Assessment of safety and immunogenicity of MHC homozygous iPSC-derived CD34+ hematopoietic progenitors in an NHP model.

Abstract

Administration of ex vivo expanded somatic myeloid progenitors has been explored as a way to facilitate a more rapid myeloid recovery and improve overall survival after myeloablation. Recent advances in induced pluripotent stem cell (iPSC) technologies have created alternative platforms for supplying off-the-shelf immunologically compatible myeloid progenitors, including cellular products derived from major histocompatibility complex (MHC) homozygous superdonors, potentially increasing the availability of MHC-matching cells and maximizing the utility of stem cell banking. However, the teratogenic and tumorigenic potential of iPSC-derived progenitor cells and whether they will induce alloreactive antibodies upon transfer remain unclear. We evaluated the safety and efficacy of using CD34+CD45+ hematopoietic progenitors derived from MHC homozygous iPSCs (iHPs) to treat cytopenia after myeloablative hematopoietic stem cell (HSC) transplantation in a Mauritian cynomolgus macaque (MCM) nonhuman primate (NHP) model. We demonstrated that infusion of iHPs was well tolerated and safe, observing no teratomas or tumors in the MCMs up to 1 year after HSC transplantation and iHP infusion. Importantly, the iHPs also did not induce significant levels of alloantibodies in MHC-matched or -mismatched immunocompetent MCMs, even after increasing MHC expression on iHPs with interferon-γ. These results support the feasibility of iHP use in the setting of myeloablation and suggest that iHP products pose a low risk of inducing alloreactive antibodies.

• Authors: Saritha S D'Souza, Akhilesh Kumar, John Maufort, Jason T Weinfurter, Matthew Raymond, Nick S Strelchenko, Elizabeth Perrin, Jennifer Coonen, Andres Mejia, Heather A Simmons, Bruce E Torbett, Matthew Reynolds, James A Thomson, Igor I Slukvin
• Journal: Blood advances (Blood Adv) Vol. 6 Issue 18 Pg. 5267-5278 (09 27 2022) ISSN: 2473-9537 [Electronic] United States
• PMID: 35404997 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Chemical References

• Antigens, CD34
• Isoantibodies
• Interferon-gamma

Topics

• Animals
• Antigens, CD34
• Hematopoietic Stem Cell Transplantation
• Induced Pluripotent Stem Cells
• Interferon-gamma
• Isoantibodies
• Macaca fascicularis
• Major Histocompatibility Complex