Publications (8)33.42 Total impact
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Article: Treatment selection for patients with metastatic renal cell carcinoma: identification of features favoring upfront IL-2-based immunotherapy.
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ABSTRACT: The availability of approved agents with distinct mechanisms of action (immunotherapy, vascular endothelial growth factor pathway, and mTOR inhibitors) has complicated treatment decisions for patients with advanced kidney cancer. High-dose IL-2 therapy is the only treatment that can produce durable complete responses; however, it has significant side effects and the vast majority of patients do not benefit. Thus, identifying the optimal patients to receive first-line IL-2 therapy is a priority. Past studies have identified some clinical features that might be associated with benefit from IL-2-based immunotherapy. Subsequent investigations of tumors from patients treated with IL-2 suggested that response was unlikely in patients with tumors with papillary features or low carbonic anhydrase IX (CAIX) expression. A model combining histologic features and CAIX expression separated patients into two groups of roughly equal size, with 96% of long-term responding patients being in the favorable prognostic group. This model is currently undergoing prospective validation. More recent studies involving gene expression profiling and array CGH have begun to identify additional features that might predict response to IL-2 therapy. Taken together, these data offer the possibility to limit the use of this toxic therapy to those most likely to benefit.Medical Oncology 02/2009; 26 Suppl 1:18-22. · 2.14 Impact Factor -
Article: Carbonic anhydrase IX as a predictive biomarker of response to kidney cancer therapy.
BJU International 07/2008; 101 Suppl 4:31-5. · 2.84 Impact Factor -
Article: Effect of melanoma on immune function in the regional lymph node basin.
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ABSTRACT: To determine if melanoma within the tumor microenvironment will result in immunosuppression within the draining lymph node as measured by down-regulation of T-cell receptor zeta (TCR zeta) expression. Patients with clinical stage I to III melanoma undergoing wide local excision and sentinel lymph node biopsy or therapeutic lymph node dissection were consented to have a portion of their lymph node sampled. Lymph nodes were classified as macroscopically involved (TI), microscopically involved (MI), noninvolved with positive wide excision (NI+), or noninvolved with negative wide excision (NI-). Lymphocytes were stained using antibodies to TCR zeta and other immune cells and analyzed via flow cytometer. Reverse transcription-PCR was used to assess for mediators of immunosuppression. Fifty patient lymph node samples (15 TI, 7 MI, 9 NI+, and 19 NI-) were evaluated. Increasing involvement of tumor in the lymph node was associated with decreasing TCR zeta chain expression (TI 56%, MI 76%, and NI- 89%). Differences between TI and MI (P = 0.005), TI and NI- (P = 0.0001), and MI and NI- (P = 0.019) were statistically significant. There was also a significant difference between TCR zeta chain expression of NI+ and NI- (73% versus 89%; P = 0.0016). A trend toward increased arginase expression in tumor-involved lymph nodes was detected by reverse transcription-PCR. Melanoma involvement of regional nodes is associated with loss of TCR zeta expression that is inversely related to tumor burden. Residual melanoma within the wide local excision specimen is associated with TCR zeta loss in noninvolved sentinel lymph nodes, suggesting that immune modulation precedes tumor spread.Clinical Cancer Research 03/2008; 14(3):654-9. · 7.74 Impact Factor -
Article: Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma.
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ABSTRACT: Similar to other molecularly targeted agents, temsirolimus, an inhibitor of mammalian target of rapamycin, has shown promising activity in advanced renal cell carcinoma. However, only a subset of patients appears to derive significant tumor responses. In an effort to identify potential predictors of response to temsirolimus, tumor samples from a subset of patients within a randomized phase II trial of temsirolimus in advanced renal cell carcinoma were studied. Paraffin-embedded tissue sections from patients who had received temsirolimus were immunostained with antibodies to carbonic anhydrase IX, phospho-S6, phospho-Akt (pAkt), and phosphotase and tensin homologue. Expression levels were correlated with objective response (partial response [PR], minor response [MR]) and clinical benefit (PR, MR, SD>or=4 cycles) to temsirolimus. In addition, von Hippel-Lindau (VHL) mutational analysis was performed and correlated with response. Tissue specimens were obtained from 20 patients who were evaluable for both tumor response and staining for phospho-S6 and carbonic anhydrase IX. In addition, 19 specimens were evaluable for pAkt, and 18 for phosphotase and tensin homologue. VHL mutational analysis was performed on 16 samples. Five patients achieved an objective response (1 PR/4 MRs) to temsirolimus. There was a positive association of phospho-S6 expression (P=.02) and a trend toward positive expression of pAkt (P=.07) with response to temsirolimus. No patient without high expression of either phospho-S6 or pAkt experienced an objective tumor response. There was no correlation of carbonic anhydrase IX and phosphotase and tensin homologue expression or VHL status with response to temsirolimus. These results suggest that phospho-S6 and pAkt expression are promising predictive biomarkers for response to temsirolimus that are worthy of further exploration for use in patient selection models for mammalian target of rapamycin inhibitors.Clinical Genitourinary Cancer 09/2007; 5(6):379-85. · 2.61 Impact Factor -
Article: What is standard initial systemic therapy in metastatic renal cell carcinoma?
