Cymerus™ iPSC-MSCs significantly prolong survival in a pre-clinical, humanized mouse model of Graft-vs-host disease

Abstract

The immune-mediated tissue destruction of graft- vs -host disease (GvHD) remains a major barrier to greater use of hematopoietic stem cell transplantation (HSCT). Mesenchymal stem cells (MSCs) have intrinsic immunosuppressive qualities and are being actively investigated as a therapeutic strategy for treating GvHD. We characterized Cymerus™ MSCs, which are derived from adult, induced pluripotent stem cells (iPSCs), and show they display surface markers and tri-lineage differentiation consistent with MSCs isolated from bone marrow (BM). Administering iPSC-MSCs altered phosphorylation and cellular localization of the T cell-specific kinase, Protein Kinase C theta (PKCθ), attenuated disease severity, and prolonged survival in a humanized mouse model of GvHD. Finally, we sevaluated a constellation of pro-inflammatory molecules on circulating PBMCs that correlated closely with disease progression and which may serve as biomarkers to monitor therapeutic response. Altogether, our data suggest Cymerus iPSC-MSCs offer the potential for an off-the-shelf, cell-based therapy to treat GvHD.

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

“…SR-aGvHD was introduced by Le Blanc and colleagues in 2004, with positive results 18 . In a previously published study in a humanized mouse model of aGvHD, the iPSC-derived MSC product CYP-001 reduced bone marrow infiltration and expression of proinflammatory molecules (NOTCH1, TBET and PKCΘ) by CD4 and CD8 T cells, attenuated disease severity and prolonged survival 19 .…”

“…The cells in CYP-001 meet the minimal criteria for defining multipotent MSCs as proposed by the International Society for Cell and Gene Therapy 19,25 . The process is highly efficient, yielding a homogenous population of CD105 + , CD73 + , CD90 + , CD43/45 -, CD31and HLA-DR − MSCs (Supplementary Table 1).…”

Shattering barriers toward clinically meaningful MSC therapies

“…At the clinical stage, efforts to overcome MSC product heterogeneity have been best exemplified by Cynata Therapeutics, who developed a strategy for obtaining highly homogeneous MSCs using induced pluripotent stem cells (iPSCs). Because iPSCs have an exponentially larger proliferation capacity without undergoing differentiation compared to MSCs, they can be easily expanded to generate large quantities of iPSCs and then differentiated into MSCs after expansion to yield commercial quantities of MSCs (iPSC-MSCs) with a low passage number (44). For example, upward of 1 × 10 22 passage 1 MSCs can be produced from a single iPSC population, with similar potency to low-passage BM-MSCs harvested from donors as assessed by T cell suppression (44,45).…”

“…Because iPSCs have an exponentially larger proliferation capacity without undergoing differentiation compared to MSCs, they can be easily expanded to generate large quantities of iPSCs and then differentiated into MSCs after expansion to yield commercial quantities of MSCs (iPSC-MSCs) with a low passage number (44). For example, upward of 1 × 10 22 passage 1 MSCs can be produced from a single iPSC population, with similar potency to low-passage BM-MSCs harvested from donors as assessed by T cell suppression (44,45). The iPSC-MSC approach serves as an excellent solution for scaling MSC manufacturing without sacrificing therapeutic potency through the passage and expansion of cells (46).…”

The Challenge of Bringing iPSCs to the Patient

“…The Australian company Cynata Therapeutics received approval to proceed with a clinical trial of allogeneic iPSC-derived mesenchymal stem cells (MSCs). They established Cymerus TM iPSC-MSCs and tested preclinical efficacy in a humanized mouse model [67]. In 2018, phase I of the trial was completed in 16 steroid-resistant GVHD patients with positive results, supporting progression to a phase II trial [52].…”