Online citations, reference lists, and bibliographies.
← Back to Search

Preoperative CTLA-4 Blockade: Tolerability And Immune Monitoring In The Setting Of A Presurgical Clinical Trial

B. Carthon, J. Wolchok, J. Yuan, A. Kamat, D. Ng Tang, Jingjing Sun, G. Ku, P. Troncoso, C. Logothetis, J. Allison, P. Sharma
Published 2010 · Medicine

Cite This
Download PDF
Analyze on Scholarcy
Share
Purpose: 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. Experimental Design: 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. Clin Cancer Res; 16(10); 2861–71. ©2010 AACR.
This paper references
American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst May 11CCR-10-0569 on the response of T cells to stimulation
(1995)
10.1073/pnas.0813175106
Anti-CTLA-4 therapy results in higher CD4+ICOShi T cell frequency and IFN-γ levels in both nonmalignant and malignant prostate tissues
H. Chen (2009)
Frequency of NY-ESO-1 and LAGE-1 expression in bladder cancer and evidence of a new NY-ESO-1 T-cell epitope in a patient with bladder cancer.
P. Sharma (2003)
10.1007/s11102-009-0193-z
Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes
T. Dillard (2009)
10.1200/JCO.2008.19.2435
Phase I/II trial of tremelimumab in patients with metastatic melanoma.
L. Camacho (2009)
10.1158/1078-0432.CCR-09-1339
Phase I Study of Ipilimumab, an Anti–CTLA-4 Monoclonal Antibody, in Patients with Relapsed and Refractory B-Cell Non–Hodgkin Lymphoma
S. Ansell (2009)
Anti–CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related www.aacrjournals.org adverse events across a spectrum of cancer
T Dillard (2010)
CD28 and CTLA-4 have opposing effects Clinical Cancer Research h. t 11, 2017
MF Krummel (2010)
The heterogeneity of the kinetics of response to ipilimumab in metastatic melanoma: patient cases.
Y. Saenger (2008)
Clinical Cancer Research on the response of T cells to stimulation
(1995)
10.1084/JEM.183.6.2533
CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells
M. Krummel (1996)
CD28 and CTLA-4 have opposing effects Clinical Cancer Research h. er 3, 2017
MF Krummel (2010)
10.1200/JCO.2008.16.1927
Phase I/II study of ipilimumab for patients with metastatic melanoma.
J. Weber (2008)
10.1172/JCI27745
CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.
S. Quezada (2006)
CD28 and CTLA-4 have opposing effects Clinical Cancer Research Preoperative CTLA-4 Blockade on the response of T cells to stimulation
MF Krummel (1995)
CD28 and CTLA-4 have opposing effects Clinical Cancer Research h. t 5, 2017
MF Krummel (2010)
Epub ahead of print
(2010)
10.1073/pnas.0400214101
Inducible costimulator-dependent IL-10 production by regulatory T cells specific for self-antigen
M. Kohyama (2004)
10.1073/pnas.1533209100
Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma
G. Phan (2003)
10.1073/pnas.0806075105
CTLA-4 blockade increases IFNγ-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients
C. Liakou (2008)
CD28mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones
FA Harding (1992)
10.1073/pnas.0911573106
Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase
M. Gigoux (2009)
10.4049/jimmunol.175.4.2340
The Role of ICOS in the CXCR5+ Follicular B Helper T Cell Maintenance In Vivo1
H. Akiba (2005)
Preoperative CTLA-4 Blockade Clin Cancer Res
(2010)
10.1084/JEM.182.2.459
CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation
M. Krummel (1995)
10.1016/S1074-7613(00)80366-0
The emerging role of CTLA-4 as an immune attenuator.
C. Thompson (1997)
Concurrent decrease in IL-10 with development of immune-related adverse events in a patient treated with anti-CTLA-4 therapy.
Jingjing Sun (2008)
10.1073/pnas.0830997100
Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients
F. S. Hodi (2003)
10.1038/ni.1690
The costimulatory molecule ICOS regulates the expression of c-Maf and IL-21 in the development of follicular T helper cells and TH-17 cells
Aurelie T Bauquet (2009)
Tumor immunotherapy: preclinical and clinical activity of anti-CTLA4 antibodies.
A. Korman (2005)
10.1056/NEJMc0904283
Anti-CTLA4 antibody-induced lupus nephritis.
F. Fadel (2009)
10.1084/JEM.190.3.355
Combination Immunotherapy of B16 Melanoma Using Anti–Cytotoxic T Lymphocyte–Associated Antigen 4 (Ctla-4) and Granulocyte/Macrophage Colony-Stimulating Factor (Gm-Csf)-Producing Vaccines Induces Rejection of Subcutaneous and Metastatic Tumors Accompanied by Autoimmune Depigmentation
A. van Elsas (1999)
American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst
(2010)
10.1126/science.271.5256.1734
Enhancement of Antitumor Immunity by CTLA-4 Blockade
D. Leach (1996)
CD28 and CTLA-4 have opposing effects Carthon et al
M F Krummel
10.1016/j.coi.2010.01.001
Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS).
Tyler R. Simpson (2010)
10.1038/356607A0
CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones
F. Harding (1992)
10.1158/1078-0432.CCR-06-2318
A Pilot Trial of CTLA-4 Blockade with Human Anti-CTLA-4 in Patients with Hormone-Refractory Prostate Cancer
E. Small (2007)
10.1158/1078-0432.CCR-09-1624
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria
J. Wolchok (2009)
10.1002/eji.200636136
Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression
Ata-Ur Rasheed (2006)



