3. PEI-DKTK-Workshop – focus on innovative cancer therapies

Genetically modified CAR ("chimeric antigen receptor") and TCR ("T-cell receptor") T-cells rank among the most promising tumour therapies and are currently also in the clinical trial stage in Germany. In some clinical trials, they showed a partly very good efficacy profile in patients with varying cancer diseases, while other therapies had failed in these patients. In some cases, these therapies even led to complete remission and the absence of visible tumour signs [1]. However, these treatments partly involve serious adverse reactions.

The medicinal products are a combination of cell therapy and gene therapy (see background) and are highly complex. Accordingly, we have to face major challenges involved in the manufacture of the investigational products, their non-clinical testing in animal models, and the transfer of the research results to clinical trials in humans. About ten times as many clinical trials are currently underway in the USA than in Europe. With its innovation office, the Paul-Ehrlich-Institut (PEI) which is responsible for the authorisation of clinical trials with such biomedicines provides early scientific advice for developers of medicinal product to encourage them to introduce potentially effective products rapidly into clinical testing. Besides, the PEI is a strategic partner of the DKTK (Deutsches Konsortium für Translationale Krebsforschung, German Cancer Consortium). The aim of the DKTK – together with the Deutsches Krebsforschungs­zentrum (German Cancer Research Center) at Heidelberg and seven other partner locations – is to concentrate the efforts in cancer research and, with the help of the cancer therapy centres in Germany as partners, to assure that new developments rapidly reach the stage of clinical use and thus the patient. "For doctors and scientists of the DKTK, the Paul-Ehrlich-Institut with its expertise is an important partner in translating promising immune therapies faster into clinical practice. A rapid development of innovative methods of treatment can only be successful if scientists and regulators intensively collaborate with each other", as PD Dr Dirk Nettelbeck, scientific co-ordinator of the DKTK, explains.

On 2 February 2016, it was already the third time within one year that experts met at the Paul-Ehrlich-Institut within the framework of a PEI-DKTK Workshop to discuss current scientific and regulatory aspects important for the transfer of research results to clinical testing in humans (translation). Dr Martina Schüßler-Lenz, Section Advanced Therapy Medicinal Products, Tissue Preparations at the Paul-Ehrlich-Institut and co-organiser of the work shop explains: "We are very pleased that representatives of the authorities of the länder also made an active contribution to this workshop. The authorities of the länder are, among other things responsible for granting manufacturing authorisations for these advanced therapy medicinal products, and, if our dialogue also includes these authorities, we can prevent pitfalls from occurring". This time, the focus of discussion was on CAR/TCR T-cells as innovative therapeutics. "In first clinical trials, these new therapies have already proved to be very successful. What is important is to develop these active substances further, and to examine in clinical trials which patients can benefit from them. For this purpose, it is absolutely required to improve the framework conditions in Germany, since clinical studies can often not be performed due to a shortage of financial means", emphasises, Professor Klaus Cichutek, president of the Paul-Ehrlich-Institut.

Participants of the Workshop in the lecture theatre of the Paul-Ehrlich-Institut Source: PEI

Background

Adoptive immune therapy with CAR and TCR T- cells

Cancer cells are often invisible to the immune system, and for this reason, can proliferate in an unhampered manner. Methods are therefore being developed which are designed to modify immune cells in such a way that they can target and kill the cancer cells without damaging the patient’s own body cells. CAR and TCR T-cells represent such modified cells. Specific immune cells (T-cells) are extracted from the cancer patient, which are then equipped with a tumour specific T-cell receptor (CAR/TCR T-cells) or a chimeric antigen receptor (CAR) in the lab using genetic engineering methods, and are then reinfused into the patients. The CAR molecule consists of three components: an extracellular antigen-binding antibody fragment which detects the selected target structure on the tumour cell; a transmembrane component which anchors the CAR in the membrane of the T-cell, and an intracellular component which forwards the antigen connection as activating signal into the interior of the T-cell. The cells thus modified are then administered to the patient with the aim of targeted killing of the cancer cells. Other immune cells, too, such as natural killer cells (NK) can be equipped with CAR (see figure).

Photo taken under a fluorescence microscope of an attack of a CAR expressing NK (natural killer) cell on a tumour cell. Source: Professor Winfried Wels, GSH Frankfurt

After the genetically modified T-cells have been infused, they replicate in the body of the cancer patient, attack the tumour cells and destroy them. In this process, adverse reactions of varying degrees occur, which frequently necessitate temporary medical care of the patient in an intensive care unit. Causes for this include a massive release of the patient’s own cytokines caused by the T-cell attacks (cytokine storm, cytokine-release syndrome) and the activation of certain immune cells (macrophages, macrophage activation syndrome), which lead to high fever and life-threatening organ damage. Another possible adverse effect is the tumour lysis syndrome which involves a massive release of the cell contents due to the decay of the tumour cells thus attacked. Besides, so-called off-tumour/on-target effects can occur if the tumour antigen is not only expressed on tumour cells but also on healthy cells.

These new therapeutics are classified as gene and cell therapies from the regulatory point of view, and, from a legal one, are summarised in Regulation (EC) No 1394/2007 relating to advanced therapy medicinal products.

DKTK – Deutsches Konsortium für Translationale Krebsforschung (German Consortium for Translational Cancer Research)

The Deutsches Konsortium für Translationale Krebsforschung (DKTK) is a joint long-term initiative of the Bundesministeriums für Bildung und Forschung (BMBF, Federal Ministry for Education and Research), the participating länder, the Deutsche Krebshilfe (German Cancer Help), and the Deutsches Krebsforschungszentrums (DKFZ, German Cancer Research Center) and was founded as one of the six German Centres of Health Research (Deutsche Zentren der Gesundheitsforschung, DZG). Research institutions and hospitals at the locations of Berlin, Dresden, Essen/Düsseldorf, Frankfurt/Mainz, Freiburg, Heidelberg, Munich, and Tübingen collaborate with the DKFZ to create optimum conditions for cancer research that meets the needs of hospitals. The consortium furthers interdisciplinary research at the interface between basic research and the hospitals as well as clinical studies for innovative therapies and diagnostic methods. Another focus is on the establishment of research platforms to speed up the use of personalised cancer therapies and to improve the diagnosis and prevention of cancer diseases.

For more information, please visit this website: http://www.dkfz.de/de/dktk

3rd PEI-DKTK Workshop
Regulatory issues relating to the development and clinical application of CAR- and TCR gene-modified ATMPs
2 February 2016, Paul-Ehrlich-Institut, Langen

Source:
[1] Rosenberg SA et al.: Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015 Apr 3;348(6230):62-8

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