Non-myeloablative allogeneic stem cell transplantation for metastatic renal cell carcinoma: section editor: robert bahnson, m.d.

Abstract

Renal cell carcinoma (RCC) has long been studied for its susceptability to the immunomodulatory effects of interferon (IFN) [1], interleukin-2(IL-2)[2] and other agents [3] as well as cell-based therapies such as Autolymphocyte Therapy (ALT) [4,5]. Lymphokine-Activated Killer (LAK) cells [6,7] and Tumor Infiltrating Lymphocytes (TIL) [8]. All of these studies have indicated that a T cell mediated immune response is capable of inducing tumor regressions among patients with metastatic RCC. Recently, investigators from the National Institute of Health (NIH) [9,10] and University of Chicago [11] have reported that durable tumor responses could be achieved among IL-2 refractory RCC patients through non-myeloablative allogeneic stem cell transplantation (NMASCT). The success of this new treatment strategy against a solid tumor has provided another piece of evidence suggesting that an acquired cellular immunity can indeed alter the natural history of human malignancies. Allogeneic stem cell transplantation following myeloablative chemotherapy/radiation has been proven to be a curative therapy for many hematological malignancies, especially in the case of chronic myeloid leukemia. Although the initial goal of such treatment was to deliver high dose chemotherapy and/or radiation that otherwise would have not been tolerated to eradicate maximal numbers of malignant cells, it was soon recognized that the success from such treatment was largely due to the graft versus leukemia (GVL) effect carried out by the engrafted allogeneic T cells [12–14]. This observation was further supported by the effectiveness of donor lymphocyte infusion (DLI) in inducing second remissions for post transplant relapses [15]. Based on this GVL effect as well as the high morbidity and mortality rates from myeloablative allogeneic stem cell transplantation, a great deal of effort has since been shifted to focus on using less intensive conditioning regimens just enough to create a hybrid host/donor hematopoiesis, or a “chimerism” [16,17]. This so-called non-myeloablative allogeneic stem cell transplantation has been shown to be highly effective against many indolent types of lymphoid malignancies with much reduced transplant related complications [18]. In the mid 1990s, Richard Childs and his group at NIH began testing the potential graft versus tumor (GVT) effect of allogeneic stem cell transplantation from HLA matched sibling donor against RCCs and melanomas that are refractory to immunotherapy. A non-myeloablative conditioning regimen consisting of 2 days of cyclophosphamide at 60 mg/ kg/d followed by 5 days of fludarabine at 25 mg/m/d was used [10]. Although none of the melanoma patients responded to such transplant, very encouraging results have been demonstrated among the transplanted RCC patients. In a recent update (Brian I. Rini, personal communication), this group reported 4 complete responses (CR) and 13 partial responses (PR) among 38 evaluable patients. For most cases, the responses have been durable with the longest follow-up being over 3 years. Interestingly, the vast majority of responders have suffered from grade III and IV acute and/or extensive chronic graft versus host disease (GVHD) prior to their responses. At the University of Chicago, we have the second largest series in the US with 15 IL-2 refractory RCC patients transplanted thus far from HLA identical sibling donors. Initially, our conditioning regimen included 4 days of fludarabine at 30 mg/m day and 1 day of cyclophosphamide at 2 g/m. This regimen was later shown to be inadequate to allow donor stem cell engraftment as 3 of our first 4 patients failed to establish sustained donor hematopoiesis. We then modified the protocol by increasing fludarabine to 5 days and cyclophosphamide to 2 days, which is similar to the NIH regimen. There have been no graft failures among the subsequent patients transplanted under this more lymphoablative regimen. For GVHD prophylaxis, mycophenolate was given for the first 60 days and tacrolimus was given for the first 100 days after the transplant followed by a rapid taper. This combination is comparable to the current NIH regimen of mycophenolate and cyclosporine A. Among the 12 patients who developed sustained donor engraftments, there are 3 partial responses documented at days 180, 270, and 180. These patients remain in PR at days 673, 411, and 231. One patient has stable disease and is alive at day 286; 1 died of disease progression at day 183; Urologic Oncology: Seminars and Original Investigations 21 (2003) 79–81