This paper is referenced by
10.1158/1078-0432.CCR-16-1432
Ipilimumab with Stereotactic Ablative Radiation Therapy: Phase I Results and Immunologic Correlates from Peripheral T Cells
C. Tang (2016)
10.1136/gutjnl-2018-316948
Enterocolitis due to immune checkpoint inhibitors: a systematic review
E. Soularue (2018)
10.3121/cmr.2013.1136
Predictors of Willingness to Participate in Window-of-Opportunity Breast Trials
K. Wisinski (2013)
10.1016/J.EUO.2019.01.002
Effect of Immunotherapy on Local Treatment of Genitourinary Malignancies.
G. Pignot (2019)
10.1016/j.cell.2015.03.030
Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential
P. Sharma (2015)
10.2147/CCID.S24246
Anti-cytotoxic T lymphocyte antigen-4 antibodies in melanoma
G. Tosti (2013)
10.1016/j.cellimm.2017.12.004
The tumor microenvironment: Thousand obstacles for effector T cells.
C. Massa (2017)
10.1038/ncomms12335
Interdependent IL-7 and IFN-γ signalling in T-cell controls tumour eradication by combined α-CTLA-4+α-PD-1 therapy
L. Shi (2016)
10.1097/SPC.0b013e3283552d19
Metastatic bladder cancer: anything new?
F. Calabrò (2012)
10.1016/j.urolonc.2016.01.006
Blocking immune checkpoints in prostate, kidney, and urothelial cancer: An overview.
Angela Alme (2016)
10.1038/cti.2013.5
The delicate balance of melanoma immunotherapy
D. Gyorki (2013)
Isolation and culture of T cell clones for adoptive immunotherapy and epitope discovery
Daniel R. Verdon (2016)
10.1146/annurev-med-112311-083918
Harnessing the power of the immune system to target cancer.
G. Lizée (2013)
This information is current as Cell Responses to Self and Tumor Tissue The Inducible Costimulator Augments Tc 17
Michelle H. Nelson (2015)
10.1146/annurev-med-092012-112807
Immune modulation in cancer with antibodies.
D. Page (2014)
10.1007/s12032-010-9794-7
Hyponatremia associated with Ipilimumab-induced hypophysitis
Zachary R Barnard (2011)
10.1155/2017/5618174
Immunotherapy for Patients with Advanced Urothelial Cancer: Current Evidence and Future Perspectives
C. Zichi (2017)
10.1016/J.CTRV.2018.08.006
Interventional therapy combined with immune checkpoint inhibitors: Emerging opportunities for cancer treatment in the era of immunotherapy.
X. Chang (2019)
10.1517/14728222.2014.987662
Novel molecular targets for urothelial carcinoma
Bishoy M. Faltas (2015)
10.1177/1756287216628784
Novel immunotherapeutic approaches to the treatment of urothelial carcinoma
A. Muthigi (2016)
10.1016/j.coi.2014.12.010
Dual antibody therapy to harness the innate anti-tumor immune response to enhance antibody targeting of tumors.
C. Chester (2015)
10.1016/j.semcancer.2015.08.006
The biological complexity of urothelial carcinoma: Insights into carcinogenesis, targets and biomarkers of response to therapeutic approaches.
P. Grivas (2015)
b-catenin and PI 3 K d inhibition expands precursor Th 17 cells with heightened stemness and antitumor activity
K. Majchrzak (2018)
10.3389/fimmu.2020.02104
ICOS+ Tregs: A Functional Subset of Tregs in Immune Diseases
D. Li (2020)
10.1016/j.semcancer.2017.10.001
Emerging targets in cancer immunotherapy.
S. Burugu (2018)
10.1016/j.eururo.2017.12.001
Phase 2 Trial of Gemcitabine, Cisplatin, plus Ipilimumab in Patients with Metastatic Urothelial Cancer and Impact of DNA Damage Response Gene Mutations on Outcomes.
Matthew D. Galsky (2018)
10.1189/jlb.5RI0217-064RR
Hypothesis: stimulation of trained immunity as adjunctive immunotherapy in cancer
M. Netea (2017)
10.1016/j.canlet.2018.05.015
Regulation of cancer immune escape: The roles of miRNAs in immune checkpoint proteins.
Q. Yang (2018)
10.1158/1078-0432.CCR-17-3763
A Multi-center Phase I Trial of Ipilimumab in Patients with Myelodysplastic Syndromes following Hypomethylating Agent Failure
A. Zeidan (2018)
10.1016/j.ctrv.2017.01.008
The expanding role of immunotherapy.
J. Martin-Liberal (2017)
10.1084/jem.20130590
Engagement of the ICOS pathway markedly enhances efficacy of CTLA-4 blockade in cancer immunotherapy
X. Fan (2014)
Immunotherapy in Urologic Cancer : Evolving Roles for Targeting of CTLA-4 , PD-1 / PD-L 1 , and HLA-G
E. Carosella (2015)
See more
Semantic Scholar Logo Some data provided by SemanticScholar