Novel immunotherapy for high-risk neuroblastoma: allogeneic stem cell transplantation and recipient leukocyte infusion.

Neuroblastoma is the most frequent extra-cranial solid tumor in childhood. More than half of patients is diagnosed with high-risk disease (non-resectable and metastasized), and is faced with poor prognosis. To date, an effective and safe treatment for such patients is not available, urgently necessitating research into novel treatment strategies.

Allogeneic hematopoietic stem cell transplantation is a cornerstone in the treatment of hematological malignancies, particularly in combination with donor leukocyte infusion (DLI), and is now also emerging as a novel treatment option for advanced solid tumors not responding to conventional therapies. The major drawback is that donor T cells not only attack malignant cells (graft-versus-tumor effect), but also target healthy recipient tissues resulting in graft-versus-host disease (GvHD), causing high morbidity and mortality.

Studies in murine leukemia models have shown that infusion of recipient-type – rather than donor-type – leukocytes (recipient leukocyte infusion, RLI) after allogeneic stem cell transplantation can also mount anti-tumor responses without producing GvHD: RLI given to mixed chimeras provoked an immune reaction against the allogeneic cells, resulting in a full rejection of the donor graft with associated anti-leukemia effects, while leaving host tissues intact. Importantly, we were the first group to show that RLI can also produce immune responses against the solid tumor neuroblastoma: in murine neuroblastoma models we showed that RLI is able to reduce local growth and metastasis of neuroblastoma, which was initiated by a complete rejection of donor T-cell chimerism. However, although local tumor growth was significantly delayed by RLI, the effect was temporarily and survival was not prolonged. Therefore, the aim of the current project was to gain a detailed insight into the nature and the dynamics of the alloreactive response following RLI, so as to understand why the biological effects are incomplete, and to explore strategies to optimize the efficacy of RLI against neuroblastoma.

In the current project, we revealed that the RLI-mediated alloreactive response  was associated with a systemic inflammatory cytokine storm, expansion of activated dentritic cells (DC) in the lymph nodes and induction of a marked systemic expansion of host-type T helper 1 cells and cytotoxic T cells that were also able to migrate into the local neuroblastoma tumor. However, although the systemic effector T cell responses persisted for -at least- 2 weeks after RLI, within the tumor the effect diminished more rapidly. Accordingly, we found that RLI not only generated effector T cell responses, but also drives a strong expansion of myeloid-derived suppressor cells (MDSC). Depletion of MDSC by low-dose 5-fluorouracil augmented the anti-tumor effects of RLI, indicating that the expanded MDSC are - at least in part - responsible for counteracting the tumor growth-inhibitory effect of RLI.