Correspondence
Treatment of Renal-Cell Cancer by Transplantation of Allogeneic Stem Cells
N Engl J Med 2001; 344:137-138January 11, 2001
- Article
To the Editor:
Childs et al. (Sept. 14 issue)1 report the spectacular success of nonmyeloablative allogeneic stem-cell transplantation in a subgroup of patients with metastatic renal-cell carcinoma. Only the patients with clear-cell carcinomas had responses. Previous work indicates that most renal-cell carcinomas with clear-cell histology are caused by mutation of the von Hippel–Lindau tumor-suppressor gene, located on chromosome band 3p26.2,3 The von Hippel–Lindau gene produces two proteins that can suppress tumor formation in clear-cell renal-cell carcinoma in a nude-mouse model.4 My colleagues and I have demonstrated that the von Hippel–Lindau gene, in addition to its tumor-suppressor function, protects cells from apoptosis mediated by ultraviolet radiation.5 I would like to suggest that the mechanism by which stem-cell transplantation induces regression of disease relates to the differential susceptibility of cells, according to whether they do or do not have a mutation in the von Hippel–Lindau gene, to signaling pathways induced in the renal-cell carcinoma cells by the donor T cells or locally released cytokines. I predict that the renal-cell carcinoma cells are negative for a von Hippel–Lindau mutation in the patients with a response and that apoptosis can be detected on biopsy of the regressing lesions. Moreover, I suggest that identification of the specific ligands responsible for the induction of regression might be sufficient to effect a response similar to that of the transplantation. These are testable hypotheses that could lead to mechanism-based therapies — the ultimate in translational research.
5 ReferencesRobert D. Burk, M.D.
Albert Einstein College of Medicine, Bronx, NY 104611
Childs R ,Chernoff A ,Contentin N , et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000;343:750-758
Full Text | Web of Science | Medline2
Gnarra JR ,Tory K ,Weng Y , et al. Mutations of the VHL tumor suppressor gene in renal carcinoma. Nat Genet 1994;7:85-90
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Latif F ,Tory K ,Gnarra J , et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317-1320
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Schoenfeld A ,Davidowitz EJ ,Burk RD . A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc Natl Acad Sci U S A 1998;95:8817-8822
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Schoenfeld AR, Parris T, Eisenberger A, et al. The von Hippel-Lindau tumor suppressor gene protects cells from UV-mediated apoptosis. Oncogene (in press).
To the Editor:
Childs et al. describe regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. Since renal-cell carcinoma may spontaneously regress when confined entirely to the kidney,1 it may be worth considering allogeneic stem-cell transplantation as neoadjuvant therapy for large, primary renal-cell carcinomas before excision nephrectomy.
1 ReferencesDavid N. Poller, M.D.
Queen Alexandra Hospital, Portsmouth P06 3LY, United Kingdom1
Hamid Y ,Poller DN . Spontaneous regression of renal cell carcinoma:a pitfall in diagnosis of renal lesions. J Clin Pathol 1998;51:334-336
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To the Editor:
Childs et al. describe striking and sustained remissions of metastatic renal-cell carcinoma that followed nonmyeloablative stem-cell transplantation. With use of our murine model,1 we have developed an approach to nonmyeloablative transplantation for the induction of mixed lymphohematopoietic chimerism followed by infusions of donor leukocytes for advanced hematologic cancers. Mixed chimerism has been reliably achieved with this strategy after bone marrow transplantation from HLA-matched or HLA-mismatched donors.2,3 In contrast to the observation by Childs et al. that regression of metastatic disease occurred only after T-cell chimerism had become complete, initial responses in our patients and the development of graft-versus-host disease have not depended on full allogeneic T-cell chimerism. The gradual achievement of complete responses in some patients, in concert with progressive conversion to complete donor–T-cell chimerism, suggests that progression to full T-cell chimerism may be a marker of durable antitumor responses.
One reason for these differences in the timing of clinical responses in relation to the development of T-cell chimerism is probably the type of cancer. In the murine model, the graft-versus-host response that follows infusions of donor leukocytes is confined to the lymphohematopoietic space and does not injure epithelial tissue. This confined graft-versus-host response might explain why graft-versus-host disease is not necessary for an antilymphoma effect. Such a confined response might not be useful against a parenchymal tumor. In the study by Childs et al., it is possible that the antitumor responses in some patients were due to the recovery of immune function after the resolution of graft-versus-host disease; this could have allowed the development of a specific response to tumor antigens (as distinguished from graft-versus-host responses).
