Greater than the sum of their parts: Combination strategies for immune regeneration following allogeneic hematopoietic stem cell transplantation

Cytoreductive conditioning regimes designed to allow for successful allogeneic hematopoietic stem cell transplantation (allo-HSCT) paradoxically are also detrimental to recovery of the immune system in general but lymphopoiesis in particular. Post-transplant immune depletion is particularly striking within the T cell compartment which is exquisitely sensitive to negative regulation, evidenced by the profound decline in thymic function with age. As a consequence, regeneration of the immune system remains a significant unmet clinical need. Over the past decade studies have revealed several promising therapeutic strategies to address ineffective lymphopoiesis and post-transplant immune deficiency. These include the use of cytokines such as IL-7, IL-12 and IL-15; growth factors and hormones like keratinocyte growth factor (KGF), insulin-like growth factor (IGF)-1 and growth hormone (GH); adoptive transfer of ex vivo-generated precursor T cells (pre-T) and sex steroid ablation (SSA). Moreover, recently several novel approaches have been proposed to generate whole thymii ex vivo using stem cell technologies and bioscaffolds. Increasingly, however, when transferred to the clinic, these strategies alone are not sufficient to restore thymopoiesis in all patients leading to the potential of combination strategies as a way to reign in non-responders. Synergistic enhancement in combination may be due to differential targets may therefore be effective in improving clinical outcomes in the transplant settings as well as in other lymphopenic states induced by high dose chemotherapy/radiation therapy or HIV, and may also be useful in improving responses to vaccination and augmenting anti-tumor immunotherapy.