Allogeneic stem-cell transplantation for renal-cell cancer

Metastatic renal-cell carcinoma (RCC) is resistant to chemotherapy, and patients with this disease have a poor outlook. Immunotherapy by use of cytokines and vaccines against tumour antigens has shown encouraging results in a small group of patients. Advances in the understanding of the graft-versus-tumour effect in haematological malignant disorders have led to the use of stem-cell transplantation for treatment of solid-organ malignant diseases such as RCC. Techniques of bone-marrow ablation have been superseded by safer conditioning regimens, with occasional complete remission and partial remission in some patients. Graft-versus-host disease, engraftment failure, and disease progression remain important obstacles to the widespread use of new techniques for metastatic RCC. Here, we summarise important issues surrounding immunotherapy for RCC, the problems encountered with use of immunotherapy, and the present use of non-myeloablative techniques for treatment of this disease.     

Allogeneic hematopoietic stem-cell transplantation for hematological malignancies

Allogeneic transplantation of hematopoietic stem cells (HSC) is a curative treatment for hematological malignancies aiming to eradicate the malignant clone using the immunological conflict inherent to donor HSC installation in the recipient. The different possible sources of HSCs (bone marrow, blood, and cord blood) and better knowledge of HLA typing has led to the development of new transplantation techniques and modalities (transplantations after non-myeloablative conditioning, haploidentical transplantations, etc.), which should improve patient survival and extend allograft indications. HSC allografting is subject to immunological reactions stemming from the histocompatibility discrepancy between donor and recipient. For the most part, these are reactions of the graft against the host (graft-versus-host disease: GVHD) and graft rejection (host-versus-graft: HVG). This immunological conflict can also be responsible for recognizing and destroying the recipient's residual tumor cells, which carry specific tumor antigens and/or minor antigens of histocompatibility (graft-versus-leukemia effect, GVL or graft-versus-malignancy effect, GVM). The posttransplantation period can also be riddled with various complications such as veno-occlusive disease, endocrine complications, as well as complications arising from infections and secondary neoplasms because of a more or less substantial and durable immune deficiency. Acute and chronic leukemias are the major indications for HSC allogeneic transplantation, for which the results are variable and closely related to the patient status, the hematological disease, and the transplant procedure. Other hematological diseases are also indications for allogeneic transplantation but are rarer, for which allogeneic transplantation remains nevertheless the only curative treatment, despite an overly high level of toxicity. Improvement in the results of unrelated transplantations, use of peripheral HSC or cord blood cells, development of non-myeloablative conditioning regimens, and techniques of ex vivo manipulation of the graft have allowed HSC allogeneic transplantation indications to be extended. The antitumor efficacy of donor lymphocytes infusion for relapses after transplantation mirrors the GVL effect and is the first stage in a targeted cellular immunotherapy using sensitized lymphocytes or dendritic cells.     

Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors

Background:An update of results from the High Risk Protocol ofthe Meta-EICESS Study, conducted at the Pediatric Stem-Cell Transplant Centersof Düsseldorf and Vienna. In order to evaluate a possible therapeuticbenefit after allogeneic SCT in patients with advanced Ewing tumors (AET), wecompared outcome after autologous and allogeneic stem-cell transplantation(SCT). Patients and methods:We analyzed 36 patients treated with themyeloablative Hyper-ME protocol (hyperfractionated total body irradiation,melphalan, etoposide ± carboplatin) between November 1986 and December1994. Minimal follow-up for all patients was five years. All patientsunderwent remission induction chemotherapy and local treatment beforemyeloablative therapy. Seventeen of thirty-six patients had multifocal primaryEwing's tumor, eighteen of thirty-six had early, multiple or multifocalrelapse, one of thirty-six patients had unifocal late relapse. Twenty-six ofthirty-six were treated with autologous and ten of thirty-six with allogeneichematopoetic stem cells. We analyzed the following risk factors, that couldpossibly influence the event-free survival (EFS): number of involved bones,degree of remission at time of SCT, type of graft, indication for SCT, bonemarrow infiltration, bone with concomitant lung disease, age at time ofdiagnosis, pelvic involvement, involved compartment radiation,histopathological diagnosis. Results:EFS for the 36 patients was 0.24 (0.21) ± 0.07.Eighteen of thirty-six patients suffered relapse or died of disease, nine ofthirty-six died of treatment related toxicity (DOC). Nine of thirty-sixpatients are alive in CR. Age 17 years at initial diagnosis (P< 0.005) significantly deteriorated outcome. According to the type ofgraft, EFS was 0.25 ± 0.08 after autologous and 0.20 ± 0.13after allogeneic SCT. Incidence of DOC was more than twice as high afterallogeneic (40%) compared to autologous (19%) SCT, even thoughthe difference did not reach significance (P = 0.08, Fisher's exacttest). Conclusions:Because of the rather short observation period,secondary malignant neoplasm (SMN) may complicate the future clinical courseof some of our patients who are currently viewed as event-free survivors. EFSin AET is not improved by allogeneic SCT due to a higher complication rate.The patient group was to small to analyze for a possiblegraft-versus-tumor effect.     

