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Report of the 2nd Cellular Therapy & Immunobiology Working Party Workshop

Cellular Therapy & Immunobiology Working Party (CTIWP)

14 January 2022 - Organized by the EBMT Cellular Therapy & Immunobiology Working Party (CTIWP), together with the GoCART Coalition and in partnership with the T2EVOLVE consortium.

Delgado J, Chabannon C, Kuball J, Ruggeri A, Hudecek M, Urbano-Ispizua A.

The emergence of chimeric antigen receptor T cells (CARTs) has revolutionized the treatment of B-cell neoplasms in the last few years. However, the high cost and complex infrastructure associated with this therapy reduces patient access across the EU. Novel point-of-care (POC) strategies, mostly developed in Academic Centers, could be beneficial for the wide dissemination of this very effective treatment.

In this workshop, the first session was devoted to vector production, currently considered one of the bottlenecks of these therapies. Several viral and non-viral strategies were discussed, considering their potential risk (e.g. genotoxicity) and cost. An important aspect of viral strategies is whether starting materials, mostly plasmid DNA and HEK293T cells, need to be good manufacturing practice (GMP)-graded or not, which clearly has an impact on its availability cost. All in all, the panel felt that there usually are long waiting times for the small batches of vectors needed for Academic-driven trials because manufacturers favor big-scale productions intended for Pharmaceutical Companies. Other non-viral strategies, such as Sleeping Beauty (transposons) and electroporation were discussed, which could also be feasible and cost-effective.

The second session was devoted to POC manufacturing of CARTs and tumor infiltrating lymphocytes (TILs). Two potential models were presented: (1) Academic non-profit POC manufacturing, with limited liability, based on extraordinary approvals; and (2) Commercial for profit model, based on a centralized authorization in well-defined cohorts of patients. The first model is patient-by-patient and non-industrial, and could be potentially approvable under the Hospital Exemption (HE) clause. However, it was also noted that the heterogeneous interpretation of the HE clause across the different EU member states could lead to inequality and restricted patient access to therapy.

The third session dealt with the different regulatory pathways for CARTs and other Advanced Therapies Medicinal Products (ATMPs). A representative from the European Medicines Agency (EMA) explained the different avenues for collaboration, including Innovation Task Forces, PRIority MEdicine (PRIME) designations and Scientific Advice, and how Academic Centers can benefit from the absence of fees. PRIME designation was particularly detailed because ATMPs such as CARTs and TILs constitute around 50% of all successful applications. These developments were also put in the context of the new revision of the Blood, Tissues and Cells (BTC) legislation, currently being drafted, and the EU grants potentially available to researchers in the field of ATMPs (e.g. Horizon Europe 2021-27, Innovative Health Initiative, etc). Finally, the session was closed by a member of the Spanish Medicines Agency who explained how the HE clause was applied to ARI-0001 cells, the first product ever approved through this pathway. In his opinion, the HE should be regarded as an intermediate step, closing the gap between initial development and centralized EMA approval, but not just in terms of collecting efficacy and safety data, but also in providing scientific advice and maintaining a close contact with the researchers.

In summary, EU Academic Centers are actively pursuing the development of their own CARTs and ATMPs, including POC initiatives. Exchanges during the workshop confirmed that some hurdles remain, particularly in terms of vector manufacturing, but there is hope that upcoming advances, both technological and regulatory, could be feasible and easily implemented in the near future. Regulators could also be open to these Academic initiatives provided that the same quality standards can be achieved.