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

ABSTRACT 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.

Download full-text


Available from: Jianda D Yuan, Sep 25, 2015
122 Reads
  • Source
    • "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
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Knowledge of the basic mechanisms of the immune system as it relates to cancer has been increasing rapidly. These developments have accelerated the translation of these advancements into medical breakthroughs for many cancer patients. The immune system is designed to discriminate between self and non-self, and through genetic recombination there is virtually no limit to the number of antigens it can recognize. Thus, mutational events, translocations, and other genetic abnormalities within cancer cells may be distinguished as "altered-self" and these differences may play an important role in preventing the development or progression of cancer. However, tumors may utilize a variety of mechanisms to evade the immune system as well. Cancer biologists are aiming to both better understand the relationship between tumors and the normal immune system, and to look for ways to alter the playing field for cancer immunotherapy. Summarized in this review are discussions from the 2013 SITC Primer, which focused on reviewing current knowledge and future directions of research related to tumor immunology and cancer immunotherapy, including sessions on innate immunity, adaptive immunity, therapeutic approaches (dendritic cells, adoptive T cell therapy, anti-tumor antibodies, cancer vaccines, and immune checkpoint blockade), challenges to driving an anti-tumor immune response, monitoring immune responses, and the future of immunotherapy clinical trial design.
    05/2014; 2(1):14. DOI:10.1186/2051-1426-2-14
  • Source
    • "In 10 patients with available matched tumor specimen and peripheral blood samples, significantly higher percentage of CD4 + FOXP3+ T-regulatory cells and lower ratio of CD8+/CD4 + FOXP3+ in the tumor compared with blood were reported. Safety of preoperative ipilimumab therapy has also been evaluated in 12 surgical patients with urothelial carcinoma of the bladder [43]. Only grade I/II toxicities were observed. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neoadjuvant therapy is an under-utilized regimen for the treatment of metastatic melanoma. The use of this approach has been increasing in other tumor types. Neoadjuvant therapy may reduce occult circulating tumor cell burden in the face of bulky disease and afford a real time evaluation of treatment effectiveness. Neoadjuvant approach can also provide preoperative histologic and molecular analysis of treated tissue that may guide the postoperative treatment planning in patients with resectable metastatic melanoma lesions. The putative benefits of better margin control and clearance of occult systemic disease would theoretically improve surgical outcome. With the advent of effective agents against metastatic melanoma, this common approach to the treatment of rectal cancer, metastatic colon cancer, and breast cancer should also be evaluated as a viable treatment strategy for advanced stage melanoma.
    11/2013; 2(1):30. DOI:10.1186/2162-3619-2-30
Show more