Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Carthon
Bradley C
BC
Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wolchok
Jedd D
JD
Yuan
Jianda
J
Kamat
Ashish
A
Ng Tang
Derek S
DS
Sun
Jingjing
J
Ku
Geoffrey
G
Troncoso
Patricia
P
Logothetis
Christopher J
CJ
Allison
James P
JP
Sharma
Padmanee
P
D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000276:immunology*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D060908:CTLA-4 Antigen; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000276:immunology / Q000601:surgery; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods; D060889:Inducible T-Cell Co-Stimulator Protein; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy / Q000276:immunology; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000601:surgery; D013519:Urogenital Surgical Procedures
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; D000074324:Ipilimumab
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