Smart manufacturing for autologous cell therapies enabled by innovative biomonitoring technologies and advanced process control

Project Information

SMARTER

Grant agreement ID: 101071054

DOI

10.3030/101071054

Project closed

EC signature date 27 June 2022

Start date 1 September 2022

End date 28 February 2026

Funded under

• The European Innovation Council (EIC)

Total cost

€ 1 364 281,25

EU contribution

€ 1 364 281,25

Coordinated by

GOTTFRIED WILHELM LEIBNIZ UNIVERSITAET HANNOVER
Germany

Periodic Reporting for period 1 - SMARTER (Smart manufacturing for autologous cell therapies enabled by innovative biomonitoring technologiesand advanced process control)

Reporting period: 2022-09-01 to 2023-08-31

Summary of the context and overall objectives of the project

Autologous immunotherapies achieved impressive treatment results in patients with blood cancers. The next-generation personalised immunotherapies include tumour-infiltrating lymphocytes (TIL) to overcome the limitations of adaptive therapy in the treatment of solid tumours. The EU-funded SMARTER consortium aims to develop a first-in-class bioprocessing platform for personalised autologous cell therapies, implementing innovative analytical technologies and smart process control systems. The project exploits the discovery of novel T cell expansion process biomarkers and novel fluorescence spectroscopy sensors for parameter monitoring of TIL biomanufacturing process. The project objective is to build the prototype platform for follow-up development of the commercial scale bioreactor.
Autologous immunotherapies have revolutionised cancer treatment providing impressive survival benefits in patients with blood cancers. The next generation of personalised immunotherapies using tumour-infiltrating lymphocytes (TIL) aims to overcome efficacy limitations of CAR-T therapies in the treatment of solid tumours. Lack of effective, fast, adaptive, controllable, and scalable manufacturing process remains one of the critical bottlenecks for clinical adoption of such complex personalised cell therapies.
In the SMARTER project, Achilles Therapeutics UK Limited (ATX), a clinical-stage company developing autologous cell therapies, partners with the centre of excellence for Cell and Gene Therapy Catapult (CGTC) and academic experts in process biomarker discovery (Instituto de Investigacion Sanitaria La Fe (HULAFE)) and bioprocess sensor development (Leibniz Universitat Hannover (LUH)). The consortium aims to develop a first-in-class, smart bioprocessing manufacturing platform for personalised autologous cell therapies, implementing for the first time in-line process analytical technologies and smart process control systems. The project exploits breakthrough discoveries of novel T cell expansion process biomarkers and development of new fluorescence spectroscopy sensors for real-time monitoring of critical process parameters, to enable adaptive process control of the precision TIL biomanufacturing process. After the project, the prototype R&D platform will be ready for follow-up development of the commercial scale bioreactor in GMP environment.
The SMARTER platform will critically improve production efficiency, reduce overall costs-of-goods (COGS), shorten manufacturing cycle times (shorter vein-to-vein time), decrease batch failures and lead to more consistent and predictable cell therapy product quality. Finally, the innovations will enable clinical implementation of a potential breakthrough personalised adoptive cell therapy for hardest-to-treat solid tumours such as lung cancer and melanoma.

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

At the beginning of this project, the team at ATX developed a scale-down model for cNeT manufacture representative of their clinical manufacture process whilst retaining the advantages of scale-down models. The model was established and tested in-house to generate baseline data, allowing for technical transfer to CGTC and LUH. Moreover, the team at ATX generated and tested (and continues to generate and test) healthy donor T-cell and iDC banks for distribution to CGTC and LUH; supplying them with the materials to be able to run their experiments. Finally, the team at ATX generated a myriad of cell culture medium sample types enabling elucidation of metabolomics relative to the cNeT process. Three batches of these samples have been sent to-date to HULAFE so that the lines of communication and paperwork needed for successful shipment have been well established and verified for future shipments.
Using HMcNeT samples generated by ATX, the HULAFE team performed an optimization of sample processing and analysis. The proposed strategy provided a good coverage of polar metabolites, including a wide variety of high abundant metabolites previously associated with T cell function. Finally, 132 samples, from one healthy donor and five patients, were analyzed. The intensities (and absolute concentrations whenever possible) of all detected metabolites were reported to ATX for biomarker selection and model development.
The team at CGTC carried out training and technology transfer sessions for process and analytics, followed by the successful completion of runs in CGTC laboratories.
The LUH team received a hands-on training at the ATX site followed by the process and analytics adaption in the LUH laboratories. Moreover, the LUH team tested multiple spectrometer and settings to enable the optimal data collection. Due to the small sample volumes, a miniaturized reference measurement was validated to be able to generate sufficient data for correlation. Furthermore, the team at LUH tested first prototypes of the sensor system. The material for the 3D-printing process was confirmed to be biocompatible and certified.
Finally, the CGTC team has begun to set up the IT infrastructure in preparation for an integration of PAT technologies and generation of an adaptive process control system.

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)

The SMARTER project will:
• Apply metabolomics to cell culture medium to identify novel analytical biomarkers which can be linked to cell quality during the process and can be monitored on-line.
• Identify novel biomarkers that could be used to optimise and control T cell manufacturing processes, potentially boosting industry-wide product efficacy, dose and consequently acceleration to commercialisation.
• Develop and integrate cutting-edge spectroscopic sensors into a CGT process and use them for bioprocess monitoring and control.
• Develop control strategies based on real-time information provided by Raman and 2D-fluorescence sensors and use this information to actively adapt processes to maintain an optimal culture environment and ensure the final quality of the cells.
• Pioneer the next wave of immunotherapy approaches by targeting the Achilles’ heel of all solid cancers – clonal neoantigens targeted by patient’s own TIL. This approach overcomes limitations of current CAR-T therapies.

The concept of SMARTER biomanufacturing platform showing breakthrough innovations and partners