**3. iPSC safety**

*Update on Mesenchymal and Induced Pluripotent Stem Cells*

After over a decade of research on iPSC, and due to fast-track facilitating procedure in Japan, several clinical studies were launched. While the first clinical trial based on the human ESC started in 2010, taking advantage of the acquired extensive knowledge of ESC biology, despite their relatively recent discovery, the first clinical study based on the iPSC-derived retinal pigmented epithelium was authorized and conducted at the RIKEN Institute in Japan in 2014 [2]. A sheet of autologous iPSC-derived retinal cells were transplanted in a patient with eye-related macular degeneration (AMD). In 2015, the RIKEN Institute decided to suspend the study due to safety concerns on the cells of the second recruited patient [3]. Nonetheless, regarding the first transplanted patient, a 25-month follow-up revealed neither serious events, nor clinical signs of rejection. Moreover, the macular degeneration progress was delayed in the treated eye compared to the untreated eye. This result corroborated all the results obtained previously in the course of the ESC-based clinical studies, where no adverse events related to transplanted cells were observed. Still this problem induced a shift in the approach from patient-specific autologous to highly securized allogeneic iPSC lines. This study was resumed in 2017 and until now five patients with AMD have been treated with

Since then, several clinical studies based on allogeneic iPSCs have been developed and approved. Until mid-2019, there have been nine ongoing clinical studies based on iPSC, mostly nationally approved in Japan, with four of them being approved in the first months of 2019, with indications including Parkinson's disease, AMD, severe cardiac failure, aplastic anemia, spinal cord injury and corneal stem cell deficiency. Furthermore, two private companies—Cynata Therapeutics, an Australian stem cell and regenerative medicine company, and Fate Therapeutics, an American clinical-stage biopharmaceutical company—have developed a line of products based on allogeneic human iPSC-derived cells. In Australia and United Kingdom, Cynata Therapeutics just concluded a phase I study using CYP-001, an iPSC-derived mesenchymoangioblast precursor administered intravenously in 15 patients with graft-versus-host disease (GVHD) occurring after an allogeneic hematopoietic stem cell transplant [4]. Currently, all patients treated so far have demonstrated at least a partial response, while no treatment-related serious adverse events or safety concerns have been observed. The product development activities of CYP-001 will be done in a phase II study in 2019 by Fujifilm in collaboration with Cynata Therapeutics. On its part, Fate Therapeutics received a first approval from Food and Drug Administration (FDA) in November 2018 to transplant an off-the-shelf iPSC-derived Natural Killer cell, FT-500, as cancer immunotherapy to treat solid tumors and for a second cell product derived from a genetically engineered iPSC, FT-516, in February 2019, for the treatment of relapsed/refractory hematologic malignancies. For the first product FT-500, all the three patients with advanced solid tumors have been treated with multiple doses of FT-500, 100 million cells per dose, and it has been well tolerated with no dose-limiting toxicities

Even though the first clinical studies have already been started, technical advances in iPSC biology have revealed that several factors could affect their safety for a larger range of medical applications, and should be taken into account for short- and long-term follow-up of patients. Two of the major concerns related to iPSC-based products are their potential tumorigenicity and immunogenicity. The scientific community is still continuing to elucidate the biological mechanisms underlying iPSC's immunogenicity and tumorigenicity and how to manage or

**2. Clinical trials with iPSC**

allogeneic iPSC-derived cells.

**16**

or adverse events [5].

overcome them.
