Hannover Medical School, Germany, received the manufacturing license for Cytomegalovirus (CMV)-specific T cells in April 2014 (Tischer et al. 2014) and for Epstein Barr (EBV) and Adenovirus (ADV) specific T cells in January 2015, respectively. A third-party T cell donor bank (allogeneic cell registry, alloCELL) with well characterized donors with regard to their active antigen-specific T cells allows the rapid recruitment of a respective donor, collection and manufacturing of antigen-specific T cells and finally treatment of patients with severe infections after stem cell or organ transplantation. In order to move forward to automation of the manufacturing process of ATMPs a new fully-automated system (CliniMACS Prodigy; Miltenyi Biotech, Germany) was used for purification of antigen-specific T cells in parallel to well established technologies leading to first promising comparable results.

To date, clinical trials with chimeric antigen receptor (CAR) expressing T cells for the treatment of patients with cancer, especially B cell malignancies have successfully entered clinical trials. The challenge now remains to extend the promise of CAR retargeting beyond T cells and to several tumor malignancies. Based on long-standing experience in manufacturing of haploidentical donor Natural Killer (NK) cells for the treatment of high risk patients with leukemia and tumors, the interest in using redirected CAR NK cells for an improved cytotoxicity and specificity against cancer is growing as shown in pre-clinical data (Schoenfeld 2015) and first clinical studies as reviewed in (Glienke et al 2015). In the latter one new tools and technologies for GMP-grade manufacturing of CAR expressing NK cells as well as regulatory issues in Europe will be discussed.

Publications:
• Tischer S, Priesner C, Heuft HG, Goudeva L, Mende W, Barthold M, Klöß S, Arseniev L, Aleksandrova K, Maecker-Kolhoff B, Blasczyk R, Koehl U*, Eiz-Vesper B*. Rapid generation of clinical-grade antiviral T cells: Selection of suitable T-cell donors and GMP-compliant manufacturing of antiviral T cells. J Translational Medicine Dec 16;12(1):336. (2014). [* both authors contributed equally to this work].

Tischer-CMV-CTls-Transl-Med-2015 (1)

• Schönfeld K, Sahm C, Zhang C, Naundorf S, Brendel C, Odendahl M, Nowakowska P, Bönig H, Köhl U, Kloess S, Köhler S, Holtgreve-Grez H, Jauch A, Schmidt M, Schubert R, Kühlcke K, Seifried E, Klingemann HG, Rieger MA, Tonn T, Grez M, Wels WS. Selective Inhibition of Tumor Growth by Clonal NK Cells Expressing an ErbB2/HER2-Specific Chimeric Antigen Receptor. Mol Ther. 2015 Feb;23(2):330-8.

Schönfeld_2015_MolTher

• Glienke W, Esser R, Priesner C, Suerth J, Schambach A, Wels W, Grez M, Kloess S, Arseniev L, Koehl U. Advantages and Applications of CAR-Expressing Natural Killer Cells. Frontiers in Pharmacology 2015 in press (Review)

Glienke-CAR-NK-Frontiers-2015