Tumor necrosis factor alpha as a new target for renal cell carcinoma: two sequential phase II trials of infliximab at standard and high dose.

PURPOSE: Tumor necrosis factor alpha (TNF-alpha) may play a role in renal cell carcinoma (RCC). We performed two sequential phase II studies of infliximab, an anti-TNF-alpha monoclonal antibody, in patients with immunotherapy-resistant or refractory RCC. PATIENTS AND METHODS: Patients progressing after cytokine therapy were treated with intravenous infliximab as follows: study 1 (19 patients), 5 mg/kg at weeks 0, 2, and 6, and then every 8 weeks; study 2 (18 patients), 10 mg/kg at weeks 0, 2, and 6, and then every 4 weeks. Treatment continued until disease progression (PD). Response was assessed according to Response Evaluation Criteria in Solid Tumors. Plasma levels of TNF-alpha, CCL2, and interleukin-6 (IL-6) were measured before and during treatment. RESULTS: TNF-alpha and its receptors were detected in malignant cells in RCC biopsies. In study 1, three patients (16%) achieved partial response (PR) and three patients (16%) achieved stable disease (SD). Median duration of response (PR + SD) was 7.7 months (range, 5.0 to 40.5+ months). In study 2, 11 patients (61%) achieved SD. Median duration of response was 6.2 months (range, 3.5 to 24+ months). One patient developed grade 3 hypersensitivity and another died as a result of pulmonary infection/sepsis. Enzyme-linked immunosorbent assay analysis of plasma revealed that higher levels of TNF-alpha at baseline and higher levels of CCL2 during treatment were associated with PD. There were also correlations between higher levels of TNF-alpha, IL-6, and CCL2 and poor survival (< 12 months). CONCLUSION: This is the first direct clinical evidence suggesting that TNF-alpha may be a therapeutic target in RCC. Plasma levels of TNF-alpha, IL-6, and CCL2 may have predictive and prognostic significance.

Bortezomib therapy in patients with relapsed or refractory lymphoma: potential correlation of in vitro sensitivity and tumor necrosis factor alpha response with clinical activity.

PURPOSE: To determine the efficacy of bortezomib in patients with lymphoid malignancy, correlating clinical response with effect on plasma cytokines and in vitro activity in primary cultures. PATIENTS AND METHODS: Patients received bortezomib (1.3 mg/m2) on days 1, 4, 8, and 11 of a 3-week cycle. Plasma tumor necrosis factor alpha (TNF-alpha) and interleukin-6 were measured before each treatment, and bortezomib activity was examined in patient samples grown in primary culture. RESULTS: Fifty-one patients received a total of 193 cycles of treatment. Twenty-four patients had mantle cell lymphoma (MCL), 13 had follicular lymphoma (FL), six had lymphoplasmacytic lymphoma, six had Hodgkin's disease (HD), and one each had diffuse large B-cell lymphoma and adult T-cell leukemia/lymphoma. Patients were heavily pretreated with a median of four previous therapies. Significant grade 3 to 4 toxicities were thrombocytopenia (n = 22), fatigue (n = 10), and peripheral neuropathy (n = 3). Seven patients with MCL responded to treatment (one complete response, six partial responses [PRs]; overall response rate, 29%). Two patients with FL achieved a late PR 3 months after discontinuing therapy. Two patients with Waldenström's macroglobulinemia and one patient with HD achieved a PR. MCL primary cultures demonstrated greater sensitivity to bortezomib than FL (median 50% effective concentration for viability, 209 nmol/L v 1,311 nmol/L, respectively; P = .07), which correlated with clinical response. A median reduction in plasma TNF-alpha of 98% was observed in six patients with MCL who responded to bortezomib compared with a reduction of 38% in six nonresponders (P = .07). CONCLUSION: Bortezomib demonstrates encouraging efficacy in MCL in heavily pretreated individuals. Response was associated with a reduction in plasma TNF-alpha and in vitro sensitivity in a small number of patients.

Study of etanercept, a tumor necrosis factor-alpha inhibitor, in recurrent ovarian cancer.

PURPOSE: Convincing data support the link between inflammation and ovarian cancer. Tumor necrosis factor-alpha (TNF-alpha), a major mediator of inflammation, is chronically produced in the ovarian tumor microenvironment and may enhance tumor growth and invasion by inducing the secretion of cytokines, proangiogenic factors, and metalloproteinases. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-alpha and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biologic activity, and therapeutic efficacy of etanercept in recurrent ovarian cancer. PATIENTS AND METHODS: We initiated a phase I-B, nonrandomized, open-label study in patients with recurrent ovarian cancer. Etanercept was administered subcutaneously at a dose of 25 mg twice weekly (cohort one) and 25 mg thrice weekly (cohort two) until disease progression. RESULTS: Thirty patients were recruited (cohort one, 17 patients; cohort two, 13 patients). Eighteen of the 30 patients (cohort one, 11 patients; cohort two, seven patients) completed > or = 12 weeks of treatment. Six patients achieved prolonged disease stabilization (cohort one, two patients [40 and 25 weeks]; cohort two, four patients [34, 24, 22, and 24 weeks]). A significant rise in immunoreactive TNF was seen in all patients (pretreatment compared with end of treatment). A phytohemagglutinin-stimulated whole-blood cytokine assay showed a significant fall in interleukin-6 (cohort one [11 of 17]) and CCL2 (cohort one [13 of 17]) levels. Common adverse effects were injection-site reactions and fatigue. CONCLUSION: We provide evidence for the biologic activity and safety of etanercept in recurrent ovarian cancer. Our data suggest possible clinical activity that must be confirmed in future studies.

A phase II study of etanercept (Enbrel), a tumor necrosis factor alpha inhibitor in patients with metastatic breast cancer.

PURPOSE: Tumor necrosis factor (TNF) alpha is a key player in the tumor microenvironment and is involved in the pathogenesis of breast cancer. Etanercept is a recombinant human soluble p75 TNF receptor that binds to TNF-alpha and renders it biologically unavailable. In the current study, we sought to determine the toxicity, biological activity, and therapeutic efficacy of Etanercept in metastatic breast cancer. EXPERIMENTAL DESIGN: We initiated a Phase II, nonrandomized, open-labeled study in patients with progressive metastatic breast cancer refractory to conventional therapy (Phase I toxicity data were available in patients with rheumatoid arthritis). Etanercept was administered subcutaneously at a dose of 25 mg twice weekly until disease progression. RESULTS: Sixteen patients were recruited [median age 53 years (range, 34 to 74)]. A total of 141.6 weeks of therapy was administered (median of 8.1 weeks). Seven patients received > or =12 weeks of therapy. The most common side effects were injection site reactions (6), fatigue (5), loss of appetite (2), nausea (1), headache (1), and dizziness (1). Brief period of disease stabilization was seen in 1 patient lasting for 16.4 weeks. Immunoreactive TNF-alpha was elevated within 24 hours of therapy and persisted until the end of treatment (days 7, 28, 56, and 84). Phytohemagglutinin stimulates the production of interleukin-6 and CCL2 in peripheral blood cells, and the ability of Etanercept to modulate this response was assessed in a cytokine release assay. A consistent decrease in interleukin-6 and CCL2 level was seen compared with pretreatment values in serial blood samples (days 1, 7, 28, 56, and 84). CONCLUSIONS: Our study shows the safety and biological activity of Etanercept in breast cancer and provides data to assess pharmacodynamic endpoints of different schedules of Etanercept and combinations with chemotherapy or other biological therapies.