Preoperative CTLA-4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical Trial

Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Clinical Cancer Research (Impact Factor: 8.72). 05/2010; 16(10):2861-71. DOI: 10.1158/1078-0432.CCR-10-0569
Source: PubMed


Cytotoxic T lymphocyte associated antigen (CTLA-4) blockade is being explored in numerous clinical trials as an immune-based therapy for different malignancies. Our group conducted the first preoperative clinical trial with the anti-CTLA-4 antibody ipilimumab in 12 patients with localized urothelial carcinoma of the bladder.
Six patients were treated with 3 mg/kg/dose of anti-CTLA-4 and six patients were treated with 10 mg/kg/dose of antibody. Primary end points of the study were safety and immune monitoring.
Most drug-related adverse events consisted of grade 1/2 toxicities. All patients had measurable immunologic pharmacodynamic effects, consisting of an increased frequency of CD4+ICOShi T cells in tumor tissues and the systemic circulation. To determine if CD4+ICOShi T cells could be a correlative marker for clinical outcome after treatment with anti-CTLA-4, a cohort of metastatic melanoma patients was studied retrospectively for frequency of CD4+ICOShi T cells and survival. Data from this small cohort of patients indicated that an increased frequency of CD4+ICOShi T cells, sustained over a period of 12 weeks of therapy, correlates with increased likelihood of clinical benefit consisting of overall survival.
Our trial shows that anti-CTLA-4 therapy has a tolerable safety profile in the presurgical setting and that a preoperative model can be used to obtain biological data on human immune responses, which can efficiently guide the monitoring of patients treated in the metastatic disease setting.

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    • "Carthon et al. at MD Anderson showed in a small dose escalation study of ipilimumab for localized urothelial carcinoma of the bladder that there was limited toxicity . They also noted an increased frequency of CD4 + ICOS high (activated T-cells) in the systemic circulation of these patients [66]. There is currently an on-going phase II clinical trial (NCT01524991) examining the combination of gemcitabine, cisplatin and ipilimumab for metastatic urothelial carcinoma with a primary outcome measurement of one-year overall survival. "

    04/2015; 1(1):15-27. DOI:10.3233/BLC-150014
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    • "This was the first study reporting immunological changes in both tumor tissues and peripheral blood after treatment with anti-CTLA-4 therapy. Furthermore, in a small retrospective study, an increased frequency of CD4+ICOShi T cells sustained over a period of 12 weeks of therapy correlated with increased likelihood of overall survival benefit in a cohort of patients with melanoma [66]. CD4+ICOShi T cells were also shown to have a specificity of ~96% as a pharmacodynamic biomarker for anti-CTLA-4 therapy [67]. "
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    • "ICOS expression is up-regulated upon T cell activation, which is enhanced in the setting of CTLA-4 blockade, thereby leading to a higher frequency of ICOS + T cells detected in cancer patients receiving anti–CTLA-4 therapy, with the ICOS + population containing the bulk of tumor-specific, IFN-–producing CD4 T cells (Liakou et al., 2008; Carthon et al., 2010; Vonderheide et al., 2010). In a retrospective study of advanced melanoma patients, we also found a significant correlation between sustained elevation of ICOS + CD4 T cells in the peripheral blood after ipilimumab treatment and increased survival (Carthon et al., 2010). These clinical studies suggested that ICOS might play an important role in the therapeutic effect of anti–CTLA-4. "
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