Allogeneic stem-cell transplantation from related and unrelated donors in older patients with myeloid leukemia.

PURPOSE: To improve outcome for older patients with poor-prognosis myeloid malignancies by using allogeneic hematopoietic stem-cell transplantation (alloHSCT) from unrelated and sibling donors after reduced-intensity conditioning (RIC). PATIENTS AND METHODS: Nineteen older patients (median age, 64 years; range, 60 to 70 years) with active myeloid malignancies were treated with an RIC regimen that was based on fludarabine, melphalan, and carmustine followed by alloHSCT from matched unrelated (n = 12) or sibling donors (n = 7). Before transplantation, patients had a median of 50% bone marrow blasts (range, 0% to 70%). Graft-versus-host-disease (GvHD) prophylaxis consisted of cyclosporine and mycophenolate mofetil or methotrexate. Eleven of 12 patients with an unrelated donor also received anti-T-lymphocyte globulin (ATG). RESULTS: Engraftment was successful for all 19 patients. Seventeen assessable patients achieved complete response (CR). Four patients experienced relapse; three achieved CR again after donor lymphocyte infusion (n = 1) or a second alloHSCT (n = 2). Six patients died as a result of relapse (n = 2), GvHD-associated complications (n = 2), or fungal infections (n = 2), resulting in a 1-year nonrelapse mortality rate of 22%. With a median follow-up of 825 days (range, 595 to 1,028 days), 13 of 19 patients are alive, resulting in a 1-year survival rate of 68% (95% confidence interval, 48% to 89%). CONCLUSION: In older patients with untreated poor-prognosis leukemia, this RIC regimen combined with alloHSCT sufficiently reduces the leukemic burden, resulting in a high CR rate. When ATG is added, matched unrelated donor transplantation can be performed safely in older patients. For these patients, early transplantation after diagnosis offers a fair chance of cure.     

Allogeneic stem-cell transplantation in patients with cutaneous lymphoma: updated results from a single institution

BackgroundCutaneous T-cell lymphomas (CTCLs) and its common variants mycosis fungoides (MF) and leukemic Sézary syndrome (SS) are rare extranodal non-Hodgkin's lymphomas. Patients who present with advanced disease and large-cell transformation (LCT) are incurable with standard treatments. In this article, we report the largest single-center experience with allogeneic stem-cell transplantation (SCT) for advanced CTCL.Patients and methodsThis is a prospective case series of 47 CTCL patients who underwent allogeneic SCT after failure of standard therapy between July 2001 and September 2013. The Kaplan–Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) curves. The method of Fine and Gray was used to fit regression models to the same covariates for these cumulative incidence data.ResultsThe Kaplan–Meier estimates of OS and PFS at 4 years were 51% and 26%, respectively. There was no statistical difference in the OS in patients who had MF alone, SS, MF with LCT, or SS with LCT. PFS at 4 years was superior in patients who had SS versus those who did not (52.4% versus 9.9%; P = 0.02). The cumulative incidences of grade 2–4 acute graft-versus-host disease (GVHD) and chronic GVHD were 40% and 28%, respectively. The cumulative nonrelapse mortality rate was 16.7% at 2 years.ConclusionAllogeneic SCT may result in long-term remissions in a subset of patients with advanced CTCL. Although post-SCT relapse rates are high, many patients respond to immunomodulation and achieve durable remissions.ClinicalTrials.govNCT00506129.     

Allogeneic stem cell transplantation for renal cell carcinoma

Allogeneic hematopoietic stem cell transplantation from a compatible donor has been utilized as adoptive immunotherapy in metastatic, cytokine-refractory renal cell carcinoma (RCC). Since the year 2000, several investigators have established that RCC is susceptible to a graft-versus-tumor effect: they reported that patients with renal cancer may have partial or complete disease responses, in the 20-40% range, after allogeneic transplantation following a reduced-intensity regimen. However, transplant-related mortality is still high in the 10-20% range, and responses are rarely durable. Experimental evidence suggests that donor-derived T cells and natural killer cells are the main mediators of the graft-versus-RCC effect upon allogeneic hematopoietic stem-cell transplantation. Isolation of CD8(+) cytotoxic T lymphocyte clones recognizing several target antigens of graft-versus-RCC effect (minor histocompatibility antigens on RCC cells; a peptide epitope derived from human endogenous retrovirus type E; the tumor-associated antigen encoded by the Wilms' tumor 1 gene) has increased our knowledge of the disease and has opened up the possibility of antigen-specific adoptive cell therapy. The introduction in the clinic of molecularly targeted agents that interfere with neoangiogenesis, both monoclonal antibodies and small tyrosine-kinase inhibitor molecules (e.g., sunitinib, sorafenib and bevacizumab), has decreased the use of allogeneic transplantation. Although not curative, novel targeted agents may be combined with allogeneic transplantation or with adoptive cell therapy in order to maximize the chances of cure.     