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ABSTRACT: Historically, systemic therapies for metastatic renal cell carcinoma RCC) have met with minimal success. Recently, an improved understanding of cancer biology has been translated into therapies that target pathways critical for RCC growth and survival and produce more robust clinical impact. The risks and benefits of several approaches to systemic therapy in metastatic RCC are reviewed. The need for chronic therapy of novel agents and potential for toxicity raise questions in regard to the timing of therapy and value of combination therapy over sequential single agents. Further insight into the biology of response, resistance, and toxicity is needed to allow for rational patient selection and enhanced application of systemic therapies. As new standard therapies for metastatic RCC emerge, clinical trial conduct remains a priority to further optimize patient outcome.Clinical Genitourinary Cancer 04/2007; 5(4):256-63. · 2.61 Impact Factor -
Article: Designing clinical trials for kidney cancer based on newly developed prognostic and predictive tools.
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ABSTRACT: Several advances have been made in our understanding of the molecular aberrations in renal cell carcinoma that have led to the identification of novel prognostic and predictive biomarkers. At the same time, several novel agents targeting these molecular aberrations have shown promising efficacy in the therapy of advanced renal cancer. As these agents enter more advanced-stage clinical trials, efforts must be made to integrate exploration of these novel prognostic and predictive markers into clinical trial design. These elements then can be combined with more traditional prognostic features to form more robust prognostic models. Finally, predictive markers and prognostic models should be validated prospectively, either as part of clinical trials designed specifically for that purpose or as part of large phase-3 trials. Once validated, these features can be used to best inform prognosis and guide therapy based on individual patient characteristics.Current Urology Reports 02/2006; 7(1):8-15. -
Article: Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer.
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ABSTRACT: Renal cancer response to interleukin 2 (IL-2) therapy and patient survival has been correlated with tumor histology and carbonic anhydrase IX (CAIX) expression. In an effort to confirm and expand these observations, we examined CAIX expression in pathology specimens from renal cancer patients who had previously received IL-2 therapy. Paraffin-embedded tissue sections of renal cancer were immunostained with the MN-75 monoclonal antibody to CAIX and expression levels were correlated with histologic findings and clinical outcome. Tissue specimens were obtained from 66 patients; 27 of whom (41%) had responded to IL-2-based therapy. Fifty-eight specimens were assessed as clear cell, with 56, 33, and 4 having alveolar, granular, and papillary features, respectively. Twenty-four (36%), 31 (47%), and 11 (17%) were classified into good, intermediate, and poor prognosis groups according to the Upton pathology model. Forty-one specimens (62%) had high CAIX expression. Twenty-one of 27 (78%) responding patients had high CAIX expressing tumors compared with 20 of 39 (51%) nonresponders (odds ratio, 3.3; P = 0.04). Median survival was prolonged (P = 0.04) and survival >5 years was only seen in high CAIX expressers. In patients with intermediate pathologic prognosis, all nine responders had high CAIX expression versus 11 of 22 nonresponders. A resultant group with good pathologic prognosis alone or with intermediate pathologic prognosis and high CAIX contained 26 of 27 (96%) responders compared with 18 of 39 (46%) nonresponders (odds ratio, 30; P < 0.01) and exhibited longer median survival (P < 0.01). CAIX expression seems to be an important predictor of outcome in renal cell carcinoma patients receiving IL-2-based therapy and may enhance prognostic information obtained from pathology specimens.Clinical Cancer Research 05/2005; 11(10):3714-21. · 7.74 Impact Factor -
Article: Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses.
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ABSTRACT: Dendritic cells (DCs) are potent antigen-presenting cells that are uniquely capable of inducing tumor-specific immune responses. We have conducted a Phase I trial in which patients with metastatic breast and renal cancer were treated with a vaccine prepared by fusing autologous tumor and DCs. Accessible tumor tissue was disrupted into single cell suspensions. Autologous DCs were prepared from adherent peripheral blood mononuclear cells that were obtained by leukapheresis and cultured in granulocyte macrophage colony-stimulating factor, interleukin 4, and autologous plasma. Tumor cells and DCs were cocultured in the presence of polyethylene glycol to generate the fusions. Fusion cells were quantified by determining the percentage of cells that coexpress tumor and DC markers. Patients were vaccinated with fusion cells at 3-week intervals and assessed weekly for toxicity, and tumor response was assessed at 1, 3, and 6 months after completion of vaccination. The vaccine was generated for 32 patients. Twenty-three patients were vaccinated with 1 x 10(5) to 4 x 10(6) fusion cells. Fusion cells coexpressed tumor and DC antigens and stimulated allogeneic T-cell proliferation. There was no significant treatment-related toxicity and no clinical evidence of autoimmunity. In a subset of patients, vaccination resulted in an increased percentage of CD4 and CD8+ T cells expressing intracellular IFN-gamma in response to in vitro exposure to tumor lysate. Two patients with breast cancer exhibited disease regressions, including a near complete response of a large chest wall mass. Five patients with renal carcinoma and one patient with breast cancer had disease stabilization. Our findings demonstrate that fusion cell vaccination of patients with metastatic breast and renal cancer is a feasible, nontoxic approach associated with the induction of immunological and clinical antitumor responses.Clinical Cancer Research 08/2004; 10(14):4699-708. · 7.74 Impact Factor
Top co-authors
Top Journals
Institutions
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2005–2009
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Beth Israel Deaconess Medical Center
- Division of Hematology/Oncology
Boston, MA, USA
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2008
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Harvard University
- Department of Medicine Brigham and Women's Hospital
Boston, MA, USA
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2007
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Cleveland Clinic
- Department of Solid Tumor Oncology
Cleveland, OH, USA
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