3 ReferencesThomas R. Spitzer, M.D.
Megan Sykes, M.D.
Massachusetts General Hospital, Boston, MA 021141
Pelot MR ,Pearson DA ,Swenson K , et al. Lymphohematopoietic graft-vs.-host reactions can be induced without graft-vs.-host disease in murine mixed chimeras established with a cyclophosphamide-based nonmyeloablative conditioning regimen. Biol Blood Marrow Transplant 1999;5:133-143
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Sykes M ,Preffer F ,McAfee S , et al. Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. Lancet 1999;353:1755-1759
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Spitzer TR ,McAfee S ,Sackstein R , et al. Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant 2000;6:309-320
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Author/Editor Response
The authors reply:
To the Editor: Dr. Burk suggests that regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic stem-cell transplantation is due to the differential susceptibility of cells, according to whether they do or do not have a mutation in the von Hippel–Lindau gene, to apoptotic signaling pathways. We are currently evaluating this attractive hypothesis by examining the relation between mutations in the von Hippel–Lindau gene in patients who do and do not have a response. In our initial report, responses were limited to patients with clear-cell carcinoma, the tumor type associated with a von Hippel–Lindau mutation, but the small number of patients who had histologic features other than those of the clear-cell type precluded any attempt to establish a correlation between the tumor subtype and the response to therapy.
Our preliminary laboratory data suggest that cytotoxic T cells of donor origin mediate graft-versus-tumor effects in renal-cell carcinoma; however, their exact target antigens remain to be elucidated. Whether nonmalignant cells also express these antigens but are protected from T-cell–mediated apoptosis by wild-type von Hippel–Lindau protein is an interesting hypothesis that will be explored once the antigens have been defined. However, the occurrence of graft-versus-host disease in normal tissues that express von Hippel–Lindau protein, such as colonic mucosa and biliary-duct epithelium,1,2 argues against expression of von Hippel–Lindau protein as the sole factor associated with differential protection from apoptosis after an immune attack.
The observation that antitumor effects can be generated in patients whose metastatic renal-cell carcinoma is refractory to conventional cytokine-based immunotherapy is evidence of the potency of the graft-versus-tumor effect generated after nonmyeloablative allogeneic transplantation. However, although beneficial antitumor effects occurred in 10 of the 19 patients, the approach is limited by its toxic effects, mostly graft-versus-host disease. For these reasons, we do not believe that it would be appropriate at the present time to use nonmyeloablative allogeneic stem-cell transplantation for adjuvant or neoadjuvant therapy.
To avoid the induction of tolerance to tumor antigens associated with mixed lymphohematopoietic chimerism, we sought to induce, and successfully achieved, profound immunosuppression by conditioning with both fludarabine and high-dose cyclophosphamide. As a consequence, mixed T-cell chimerism in our patients was typically short-lived; most had conversion to full donor–T-cell chimerism within one to two months after transplantation. The relative transience of mixed T-cell chimerism makes it difficult to know whether full donor–T-cell chimerism is actually required to generate the graft-versus-tumor effect in renal-cell carcinoma. However, we observed no relation between the establishment of 100 percent donor–T-cell chimerism and the duration of the response. It should be noted that unlike hematologic cancers, in which initial disease regression may be mediated either by an immune effect or by the effects of cytotoxic agents given during conditioning, renal-cell carcinoma is completely refractory to chemotherapy. The absence of this confounding factor provided us with the unique opportunity to determine with confidence the factors associated with the generation of an immune-mediated antitumor effect.
2 ReferencesRichard Childs, M.D.
A. John Barrett, M.D.
National Heart, Lung, and Blood Institute, Bethesda, MD 20892W. Marston Linehan, M.D.
National Cancer Institute, Bethesda, MD 208921
Los M ,Jansen GH ,Kaelin WG ,Lips CJ ,Blijham GH ,Voest EE . Expression pattern of the von Hippel-Lindau protein in human tissues. Lab Invest 1996;75:231-238
Web of Science | Medline2
Corless CL ,Kibel AS ,Iliopoulos O ,Kaelin WG Jr . Immunostaining of the von Hippel-Lindau gene product in normal and neoplastic tissues. Hum Pathol 1997;28:459-464
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- Citing Articles (1)
Citing Articles
1
Cherry I. Kingsley, Satish N. Nadig, Kathryn J. Wood. (2007) Transplantation tolerance: lessons from experimental rodent models. Transplant International 20:10, 828-841
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