Allogeneic stem cell transplantation for renal cell carcinoma

Allogeneic hematopoietic stem cell transplantation from a compatible donor has been utilized as adoptive immunotherapy in metastatic, cytokine-refractory renal cell carcinoma (RCC). Since the year 2000, several investigators have established that RCC is susceptible to a graft-versus-tumor effect: they reported that patients with renal cancer may have partial or complete disease responses, in the 20–40% range, after allogeneic transplantation following a reduced-intensity regimen. However, transplant-related mortality is still high in the 10–20% range, and responses are rarely durable. Experimental evidence suggests that donor-derived T cells and natural killer cells are the main mediators of the graft-versus-RCC effect upon allogeneic hematopoietic stem-cell transplantation. Isolation of CD8⁺ cytotoxic T lymphocyte clones recognizing several target antigens of graft-versus-RCC effect (minor histocompatibility antigens on RCC cells; a peptide epitope derived from human endogenous retrovirus type E; the tumor-associated antigen encoded by the Wilms’ tumor 1 gene) has increased our knowledge of the disease and has opened up the possibility of antigen-specific adoptive cell therapy. The introduction in the clinic of molecularly targeted agents that interfere with neoangiogenesis, both monoclonal antibodies and small tyrosine-kinase inhibitor molecules (e.g., sunitinib, sorafenib and bevacizumab), has decreased the use of allogeneic transplantation. Although not curative, novel targeted agents may be combined with allogeneic transplantation or with adoptive cell therapy in order to maximize the chances of cure.     

Allogeneic hematopoietic stem-cell transplantation: the next generation of therapy for metastatic renal cell cancer

The management of metastatic renal cell carcinoma (mRCC) remains a therapeutic challenge; less than 10% of patients survive for longer than 5 years. The resistance of renal cancer to chemotherapy may be explained by high levels of the multidrug resistance gene, MDR1. Immune-based treatments for renal cancer have been explored because of their unusual susceptibility to immunological assault. However, response rates to cytokines such as interleukin-2 and interferon-alpha have ranged from only 10% to 20%, prompting other immunotherapy approaches, such as allogeneic stem-cell transplantation, to be investigated. Several clinical trials have provided evidence of partial or complete disease regression in refractory mRCC following nonmyeloablative stem-cell transplantation. This effect is because of a donor antimalignancy effect mediated by immunocompetent donor T cells, called graft-versus-tumor effect. Unfortunately, less than 30% of patients who could have this procedure will have a human-leukocyte-antigen-compatible sibling, and attention is focusing on alternative donors such as matched unrelated donors and partially mismatched related donors. Despite the improved safety of nonmyeloablative conditioning regimens, transplant-related toxic effects (particularly graft-versus-host disease) remain obstacles to the safe and effective use of this treatment. Regardless of these limitations, innovative approaches have attempted to harness the potential of the graft-versus-tumor effect in mRCC and other solid tumors.     

High-dose toremifene in advanced renal-cell carcinoma

 Toremifene (Fareston) – a novel antiestro-genic drug with a triphenylethylene structure – is effective in the treatment of postmenopausal breast cancer patients. It can be safely given even at high doses of up to 300 mg/day. The purpose of the present study was to investigate the effect and tolerability of high-dose toremifene in the treatment of patients with advanced renal-cell carcinoma (RCC). A total of 36 patients started treatment with toremifene at 300 mg/day, including 26 men and 10 women. Their mean age was 56 years (range 35–75 years). In all, 19 patients were nephrectomized. One patient was not evaluable for response because of insufficient treatment time. The response rate was 17%, including one complete response (CR, 3%) lasting for 121+ weeks and five partial responses (PRs, 14%) with a mean duration of 40+ weeks. Ten cases of no change (NC, 28%) had a mean duration of 24 weeks. There was no significant difference in the response rate when patients with lung metastases alone were compared with patients showing metastases of other sites with or without lung metastases. Total pain control was achieved in 45% of the patients who had pain at the beginning of the treatment, and partial control was attained in 20%. Ten patients (28%) developed adverse reactions, which led to discontinuation of the treatment in one case. Blood samples were taken from 16 patients on days 0, 1, 3, 7, 14, and 28 for drug analyses. The concentration of toremifene and its main metabolites measured in serum were about 1.5 times that detected after a conventional dose of 60 mg/day. It can be concluded that high-dose toremifene is an effective and safe palliative treatment in advanced RCC. Received: 5 May 1996 / Accepted: 5 November 1996     

