The role of the conditioning regimen for autologous and ex vivo genetically modified hematopoietic stem cell-based therapies: recommendations from the ISCT stem cell engineering committee.

Background: The advent of autologous gene modified cell therapies to treat monogenic disorders has been a major step forward for the field of hematopoietic stem cell transplantation (HCT) and cellular therapies. The need for disease-specific conditioning to enable these products to provide a potential cure has required extrapolation from experience in myeloablative and non-myeloablative HCT for these disorders.
Methods: In this manuscript, we review the current datasets and clinical experience using different conditioning regimens for autologous gene therapies in hemoglobinopathies, metabolic and lysosomal disorders, inborn errors of immunity (IEI) and bone marrow failure (BMF) syndromes.
Results: The disease specific and unique conditioning requirements of each disorder are considered in order to achieve maximal benefit while minimizing associated toxicities.
Conclusions: Standardized recommendations based on these data are made for each set of disorders to harmonize treatment. Future directions and the possibility of non-genotoxic conditioning regimens for autologous gene therapies are also discussed. Ethical Statement: The authors followed all relevant ethical considerations in writing this manuscript.
Competing Interests: Declaration of Competing Interest Joseph Oved received consulting fees and/or honoraria from Emendo Bio, Turn.Bio, Grifols, Ensoma, Sobi and Amgen. He receives research support from Sobi and is the site PI for the Jasper SCID trial (NCT02963064). Akshay Sharma has received consultant fee from Spotlight Therapeutics, Medexus Inc., Vertex Pharmaceuticals, BioLineRx, Sangamo Therapeutics and Editas Medicine. He is a medical monitor for RCI BMT CSIDE clinical trial for which receives financial compensation. He has also received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education. Dr Sharma is the St. Jude Children's Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907) and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which includes salary support paid to Dr Sharma's institution. Dr Sharma has no direct financial interest in these therapies. Amy E DeZern participated in advisory boards and/or had a consultancy with and received honoraria from Celgene/BMS, Agios, Novartis, Appellis and Gilead. AED served on clinical trial committees or DSMB for Novartis, Abbvie, Kura, Geron, Servier, Keros, Shuattuck labs and Celgene/BMS. SEP receives support for the conduct of clinical trials through Boston Children's Hospital from AlloVir, Atara, and Jasper Therapeutics. Honoraria from Pierre Fabre, and Regeneron. Consulting for Century, CellEvolve and VOR. Carmem Bonfim consults for Zodiac, Amgen and Novartis. Duncan Purtill receives honoraris (to Fiona Stanley Hospital and not the author) from Novartis, Gilead, BMS-Celgene and Jazz Pharmaceuticals. Sandeep Soni is employed by CRSPR Therapeutics AG. Jaap Jan Boelens consults for Advanced Clinical, Sanofi, Sobi, Immusoft, SmartImmune and Merck and receives research funding from Sanofi. Allistair Abraham served on the safety monitoring committee for Sangamo Therapeutics and has no financial interest in the development of gene therapies. Remaining authors have no conflicts of interest.
(Copyright © 2024 International Society for Cell & Gene Therapy. All rights reserved.)