Seminars in oncology
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Seminars in oncology · Oct 1999
Clinical TrialStem cell function and engraftment is not affected by "in vivo purging" with rituximab for autologous stem cell treatment for patients with low-grade non-Hodgkin's lymphoma.
The chimeric anti-CD20 monoclonal antibody rituximab (Rituxan; IDEC Pharmaceuticals, San Diego, CA, and Genentech, Inc, San Francisco, CA) has recently been approved by the US Food and Drug Administration as single-agent treatment of relapsed/refractory low-grade or follicular non-Hodgkin's lymphoma. Initial results from the pivotal clinical trial revealed that response rates to rituximab were higher in patients who previously had high-dose therapy and autologous stem cell transplantation. We have initiated a clinical trial that combines the use of rituximab with high-dose chemotherapy followed by autologous stem cell transplantation for patients with chemosensitive relapsed follicular small cleaved or mantle cell lymphoma. ⋯ The median number of platelet transfusions was two for patients receiving rituximab and 2.5 for the control group. Assessment of serum cytokines immediately before the rituximab infusion during the stem cell mobilization and immediately after revealed a twofold to sevenfold increase in interleukin-1beta, tumor necrosis factor-alpha, and interleukin-6. The polymerase chain reaction analysis for minimal residual disease in stem cell collections and in peripheral blood and bone marrow samples of these patients will help to determine the efficacy of rituximab in vivo purge on disease progression.
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Seminars in oncology · Aug 1999
Clinical TrialCombination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity.
The anti-HER-2/neu antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) interferes with DNA repair induced by cisplatin and, as a result, promotes cytotoxicity in HER-2/neu-overexpressing tumor target cells in a synergistic fashion. This effect of trastuzumab, termed receptor-enhanced chemosensitivity, is specific for HER-2/neu-overexpressing cells, having no effect on cells without overexpression. Based on these findings, we conducted phase I and II clinical trials of trastuzumab plus cisplatin to determine the toxicity, pharmacokinetics, response rate, and response duration of this combination in patients with HER-2/neu-overexpressing metastatic breast cancer who had demonstrated disease progression (chemoresistance) while on active chemotherapy just prior to study entry. ⋯ Moreover, the pharmacokinetics of trastuzumab were unaltered by coadministration of cisplatin. We conclude that the combination of trastuzumab and cisplatin results in response rates higher than that reported for either single agent alone. Such receptor-enhanced chemosensitivity offers a new approach to target overexpressed growth factor receptors in a variety of cancers, which will lead to new, biologically based therapeutic strategies for clinical intervention.
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Seminars in oncology · Aug 1999
ReviewOverview of the trastuzumab (Herceptin) anti-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin Multinational Investigator Study Group.
The recombinant humanized anti-HER2 monoclonal antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) was evaluated in human clinical trials for treatment of women with metastatic breast cancer who have tumors that overexpress HER2. The trastuzumab clinical program consisted of a series of phase I, phase II, and phase III clinical trials. ⋯ Preliminary results of the pivotal clinical trials that have been presented at national meetings are summarized below. The data suggest that trastuzumab will be an important new treatment option for women with HER2-overexpressing metastatic breast cancer.
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Seminars in oncology · Aug 1999
ReviewNonclinical studies addressing the mechanism of action of trastuzumab (Herceptin).
HER2 is a ligand-less member of the human epidermal growth factor receptor or ErbB family of tyrosine kinases. In normal biological systems, HER2 functions as a co-receptor for a multitude of epidermal growth factor-like ligands that bind and activate other HER family members. HER2 overexpression is observed in a number of human adenocarcinomas and results in constitutive HER2 activation. ⋯ Trastuzumab treatment of mouse xenograft models results in marked suppression of tumor growth. When given in combination with standard cytotoxic chemotherapeutic agents, trastuzumab treatment generally results in statistically superior antitumor efficacy compared with either agent given alone. Taken together, these studies suggest that the mechanism of action of trastuzumab includes antagonizing the constitutive growth-signaling properties of the HER2 system, enlisting immune cells to attack and kill the tumor target, and augmenting chemotherapy-induced cytotoxicity.
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Seminars in oncology · Aug 1999
Clinical TrialPhase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer.
The HER2/neu proto-oncogene is overexpressed in 25% to 30% of patients with breast cancer. Trastuzumab (Herceptin; Genentech, San Francisco, CA), a recombinant humanized monoclonal antibody with high affinity for the HER2 protein, inhibits the growth of breast cancer cells overexpressing HER2. In this phase II study the efficacy and toxicity of weekly administration of trastuzumab was evaluated in 46 patients with metastatic breast cancer whose tumors overexpressed HER2. ⋯ Minor responses (seen in 2 patients) and stable disease (14 patients) lasted for a median of 5.1 months. These results demonstrate that trastuzumab is well tolerated and clinically active in patients with HER2-overexpressing metastatic breast cancers who have received extensive prior therapy. The regression of human cancer through the targeting of putative growth factor receptors such as HER2 warrants further evaluation of trastuzumab in the treatment of breast cancer.