We report a 69-year-old man with cytokine-resistant metastatic renal cell carcinoma treated with reduced-intensity unrelated cord blood transplantation. The patient achieved durable donor engraftment with minimal graft-versus-host disease. The patient showed regression of metastatic disease, providing the first evidence of a graft-versus-tumor effect on a solid tumor resulting from cord blood graft.
Metastatic renal cell carcinoma (RCC) is resistant to standard radiotherapy or chemotherapy, and patients with this disease have a poor outlook.1 Although immunotherapy with cytokines such as interleukin 2 and interferon alpha can lead to regression of RCC in some patients, the response rate for these treatments remains around 10–20%, and response is usually temporary.2 Recently, allogeneic stem cell transplantation utilizing mobilized peripheral blood from a matched donor has been investigated as an alternative immunotherapeutic strategy for the treatment of advanced RCC. The results of pilot reduced-intensity transplant trials for metastatic RCC are encouraging and show that responses can occur in patients with advanced metastatic disease that has failed to respond to conventional cytokine-based therapy.1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15
Unrelated cord blood (UCB) is considered an alternative hematopoietic stem cell source for transplantation, and its use in adult patients with hematologic disorders is increasing.16, 17, 18, 19, 20, 21 Thus far, UCB transfer has not been attempted in patients with a solid-organ malignancy such as RCC. Here, we report a patient with metastatic RCC treated with reduced-intensity unrelated cord blood transplantation (RI-UCBT).
A 56-year-old man with clear cell RCC of his right kidney underwent a right nephrectomy in March 1991. Six years later, metastatic diseases were found in the right upper jaw and pancreas and were partially removed. The remaining metastases grew and new metastases developed in the left lung, left kidney, retroperitoneal space and subcutaneous space. The patient was treated with a 12-week course of combination therapy of subcutaneous interferon alpha 2 MU/m2 and interferon gamma 2 MU/m2 five times per week. However, these metastases showed a progressive increase in the size. Because of the low probability of response to further conventional treatment for metastatic RCC, the patient was referred to our institute in February 2004 at the age of 69 years. Then, serum LDH level was 286 IU/l (normal range, 0–250), hemoglobin level 10.6 g/dl, serum calcium level 9.3 mg/dl and erythrocyte sedimentation rate 38 mm/h. Reduced-intensity allogeneic stem cell transplantation was considered in order to decrease regimen-related toxicity, but because of the lack of a suitable donor candidate among his family members, unrelated RI-UCBT was planned. The patient gave written informed consent to participate in an institutional review board-approved investigational protocol designed to evaluate graft-versus-tumor (GVT) effects in metastatic RCC after nonmyeloablative allogeneic transplantation. The preparative regimen, which was based on a previous report,22 consisted of cyclophosphamide, 50 mg/kg, on day −6, fludarabine, 40 mg/m2, daily on days −6 to −2, and a single dose of 200 cGy of total body irradiation on day −1. UCB, phenotypically mismatched at one HLA-B antigen and one DRB1 antigen, was obtained through the Japanese Cord Blood Bank Network (J-CBBN). The patient received a UCB graft at a dose of 2.0 × 107 nucleated cells/kg of recipient body weight in March 2004. To prevent rejection of the graft and graft-versus-host disease (GVHD), intravenous cyclosporine A (1.5 mg/kg b.i.d.) and oral mycophenolate mofetil (15 mg/kg b.i.d. until neutrophil engraftment) were started 3 days before transplantation. Granulocyte colony-stimulating factor (G-CSF) was initiated on day 1. The patient developed poor engraftment with at most 50% of peripheral blood granulocytes of donor origin. This resulted in graft rejection, with complete autologous recovery on day 41. One hundred and six days after first transplant, the patient received a second UCB graft from J-CBBN containing 2.2 × 107 nucleated cells/kg of recipient body weight, which was phenotypically mismatched at one HLA-B antigen and one DRB1 antigen. Conditioning therapy consisted of fludarabine, 25 mg/m2, daily on days −7 to −3, melphalan, 80 mg/m2, on day −2 and a single dose of 400 cGy of total body irradiation on day −1, as previously reported.18 A continuous infusion of tacrolimus, 0.03 mg/kg, was started from 3 days before transplant for prophylaxis of GVHD and graft rejection. G-CSF was started on day 1. The patient tolerated the conditioning regimen well and exhibited rapid engraftment, with neutrophils rising above 5 × 108/l by day 15. Chimerism analysis of blood on day 20 after second transplant revealed 100% donor origin in both myeloid and T-lymphoid lineages. On day 47, grade II acute GVHD of the skin and gut developed. Acute GVHD improved rapidly after increasing doses of tacrolimus without corticosteroid therapy, but it became dependent on the treatment of tacrolimus. The tacrolimus was finally tapered off at 11 months, and thereafter no GVHD developed. Treatment response was evaluated monthly after transplantation according to the Response Evaluation Criteria in Solid Tumors (RECIST).23 A computed tomography (CT) scan at 2 months showed substantial regression of metastasis in the left kidney and retroperitoneal space (Figure 1), and the patient was determined as partial remission (PR). The PR had lasted for 3 months until new metastatic lesions in the liver and pancreas appeared at 5 months after second transplantation, defined as progressive disease (PD). At the onset of PD, he had active GVHD of the gut, which was treated with oral tacrolimus alone. Metastatic lesions progressed in size very slowly until 18 months after second transplantation, but since then, they have been unchanged until the time of this writing. The association of the onset of GVHD with the development of PR as well as that of discontinuation of the immunosuppression with no further progression of disease is suggestive of a GVT effect in this patient. The patient continues to show a good performance 26 months after second transplantation without active GVHD.
