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Report of the CTIWP Workshop on “European Academic CAR-T Cells and IECs Clinical Trials”

Cellular Therapy & Immunobiology Working Party (CTIWP)

June 4, 2021 - Organized by the EBMT Cellular Therapy & Immunobiology Working Party (CTIWP), together with the GoCART Coalition and in partnership with the T2EVOLVE consortium.

Álvaro Urbano-Ispizua, Christian Chabannon, Jürgen Kuball, Annalisa Ruggeri

The efficacy of chimeric antigen receptor T cells (CARTs) in B cell neoplasms has been one of the great achievements in the fight against cancer during the last decades (CAR-T cells: the narrow path between hope and bankruptcy?). However, there is still a need to increase the proportion of responses and to decrease the proportion of relapses after CART therapy. More importantly, the excellent results with CARTs in B cell neoplasms have not been reproduced so far for T cell neoplasms, myeloid leukemias, and solid tumors. As a reflection of the necessary research efforts to expand the efficacy of the CARTs, more than 500 clinical trials are currently underway in the world, mostly led by American or Chinese groups. European institutions have been and unfortunately remain under-represented in the field of CART development.

To better understand how EU centers address these challenges and what are the similarities and differences with the situation in China and in the USA, we convened a one-day event with representatives of academic European groups working in the field. The event was organized by the EBMT Cellular Therapy & Immunobiology Working Party, in collaboration with the GoCART coalition and with the partnership of the T2EVOLVE consortium.

The workshop was divided in two parts:

The first part included a string of presentations that aimed at identifying common difficulties, uncertainties, and successes when running academic clinical trials, also encouraging participation and inclusion of patients from other European groups.

The second part of the symposium consisted in two round tables, which focused on such aspects as sustainability, regulatory issues, synergies and political lobbying. The global aim of the workshop was to foster and coordinate European academic initiatives in the CART field.

On a positive note, we identified more (n=36) clinical trials promoted by European groups than we anticipated. Of them, 20 are initiatives from academic institutions and 16 emanate from European companies allied with European academic institutions. Twelve European institutions are responsible for 20 academic clinical trials (University College London, n=4; Hospital Clinic of Barcelona, n=3; Great Ormond, n=2; Bambino Gesù, n=2; University of Uppsala, n=2; King’s College, n=1; University of Monza, n=1; Hospital Sant Pau, n=1; University of Heidelberg, n=1; and University of Wurzburg, n=1). Although this sample may not be fully representative of ongoing activities, it is noticeable that some EU countries such as France Austria, Belgium, Sweden, Poland and others were not represented during these presentations. The most frequent target by far, is CD19 (n=12; for ALL, n=5; NHL, n=1; all B-lymphoid neoplasms, n=6), which is also the main tumor antigen targeted by approved and commercially available CART. Other targets are: BCMA (n=1; MM), CD30 (n=1; HL and T-NHL), SLAMF7 (n=1; MM), GD2 (n=2, neuroblastoma), ErbBR (n=1, neck and head tumors), Fap (n=1, mesothelioma), and IL-1 RAP (n=1, CML). Of the 20 clinical trials, 8 included only adults, 5 only pediatrics, and 7 all ages. There are 16 additional clinical trials promoted by seven European pharma companies (Autolous, n=6; Miltenyi, n=3; Servier, n=2; MolMed, n=1; Celyad, n=1; Cellectis, n=1; TcBiopharm, n=1, BioNTech, n=1). The most frequent target is again CD19 (n=4; for ALL, n=2; NHL, n=1; all B-lymphoid neoplasms, n=1). Other targets are: Dual CD19/CD20 or CD19/CD22 (n=3; ALL, n=1; NHL, n=2), CD20 (n=2; Melanoma, Lymphoma), BCMA (n=1; MM), CD123 (n=1; AML), CD33 (n=1, AML), NKG2D (n=1, colon cancer), CD44v6 (n=1, MM), TRCDB1 (n=1, T-NHL), and CLDN6 (n=1; colon cancer).

At the workshop, detailed information, such as the characteristics of genetic construct (type of co-stimulatory molecule, 2nd, or third generation CAR), the vector (viral vs non-viral), the method of expansion (automated, manual), and plans of these groups to provide access to their CART beyond the conduct of clinical trials (i.e. applying for small to middle-scale manufacturing in the context of the hospital exemption or applying for marketing approval using the centralized procedure overseen by EMA authorization) were presented. In summary, the first part of the workshop illustrated that there are several academic European institutions with the strategy and resource (skills, knowledge, and infrastructure) to develop their own genetic constructs and CARTs, and that able to bring these technologies to the point where they are in a position to conduct a clinical trial. A few of them are collaborating with small to medium size companies to pursue their projects.

During the second part of the symposium, the technical difficulties encountered when working towards the initiation of a CART clinical trial, the stringency and variability of regulatory requirements across European countries, departments and districts within in one country, ways to apply to the EMA for central authorization, and the opportunities to lobby at EMA and at the European commission so that the voice of the academic community can be heard, were all discussed.

In summary, European centers are increasingly active in developing CARTs, and our goal is to provide some guidance and help other institutions start similar activities. Exchanges during the workshop confirmed that regulatory hurdles slowed down many initiatives to start a clinical trial in this field, especially in some countries. They also find it very unrealistic to attempt decentralized approval of an academic CART by the EMA for further distribution in Europe, without the support of a private partner. This could lead to a commercial development post authorization with costs like current commercial CARTs, again making it difficult for low-income countries to access these revolutionary treatments. Some initiatives to foster academic European CART development initiatives would be to work in establishing a limited number of centralized clean room facilities for preparing vectors from different centers, dissemination of production of the CART at PoC, and to lobby with EMA and the EC for the implementation of simplified procedures for approval, and create awareness within the European commission in order assist by simplifying directives which regulate ATMP productions.

We are convinced that patient access can be improved by such public/academic cooperation. European centers should work as just one group to face this challenge. EBMT, EHA, GoCART, ant T2 EVOLVE are excellent forums for designing a joint strategy.