Table 3.

ATMPs with a valid central European marketing authorisation by August 2018.

Holoclar®	Holoclar® was the first stem cell based ATMP approved by the European Union. The product is based on ex vivo expanded autologous human corneal epithelial cells [10]. The cells are isolated from a limbus tissue biopsy, expanded in vitro and cryopreserved for alignment with the patient´s medical care. After thawing, the cells are seeded onto a fibrin matrix for transplantation [11].
Imlygic®	Imlygic®was the first oncologic gene therapy reaching EMA approval. The product is based on a genetically modified oncolytic virus replicating within the tumoral tissue to produce granulocyte-macrophage colony stimulating factor (GM-CSF). Intratumoral application leads to tumor cell lysis and the release of tumor-derived antigens, which – in combination with GM-CFS – amplify the body´s anti-tumoral immune response [12].
Strimvelis®	Strimvelis® is designed to treat severe combined immunodeficiency (SCID) due to Adenosin desaminase deficiency (ADA-SCID) in patients who cannot be treated with a bone marrow transplant due to lack of a suitable donor [13]. The product is based on autologous CD 34+ cells transduced with a retroviral vector encoding for the human ADA cDNA sequence [10].
Zalmoxis®	Zalmoxis® is a patient specific immunogenic therapy serving as adjunctive treatment in haplo-identical haematopoietic stem cell transplantation in patients with leukaemia and high-risk haematological malignancies [14]. Data from 45 patients treated with Zalmoxis showed a survival rate of 49% after one year. Survival in the control group was 37% [15].
Spherox®	Spherox® are spheroids of human autologous matrix-associated chondrocytes for treatment of cartilage defects in the knee joint [16]. Data of 30 patients after an average follow-up of 3 years demonstrate a significant increase in quality of life, pain reduction and an improvement of joint function [17].
Alofisel®	Alofisel® consists of adipose tissue derived allogeneic mesenchymal stem cells for injection into the perianal fistula tract in Cohn’s disease [18]. Local application of Alofisel® in conjunction with surgical preparation of the fistula tract has been shown to induce and maintain fistula closure, but a high placebo effect due to background therapies was noted in the phase III clinical trial [19].
Kymriah®	Kymriah® (CTL019/tisagenlecleucel) is intended for children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia and for adult patients with diffuse large B-cell lymphoma who are ineligible for stem cell transplantation. In paediatric patients, an overall remission rate of 81% was achieved in the ELIANA trial [20]. Adult patients with diffuse large B-cell lymphoma achieved an overall response rate of 52% [21]. Treatment related adverse events occurred in 95% of the patients, mostly as cytokine release syndrome.
Yescarta®	Yescarta® (axicabtagene ciloleucel) is a chimeric antigen receptor T-cell therapy to treat aggressive non-Hodgkin´s lymphomas. In patients with large B-cell lymphoma, primary mediastinal B-cell lymphoma and transformed follicular lymphoma, the overall response rate was 71%. Complete remission was achieved in 57% (5/7) of the patients [22]. Adverse events include anaemia, neutropenia and decreased white blood cell count. Grade III or higher cytokine release syndrome is observed in 13% and neurologic events in 28% of the patients [23]. 71% of the patients treated for relapsed or refractory B-precursor acute lymphoblastic leukaemia (ALL) responded to the treatment either as complete response or complete response with incomplete hematologic recovery [24]. However, one patient experienced a fatal cytokine release syndrome [25].