What's past is prologue: lessons learned and the need for further development of allogeneic hematopoietic stem cell transplantation for renal cell carcinoma.

e ( c s r G p w r a c o r d S d f U Rini and colleagues [1] recently reported the reults of a multi-institutional study by the Cancer and eukemia Group B (CALGB) investigating nonmyloablative hematopoietic cell transplantation in paients with advanced renal cell carcinoma (RCC). wenty-two patients received conditioning with cylophosphamide and fludarabine followed by a granlocyte colony-stimulating factor mobilized periphral blood stem cell transplant from an HLA-matched ibling. Patients were eligible to receive donor lymhocyte infusions and/or interferonto treat disease rogression. Sustained engraftment was observed in 1 patients, with 17 patients achieving 90% donor T ell chimerism by day 120. Progression-free survival 3 months) and overall survival (5.5 months) were xtremely short. Despite the presence of grade II-IV cute and chronic graft-versus-host disease (GVHD; 2% and 23% of patients, respectively), no objective isease responses were observed. This report brings to ind prior early experiences of allogeneic transplanation for hematologic diseases and highlights the eed for further research of allogeneic transplantation or metastatic RCC. Several decades ago, when the use of allogeneic ransplantation for chronic myelogenous leukemia CML) was first reported by Thomas et al [2], the esults were exciting and disappointing; exciting in the ense that a proportion of patients was cured, but isappointing in terms of poor overall efficacy and ubstantial toxicity. As time went on, it became clear hat the limited efficacy of the approach was largely elated to selecting patients with advanced CML (blast e risis) and that a substantial proportion of the moridity and mortality of the procedure occurred as a onsequence of ineffective supportive care. By the end of he 20th century, with better patient selection criteria nd the advent of more effective supportive care meaures, approximately 80% of patients with chronic phase ML could be expected to be cured after allogeneic ematopoietic cell transplantation [2]. Although the suitbility of solid tumors as targets for allogeneic immunoherapy remains under investigation, this report from the ALGB makes us ask whether history may be repeating tself, this time for metastatic RCC. Several analogies can be drawn from the experince of Thomas et al. First, a graft-versus-tumor GVT) effect can be evoked against RCC; proof of oncept was established in 2000 and 9 small case eries since that time have reported delayed tumor egression after transplantation consistent with a VT effect, with long-term and occasionally comlete responses being observed in some patients with idely metastatic disease (Table 1) [3]. Although curent transplantation strategies enrolling patients with dvanced tumors and short anticipated survival may onsiderably limit the efficacy of this approach, proof f concept and the observation of durable complete esponses provide a foundation on which to further evelop more effective transplantation approaches. econd, it has been clear from the first report of a elayed GVT effect against RCC that a number of actors can limit a successful transplantation outcome. nfortunately, patients are often referred for considration of an allogeneic transplant too late in the