Two-year safety outcomes of iPS cell-derived mesenchymal stromal cells in acute steroid-resistant graft-versus-host disease.

The first completed clinical trial of induced pluripotent stem cell (iPS cell)-derived cells was conducted in 15 participants with steroid-resistant acute graft-versus-host disease. After intravenous infusion of mesenchymal stromal cells (CYP-001 derived from a clone of human iPS cells), we reported the safety, tolerability and efficacy within the primary evaluation period at day 100. We now report results at the 2-year follow-up: 9 of 15 (60%) participants survived, which compares favorably with previously reported outcomes in studies of steroid-resistant acute graft-versus-host disease. Causes of death were complications commonly observed in recipients of allogeneic hematopoietic stem cell transplantation, and not considered by the investigators to be related to CYP-001 treatment. There were no serious adverse events, tumors or other safety concerns related to CYP-001. In conclusion, systemic delivery of iPS cell-derived cells was safe and well tolerated over 2 years of follow-up, with sustained outcomes up to 2 years after the first infusion. ClinicalTrials.gov registration: NCT02923375 .

Production, safety and efficacy of iPSC-derived mesenchymal stromal cells in acute steroid-resistant graft versus host disease: a phase I, multicenter, open-label, dose-escalation study.

The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases1, including steroid-resistant acute graft versus host disease (SR-aGvHD)2. However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes3,4. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation5,6. Nonetheless, human clinical trials of iPSC-derived cells have not previously been completed. CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. We conducted a phase 1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohort A or cohort B (n = 8 per group). One subject in cohort B withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days 0 and 7, at a dose level of either 1 × 106 cells per kg body weight, to a maximum of 1 × 108 cells per infusion (cohort A), or 2 × 106 cells per kg body weight, to a maximum dose of 2 × 108 cells per infusion (cohort B). The primary objective was to assess the safety and tolerability of CYP-001, while the secondary objectives were to evaluate efficacy based on the proportion of participants who showed a complete response (CR), overall response (OR) and overall survival (OS) by days 28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases.

Immunoreactive AR and genetic alterations in subjects with androgen resistance and undetectable AR levels in genital skin fibroblast ligand-binding assays.

Defects of the AR cause a wide range of abnormalities of male development, ranging from individuals with mild defects of virilization to those with complete female phenotypes. In parallel with this phenotypic spectrum, a large number of different mutations have been identified that alter the synthesis or functional activity of the receptor protein. This report aims to categorize the alterations of immunoreactive AR (IRAR) expression and the underlying genetic changes in a single category of patient: those in whom ligand binding is undetectable in genital skin fibroblasts. Our study found a wide range in the levels of IRAR that are detectable in fibroblast strains established from 27 such individuals. A large proportion (19 of 27) express significant amounts of AR protein, as detected using a sensitive Western blot technique. In a smaller number (8/27), AR expression was undetectable. Intact IRAR was identified in16 of the 19 fibroblast strains in which AR expression could be detected. The AR gene was analyzed in 14 strains from this group. In 13 instances, single amino acid substitutions were identified within the ligand-binding domain of the receptor protein. In three of the remaining patients (3 of 19), truncation of the receptor protein was suggested by the rapid migration of the IRAR in SDS-polyacrylamide gels. In those three patients, production of the shortened immunoreactive receptor was traced to mutations that interrupted the AR open reading frame. By contrast, only one of the eight patient samples with no detectable IRAR carried a mutation that resulted in a single amino acid substitution. An interruption of the AR open reading frame was identified in six of the eight strains in which immunoreactive receptor was absent. In the remaining strain, no mutation was present within or surrounding the eight coding exons. This study serves to define the effects that mutations of the AR have on the levels of expressed immunoreactive receptor protein. In addition, it demonstrates the type of information that can be obtained if an immunoblot assay were to be used as a component of a screening method to analyze samples from patients with defects of the AR. Finally, the study suggests that in some androgen-resistant patients, defects outside the AR open reading frame may result in major alterations of AR expression.