Systematic Review on CAR-T Cell Clinical Trials Up to 2022: Academic Center Input

Abstract

The development of Chimeric Antigen Receptor T cells therapy initiated by the United States and China is still currently led by these two countries with a high number of clinical trials, with Europe lagging in launching its first trials. In this systematic review, we wanted to establish an overview of the production of CAR-T cells in clinical trials around the world, and to understand the causes of this delay in Europe. We particularly focused on the academic centers that are at the heart of research and development of this therapy. We counted 1087 CAR-T cells clinical trials on ClinicalTrials.gov (Research registry ID: reviewregistry1542) on the date of 25 January 2023. We performed a global analysis, before analyzing the 58 European trials, 34 of which sponsored by academic centers. Collaboration between an academic and an industrial player seems to be necessary for the successful development and application for marketing authorization of a CAR-T cell, and this collaboration is still cruelly lacking in European trials, unlike in the leading countries. Europe, still far behind the two leading countries, is trying to establish measures to lighten the regulations surrounding ATMPs and to encourage, through the addition of fundings, clinical trials involving these treatments.

Keywords: Chimeric Antigen Receptor T cell; academic center; clinical trial; regulation.

Figure 1

Generalities on CAR-T cell development and their industrial and hospital management. (A) The way to marketing authorization of the different available CAR-T cells: academic discoveries led either (i) to start-up creation (Juno Therapeutics, Celgene, Kite pharma) to allow the development of clinical trials, before getting acquired by pharmaceutical companies or (ii) to the licensing to a pharmaceutical company. CAR: Chimeric Antigen Receptor; DLBCL: Diffuse Large B-Cell Lymphoma; EMA: European Medicines agency; FDA: Food and Drug Administration; NIC: National Cancer Institute; NIH: National Institutes of Health; r/r: relapsed refractory [2,10,11] (B) The logistic to allow the production of autologous CAR-T cells by pharmaceutical companies. Unlike other medicinal products, the raw material is specific to each CAR-T cell production. This required the participation of academic centers on crucial step such as collection of the leukapheresis or preservation of the ATMP and thawing before infusion into the patient. Different steps are not under the pharmaceutical company control, unless an audit validates the compliance with the company procedures.

Figure 2

Distribution of CAR-T cell clinical trials in the world in 2022. (A) Geographical distribution: The United States and China dominate in number of studies, with 377 (34.7%) and 636 (58.5%) studies, respectively. North America is also represented by Canada (3 studies). Apart from China, the Asian countries have 9 studies (0.8%) with Japan (4), South Korea (4), Malaysia (1) and Iran (1). Europe has 58 studies (5.3%): UK (17), Germany (9), Italy (6), Belgium (4), Spain (4), Sweden (3), Israel (3), Switzerland (2), Czech Republic (2), Russia (2), France (2), Lithuania (1), Netherlands (1), Austria (1), and Finland (1). Mapchart.net. (B) Status distribution: 117 studies have not started the recruitment (10.8%), 583 are currently recruiting patients (53.6%), 110 are active (10.1%), 51 have been completed (4.7%), 56 have been discontinued (5.2%), and 170 have unknown status (15.6%). (C) Study phases: 665 studies are in phase I (61.2%), 278 in phase I/II (25.6%), 73 in phase II (6.7%), 6 in phase II/III (0.6%), and 7 in phase III (0.6%). One study is in phase IV (0.1%) and 57 studies did not mention the information (5.2%). NS = not specified. (D) Distribution of clinical trials according to investigators and collaborators: out of 1087 clinical trials, 385 are mentioned only with an academic institution (35.4%), 258 are carried out only by a pharmaceutical industry (23.7%), 369 are carried out by an academic center in collaboration with an industrial company (33.9%), 62 are carried out by an academic center in collaboration with a governmental institution such as the NIH (5.7%), and finally 13 of the trials are carried out by a collaboration between these three actors (1.2%). (E) Distribution of clinical trials according to investigators and collaborators: number of academic clinical trials or in collaboration with an industry or in collaboration with a governmental institution according to the phases. The trials led by the three actors at the same time were added to the industrial collaboration group.

