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Successes and challenges of leukaemia treatment using CAR-T cells – where are we now?

Treatment of leukaemia and lymphomas using genetically modified immune cells of the patient (CAR-T cells) has produced impressive results in clinical trials, especially for the treatment of B-cell malignancies. However, serious adverse events were reported as well, partly with fatal outcome. A detailed summary of previously published results and a discussion of the reasons why less than ten percent of the clinical trials are conducted in Europe have been published by researchers under the supervision of the Paul-Ehrlich-Insitute in EMBO Molecular Medicine (Online Early View, 01 August 2017; DOI: 10.15252/emmm.201607485).

10 / 2017

For many decades, cancer therapy consisted of surgery, chemotherapy and radiotherapy as well as blood stem cell transplantations. A novel and very promising therapy concept is the stimulation of the patient’s immune system. This stimulation enables the immune system to recognise and kill cancer cells. In this so-called adoptive immunotherapy, particular immune cells (T cells) are removed from the patient and are genetically modified to express a cancer cell specific antigen receptor on their surface. These CAR-T cells are then reinfused into the patient. Upon recognition of a specific surface antigen on the cancer cell, the CAR-T cell gets stimulated, starts to replicate and subsequently kills the cancer cell.

CAR-T cells are a very complex medicinal product. Consisting of patient's own body cells, the product can replicate and persist in the patient over longer periods – up to several years. Thus, translation of these new therapies from pre-clinical development to the application in humans is particularly challenging for the pharmaceutical industry, academia, as well as regulatory authorities.

Experts of the Paul-Ehrlich-Institut under the supervision of Professor Christian Buchholz, project leader of the Horizon2020-funded EU-research project 'CARAT', have analysed all data available from clinical trials with CAR-T cells world-wide, which are either still ongoing or already completed. This work was supported by the CARAT consortium. The aim of the analysis, among other things, was to identify essential obstacles for clinical development of this new group of active substances. On the basis of this analysis, the researchers developed suggestions about how the process of translation, i.e. the process from research to clinical use of CAR-T cells could be pushed ahead, especially in Europe.

The first CAR-T-cell study was initiated around 20 years ago. At that time, CAR-T cell clinical studies showed little therapeutic benefit. After major progress was made demonstrating clear evidence of efficacy, 220 clinical trials with CAR-T cells, both for the treatment of malignant haematological disorders (disorders concerning the blood formation) and solid tumours were documented at the end of 2016, of which 188 were ongoing.

At the current state of development, CAR-T cell therapy seems to be particularly effective in the treatment of malignant CD19-positive B-cell disorders. This type of cancer disease is caused by malignantly altered blood cells (B-lymphocytes) carrying the CD19 surface antigen. Despite the partly unexpectedly high – therapeutic efficacy, there is the risk of serious adverse effects. Especially cytokine storms can be life-threatening, due to the release of high amounts of cytokines by the activated immune cells. Another possible serious adverse reaction is neurotoxicity, a usually transient impairment of the brain and its functions.

Three CAR-T cell products from three pharmaceutical companies are currently undergoing the European PRIME procedure. This accelerated centralised marketing authorisation procedure is an option for medicines which were developed for diseases with no or only limited treatment options available. The first granting of a marketing authorisation for CD19-specific CAR-T cell could follow as early as this year.

A substantial part of clinical trials which investigate new groups of medicines are usually conducted in Europe, however this is not the case for CAR-T cells. Less than ten percent of all CAR-T cell clinical trials are performed in Europe. A significant problem in Europe might be an inadequate infrastructure that is required to combine basic research, production sites in which genetically modified cells are manufactured according to 'Good Manufacturing Practice' (GMP), and clinicians with access to patients within the scope of a clinical trial. "With the use of personalised medicinal products based on genetically modified cells for the treatment of cancer, the pharmaceutical industry is mainly entering new territory. To develop and further improve such innovative therapy approaches interconnection of academic researchers, clinicians and the pharmaceutical industry as well as intensive advice by regulatory experts from the Paul-Ehrlich-Institut is mandatory", claims Professor Klaus Cichutek, president of the Paul-Ehrlich-Institut.

Schematic representation of the CAR-T cell therapy process Schematic representation of the CAR-T cell therapy process. In the first step, T cells are isolated from blood of the patient. After activation, the cells are genetically modified to express the cancer cell specific antigen receptor, the so called CAR (chimeric antigen receptor). The CAR-T cells undergo an ex vivo expansion step, before they are formulated into the final product. In the end, the CAR-T cell product is infused into the patient with or without prior conditional chemotherapy.Schematic representation of the CAR-T cell therapy process: In the first step, T cells are isolated from blood of the patient. After activation, the cells are genetically modified to express the cancer cell specific antigen receptor, the so called CAR (chimeric antigen receptor). The CAR-T cells undergo an ex vivo expansion step, before they are formulated into the final product. In the end, the CAR-T cell product is infused into the patient with or without prior conditional chemotherapy. Source: EMBO Molecular Medicine

Original Publication

Hartmann J, Schüßler-Lenz M, Bondanza A, Buchholz CJ (2017): Clinical development of CAR-T cells – challenges and opportunities in translating innovative treatment concepts.
EMBO Mol Med 9: 1183-1197.
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The Paul-Ehrlich-Institut, the Federal Institute for Vaccines and Biomedicines, in Langen near Frankfurt/Main is a senior federal authority reporting to the Federal Ministry of Health (Bundesministerium für Gesundheit, BMG). It is responsible for the research, assessment, and marketing authorisation of biomedicines for human use and immunological veterinary medicinal products. Its remit also includes the authorisation of clinical trials and pharmacovigilance, i.e. recording and evaluation of potential adverse effects.

Other duties of the institute include official batch control, scientific advice and inspections. In-house experimental research in the field of biomedicines and life science form an indispensable basis for the manifold tasks performed at the institute.

The Paul-Ehrlich-Institut, with its roughly 800 members of staff, also has advisory functions nationally (federal government, federal states (Länder)), and internationally (World Health Organisation, European Medicines Agency, European Commission, Council of Europe etc.).

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