Metastatic RCC is the solid tumor in which a GVT effect has been most expected. Childs et al.3 and Childs and Otterud24 have reported that of 50 patients with metastatic RCC who underwent allogeneic peripheral blood stem cell transplantation (PBSCT), 22 (44%) showed a disease response including four complete responses and 18 PRs, and five (10%) patients had a mixed response. However, the worldwide clinical experience of allogeneic SCT for metastatic RCC is limited, with approximately 200 cases reported in the literature.3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 24 One of the major restrictions of this approach is the requirement that transplant candidates have an HLA-identical related donor. This requirement may limit the use of allogeneic stem cell transplantation to a minority of patients with metastatic RCC. Our patient achieved long-term survival following RI-UCBT, despite the lack of a suitable donor candidate among his family members.
Cord blood, which is collected from the umbilical cord and placenta of healthy newborns, is an alternative source of hematopoietic stem cells.25 Compared to adult peripheral blood or bone marrow, cord blood contains a greater proportion of highly proliferative hematopoietic progenitor cells,26 which may account for myeloid and lymphoid reconstitution after cord blood transplantation (CBT) despite the presence of fewer cells (by 1–2 logs) in cord blood than in bone marrow or mobilized peripheral blood.
It was originally thought in CBT that the immunological naivety of cord blood lymphocytes26 might produce a lowered GVT effect at the expense of a lower GVHD incidence. However, clinical studies revealed similar rates of disease relapse and lower rates of acute and chronic GVHD in adult patients with hematologic malignancies receiving CBT compared to those receiving allogeneic bone marrow transplantation or PBSCT.17, 19, 21 Although it remains unclear whether such favorable effects also occur in patients with metastatic RCC who undergo CBT, several observations support the hypothesis that similar alloimmune effects mediated by donor T cells could work in these patients.24, 27, 28, 29, 30 Although the target antigens in GVT effects after allogeneic transplantation against metastatic RCC have not been determined, clinical and laboratory observations suggested that minor histocompatibility antigens (mHAs) could be mainly involved as target antigens in GVT effects for metastatic RCC after PBSCT, and donor T cells responding to mHAs could be generated.24, 27, 28 The fact that cord blood can generate cytotoxic T cells specific for the mHA in the same way as peripheral blood and bone marrow29, 30 might imply that mHA-specific donor T cells contributive to a GVT effect against metastatic RCC are inducible in a patient receiving a cord blood graft as well.
As allogeneic stem cell transplantation is associated with many and sometimes severe toxic effects, we used a reduced-intensity conditioning regimen as described in previous reports,18, 22 which included low-dose total body irradiation in combination with cyclophosphamide and fludarabine or with melphalan and fludarabine. This RI-UCBT regimen proved to be well tolerated and achieved durable donor engraftment with minimal GVHD. Although our patient required a second RI-UCBT because of graft refection after first RI-UCBT, the demonstrated feasibility of secondary transplantation may be of benefit in the treatment of older cancer patients with RI-UCBT. Of note, the observation in the patient that retroperitoneal and renal metastasis regressed, despite a mixed response, provides the first evidence of a GVT effect by a cord blood graft on RCC.
The advantages of CBT are the immediate availability of cells, the absence of risk to the donor and a lower need for HLA compatibility between the donor and the recipient.16, 17, 18, 19, 20, 21, 22 Because of the establishment of many cord blood banks, nearly every patient can find a potential cord blood graft, suggesting that CBT could substantially expand the use of allogeneic transplantation in patients with metastatic RCC. Despite these potential advantages, there are several disadvantages such as susceptibility to graft rejection, prolonged recovery of hematopoiesis and unavailability of donor lymphocyte infusions. A clinical study focusing on minimizing toxicities and controlling infectious complications as well as enhancing GVT effects is needed to optimize the success of CBT for treatment of advanced RCC.
This work was supported in part by Grant-in-Aids for Scientific Research from the Ministry of Education, Science, Technology, Sports and Culture (KAKENHI 15790490) and from the Ministry of Health, Labor and Welfare, Japan. We are indebted to the patient and his family for participating in this study, to the staff at the Division of Hematology and Oncology at Kanazawa University Hospital, to the Japan Cord Blood Bank Network for processing the cord blood units, to Dr Richard Childs for valuable suggestions for the current study and to Megumi Yoshii and Arisa Hamano for their excellent technical assistance.