Autologous and Allogeneic Cellular Therapies for High-risk Pediatric Solid Tumors

Since the 1950s, the overall survival (OS) of children with cancer has gone from almost zero to approaching 80%. While there have been notable successes in treating solid tumors such as Wilms tumor, some childhood solid tumors, exemplified by diseases like high-risk neuroblastoma and metastatic sarcomas, have continued to elude effective therapy[1]. With the use of megatherapy techniques such as tandem transplantation, dose-escalation has been pushed to the edge of dose-limiting toxicities, and any further improvements in event-free survival (EFS) will have to be achieved through novel therapeutic approaches. In this chapter, we will review the status of autologous and allogeneic hematopoietic stem cell transplantation (HSCT) for many pediatric solid tumor types. The vast majority of the clinical experience in transplant for pediatric solid tumors is in the autologous setting, so we will review some general principles of autologous HSCT, followed by an examination of HSCT for diseases such as Hodgkin disease, Ewing sarcoma, and neuroblastoma. Finally, we will look to the future of cell-based therapies by considering some experimental approaches to effector cell therapies. (1) Principles of autologous HSCT Prior to the introduction of high-dose chemotherapy (HDC) with autologous stem cell rescue (also called autologous HSCT), marrow tolerance was the limiting factor in the escalation of chemotherapy for the treatment of malignancies. With the ability to safely harvest, store and re-infuse a patient’s own hematopoietic stem cells, doses of cytotoxic therapies for cancer could safely proceed beyond marrow tolerance, thereby allowing more intense treatment of certain malignancies. Two approaches to the use of HDC with stem cell rescue include: (1) myeloablative regimens, meaning that no hematopoietic recovery can occur without the stored HSCs; and (2) sub-myeloablative HDC regimens in which stem cell rescue is used to speed recovery, decrease toxicity and decrease the interval between courses of chemotherapy, although it is not absolutely required for engraftment[2–3]. Although the increased treatment intensity may improve disease-free survival for patients with some malignancies, this must be balanced with the increased treatment-related mortality associated with the higher doses of cytotoxic agents, as well as the potential late effects of more intense cytotoxic treatments and radiotherapeutic regimens in young children. Criteria that may help define circumstances in which HDC with stem cell rescue would be most beneficial include: (1) a tumor with good response to induction chemotherapy, but a poor 3 or 5-year EFS; and (2) a HDC regimen that can utilize multiple agents active against the disease, especially if the agents differ from those used during induction therapy. Although the use of HDC with stem cell rescue is controversial in most diseases, diseases such as Hodgkin disease and high-risk neuroblastoma (discussed below) meet the design criteria listed above and have demonstrated improved outcomes in clinical trials.