Ex vivo expansion of human hematopoietic progenitors and cells to support high-dose chemoradiation therapy: Five years of clinical experience

The identification of cytokines-soluble or membrane-bound regulators of hem atopoietic stem and progenitor cell survival, proliferation, and differenti ation - and the definition of culture conditions that enable cell and proge nitor expansion, has lead to the first clinical trials using cultured cells in addition to or in place of unmanipulated cells. The use of ex vivo expa nded cells can improve several aspects of autologous and allogeneic hematop oietic cell and progenitor transplantation, such as reducing or abolishing the nadir that follows high-dose chemoradiation therapy regimens, or reduci ng the clinical risks associated with the use of small numbers of progenito rs as in cord blood transplantation and in autologous transplantation for p oor mobilizers. In addition, biological questions raised by ex vivo expansi on are shared by scientists and clinicians interested in gene transfer into hematopoietic stem cells. We here review the biological problems associate d with ex vivo expansion: defining efficient culture conditions, considerin g not only scientific and biological issues but also regulatory and commerc ial issues, defining appropriate surrogate endpoints that predict engraftme nt and superior clinical efficacy to that obtained with the use of unmanipu lated grafts. We also review the results of the first clinical trials that have demonstrated the feasibilty of this approach, and have shown some of i ts limitations; demonstration of clinical efficacy will require more precli nical and clinical work.