Sunitinib re-challenge in advanced renal-cell carcinoma

Despite offering significant clinical benefits in advanced renal-cell carcinoma (RCC), the effectiveness of targeted therapies eventually declines with the development of resistance. Defining optimal sequences of therapy is therefore the focus of much current research. There is also evidence that treatment ‘re-challenge'' may be an effective strategy in some patients. We review evidence to evaluate whether sunitinib may have value as re-challenge therapy in patients who have progressed on prior targeted therapy with sunitinib and/or an alternative tyrosine kinase inhibitor or mammalian target of rapamycin inhibitor. Re-challenge with sunitinib appears to be of clinical benefit, thus representing a feasible therapeutic option for patients with advanced RCC who are refractory to other treatments and are able to receive further therapy. These observations support hypotheses that resistance to targeted agents is transient and can be at least partially reversed by re-introduction of the same agent after a treatment break. Median progression-free survival durations appear to be shorter and response rates lower on re-challenge than following initial treatment, although a wider interval between treatments appears to increase response to sunitinib re-challenge.     

The etiology of renal-cell carcinoma

Experimental renal-cell carcinoma can be induced by many different chemical carcinogens; dimethyl nitrosoamine has been most studied. The disease so induced in experimental animals closely resembles the spontaneous disease in man in histopathology, course, and other characteristics. Two agents that are probably etiological of renal-cell cancer in man are tobacco and the analgesic, phenacetin; however, these materials can account for only a minority of the cases. The predominance of males in adult renal carcinoma might be explained by the more efficient metabolic activation of carcinogens by renal enzymes that are induced by male hormones. Mouse experiments support this hypothesis. Studies utilizing human kidney tissues that would test the hypothesis in man can and should be done. No obvious clues have emerged to explain the wide geographic differences in incidence of renal carcinoma. No group of industrial workers, or of others with a unique environment, has yet been described that has an especially high incidence of renal-cell carcinoma. A minority of renal carcinomas are familial. They represent a number of different diseases, one of which is associated with the von Hippel-Lindau disease. The hereditary renal-cell carcinoma of the Ecker rat, which is transmitted as an autosomal dominant, provides a useful laboratory model for hereditary carcinoma of man. Recently, two human families with renal-cell carcinoma were described in which there were unique chromosomal abnormalities associated with the disease. Such changes have been linked with oncogene activation in the instance of other tumors. Further studies of chromosomal abnormalities in renal-cell carcinoma will probably define a common pattern of chromosomal rearrangements. While estrogen readily induces renal-cell carcinoma in hamsters other species, including man, appear resistant. An excess of renal-cell carcinoma has not been reported in men on chronic estrogen therapy for prostatic carcinoma, nor has it been associated with the DES syndrome. A virus etiology for renal-cell carcinoma in man comparable to that of the Lucke tumor in frogs is unlikely on epidemiologic, ultrastructural morphologic, and other grounds. There is nothing suggesting horizontal transmission in the human disease, and a unique excess of renal-cell carcinomas in immunosuppressed patients or patients with the acquired immunodeficiency syndrome (AIDS) is not apparent. There is overwhelming evidence that renal adenomas represent early adenocarcinomas, or at least precursor lesions; certainly they are closely related to renal-cell carcinomas.(ABSTRACT TRUNCATED AT 400 WORDS)     

Molecular biology of renal-cell carcinoma

Renal-cell cancer (RCC) is an heterogeneous disease consisting of different subtypes that show peculiar histological features and genetic alterations. Although inherited or familial predisposition occurs in less than 4% of renal cancers, most of the available information on the genetic alterations involved in the pathogenesis of RCC derives from the study of the inherited forms of kidney cancer: von Hippel-Lindau (VHL gene), hereditary papillary renal carcinoma (MET proto-oncogene), hereditary leiomyomatosis and renal-cell cancer (fumarate hydratase gene), and Birt–Hogg–Dube (BHD gene) syndromes. Such genetic alterations have also been detected in sporadic RCCs. In particular, inactivation of VHL gene by mutation or hypermethylation has been found in up to 70% of sporadic clear-cell RCC, and it has been associated with increased hypoxia-inducible factor (HIF) activity. The knowledge of these deregulated genes and their downstream pathways provides the rationale for the development of target-based approaches for RCC.