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Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach

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Abstract

Adoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge about the intricate regulatory requirements of the academic developers as well as limitations of funds for clinical testing. A suitable good manufacturing practice (GMP) environment is a key prerequisite and platform for the development, validation, and manufacture of such cell-based therapies, but may also represent a bottleneck for clinical translation. The German Cancer Consortium (DKTK) and the Paul-Ehrlich-Institut (PEI) have initiated joint efforts of researchers and regulators to facilitate and advance early phase, academia-driven clinical trials. Starting with a workshop held in 2016, stakeholders from academia and regulatory authorities in Germany have entered into continuing discussions on a diversity of scientific, manufacturing, and regulatory aspects, as well as the benefits and risks of clinical application of CAR/TCR-based cell therapies. This review summarizes the current state of discussions of this cooperative approach providing a basis for further policy-making and suitable modification of processes.

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Abbreviations

ATMP:

Advanced therapy medicinal product

CARTOX:

CAR-T-Cell-associated toxicity

CREST:

chimeric antigen receptor (CAR)-T cell related encephalopathy syndrome

CRS:

cytokine release syndrome

DKFZ:

Deutsches Krebsforschungszentrum (German Cancer Research Center)

DKTK:

Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium)

DLI:

donor lymphocyte infusion

DZG:

Deutsche Zentren der Gesundheitsforschung

EGFR:

epidermal growth factor receptor

ErbB2, HER2/neu:

human epidermal growth factor receptor 2

GMO:

genetically modified organism

GMP:

good manufacturing practice

GTMP:

gene therapy medicinal product

HZDR:

Helmholtz Zentrum Dresden Rossendorf

IMP:

investigational medicinal product

NCT:

Nationales Centrum für Tumorerkrankungen

PEI:

Paul-Ehrlich-Institut

TUM:

Technische Universität München

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Correspondence to Angela M. Krackhardt.

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Krackhardt, A.M., Anliker, B., Hildebrandt, M. et al. Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies—the German Cancer Consortium approach. Cancer Immunol Immunother 67, 513–523 (2018). https://doi.org/10.1007/s00262-018-2119-y

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