trial with ATMPs in Germany, according to the applicable law, requires:
i. a manufacturing license to produce the cell product in an accredited GMP clean room facility (issued by the local state authorities, i.e. in Munich and Würzburg, respectively);
ii. a clinical trial authorization to treat patients at an approved clinical trial site (issued by the Federal Agency for Biomedicines and Vaccines, the Paul-Ehrlich-Institute, PEI);
iii. an ethics approval for the clinical trial (issued by the Institutional Review Board, IRB at the respective clinical trial site).
Accordingly, the PIs of this project Z02 have been selected based on their distinguished expertise in clinical trial design and conduct in cellular therapy (Einsele), regulatory affairs and GMP manufacturing (Hildebrandt / Priesner), and ethical aspects in personalized medicine (Marckmann).
Several CRC/TRR projects are developing innovative cell products that involve CRISPR/Cas9 gene-engineering, including orthotopic T cell receptor replacement (OTR) and genome-editing to enhance the safety and efficacy of TCR-transgenic and CAR-T cell products. The ambition in project Z02 is to pave the way for a first manufacturing license for a T cell product that involves CRISPR/Cas9-based gene-engineering in Germany. As proof-of-concept ATMPs, we will develop CMV-specific T cells that were gene-engineered by OTR to treat refractory CMV infection (project A01, Busch) and FLT3-specific CAR-T cells for the treatment of acute myeloid leukemia (AML; project A02, Hudecek). Both projects use a ‘common trunk’ in the GMP manufacturing process to accomplish targeted insertion of TCR vs. CAR into the TCR locus. In the first CRC/TRR funding period, we aim to bring the process of CRISPR/Cas9 gene-engineering of T cells to GMP compliance, to be established as a common trunk at the two GMP facilities in Munich and Würzburg. As such, Project Z02 will provide a platform for the bench-to-bedside translation of ATMPs that can subsequently be exploited by other CRC/TRR projects.
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