Figure 3

Comparison of European CAR-T cell clinical trials compared with international trials. (A) Status distribution: 6 studies have not started the recruitment, 34 are currently recruiting patients, 9 are active, 7 have been completed, and 4 have been discontinued. (B) Study phases: 24 studies are in phase I, 23 in phase I/II, 9 in phase II, 1 in phase II/III, and 1 study in phase III. (C) Distribution of clinical trials according to investigators and collaborators: out of 58 clinical trials: 34 are carried out by an academic center, 21 are carried out by a pharmaceutical industry, and 3 are carried out by an academic center in collaboration with an pharmaceutical company. (D) Distribution of conditions: hematological malignancies were studied in 45 European studies and solid tumors in 12 European studies. If we compare with international trials outside Europe, we can see that hematological malignancies were studied in 853 studies and solid tumors in 473 studies. In this graph, studies can target multiple conditions, which explains the greater number of conditions investigated compared to the number of studies. NS = not specified.

Figure 4

Conditions and targets studied in international and European CAR-T cells clinical trials. (A) Focus on hematologic malignancies: 21 European studies focus on lymphomas all combined, 15 studies on lymphoblastic leukemia, 8 studies on multiple myeloma and 5 studies on acute myeloid. BPDCN: Blastic plasmacytoid dendritic cell neoplasm. (B) Focus on solid tumors: 3 European studies focus on colorectal cancer, 2 studies on each glioblastoma and neuroblastoma and one study focuses on prostate cancer, malignant pleural mesothelium, melanoma and head and neck cancers. (C) Focus on targets investigated in hematologic malignancies: 28 European studies focus on CD19 targeting, 4 studies on BCMA and the following are investigated in 2 studies: CD123, CD20, CD30, dual targeting of CD19 combined with CD22 and CD19 combined with CD20. Finally, one study is investigating NKG2D, SLAMF7, TRBC1 and CD44V6 alone and the dual targeting of BCMA and TACI. These targets were studied in 45 European studies of 1087 international studies of hematological malignancies. BAFF: B-cell activating factor; BCMA: B-cell maturation antigen; CD: Cluster of differenciation; CLL-1: C-type lectin-like molecule-1; FLT3: FMS-like tyrosine kinase 3; GPRC5D: G protein–coupled receptor, class C, group 5, member D; Ig: Immunoglobulin; NKG2D: Natural Killer Group 2 membrane D; SLAMF7: Signaling Lymphocytic Activation Molecule Family Member 7; TACI: Transmembrane activator and Calcium modulating ligand interactor; TRBC1: T-cell Receptor Constant β Chain-1. (D) Focus on targets investigated in solid tumors: 4 European studies are investigating NKG2D and GD2, and the following targets are investigated in 1 study: CLDN6/Claudin18.2, PSMA, FAP and T4. These targets were studied in 12 European studies of 221 international solid tumor studies. B7-H3: B7 homolog 3 protein; BT-001: not specified; CD: Cluster of Differenciation; CEA: Carcinoembryonic Antigen; EGFR: Epidermal Growth Factor Receptor; FAP: Fibroblast Activation Protein Alpha; GD2: Disialoganglioside; GPC3: Glypican-3; GUCY2C: Guanylate Cyclase 2C; HER-2: Human Epidermal Growth Factor Receptor-2; MUC-1: Mucin 1; MMP-2: Matrix Metalloproteinase-2; NKG2D: Natural Killer Group 2 membrane D; PSMA: Prostate-Specific Membrane Antigen; ROR-1: Receptor Tyrosine Kinase Like Orphan Receptor 1; T4: Thyroxin 4; TAG72: Tumor-associated glycoprotein 72.