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Anti-CTLA-4 Antibody Therapy: Immune Monitoring During Clinical Development Of A Novel Immunotherapy.

M. Callahan, J. Wolchok, J. Allison
Published 2010 · Medicine

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Cytotoxic T-lymphocyte-associated antigen (CTLA-4), also known as CD152, is a co-inhibitory molecule that functions to regulate T-cell activation. Antibodies that block the interaction of CTLA-4 with its ligands B7.1 and B7.2 can enhance immune responses, including antitumor immunity. Two CTLA-4-blocking antibodies are presently under clinical investigation: ipilimumab and tremelimumab. CTLA-4 blockade has shown promise in treatment of patients with metastatic melanoma, with a recently completed randomized, double-blind phase III trial demonstrating a benefit in overall survival (OS) in the treated population. However, this approach appears to benefit only a subset of patients. Understanding the mechanism(s) of action of CTLA-4 blockade and identifying prognostic immunologic correlates of clinical endpoints to monitor are presently areas of intense investigation. Several immunologic endpoints have been proposed to correlate with clinical activity. This review will focus on the endpoints of immune monitoring described in studies to date and discuss future areas of additional work needed.
This paper references
Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer.
E. Kwon (1997)
Tumor Regression and Autoimmunity in Patients Treated With Cytotoxic T Lymphocyte–Associated Antigen 4 Blockade and Interleukin 2: A Phase I/II Study
A. Maker (2005)
CTLA-4 Control over Foxp3+ Regulatory T Cell Function
K. Wing (2008)
A new member of the immunoglobulin superfamily—CTLA-4
J. Brunet (1987)
Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.
E. Tivol (1995)
Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206.
A. Ribas (2005)
Cutting edge: lymphoproliferative disease in the absence of CTLA-4 is not T cell autonomous.
M. Bachmann (1999)
Elucidating the Autoimmune and Antitumor Effector Mechanisms of a Treatment Based on Cytotoxic T Lymphocyte Antigen-4 Blockade in Combination with a B16 Melanoma Vaccine
A. van Elsas (2001)
Association of baseline and on-study tumor biopsy markers with clinical activity in patients (pts) with advanced melanoma treated with ipilimumab.
O. Hamid (2009)
CTLA-4 blockade enhances clinical disease and cytokine production during experimental allergic encephalomyelitis.
P. Perrin (1996)
CTLA-4 blockade with ipilimumab increases peripheral CD8+ T cells: Correlation with clinical outcomes.
Arvin S. Yang (2010)
Erratum: TH 17 cells in tumour immunity and immunotherapy (Nature Reviews Immunology (2010) 10 (248-256))
W. Zou (2011)
CTLA4 blockade and GM-CSF combination immunotherapy alters the intratumor balance of effector and regulatory T cells.
S. Quezada (2006)
ICOS Controls the Pool Size of Effector-Memory and Regulatory T Cells1
Y. Burmeister (2008)
Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti–CTLA-4 antibodies
K. Peggs (2009)
Intratumoral Immune Cell Infiltrates, FoxP3, and Indoleamine 2,3-Dioxygenase in Patients with Melanoma Undergoing CTLA4 Blockade
A. Ribas (2009)
Intrapatient Dose Escalation of Anti–CTLA-4 Antibody in Patients With Metastatic Melanoma
A. Maker (2006)
Cytotoxic T-lymphocyte-associated antigen-4 blockage can induce autoimmune hypophysitis in patients with metastatic melanoma and renal cancer.
J. Blansfield (2005)
Preoperative CTLA-4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical Trial
B. Carthon (2010)
Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Can Regulate Dendritic Cell–induced Activation and Cytotoxicity of CD8+ T Cells Independently of CD4+T Cell Help
K. McCoy (1999)
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4
P. Waterhouse (1995)
Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.
P. Attia (2005)
Prognostic Factors Related to Clinical Response in Patients with Metastatic Melanoma Treated by CTL-Associated Antigen-4 Blockade
Stephanie G Downey (2007)
Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer.
E. Woo (2001)
CTLA-4 blockade enhances polyfunctional NY-ESO-1 specific T cell responses in metastatic melanoma patients with clinical benefit
J. Yuan (2008)
Secondary but not primary T cell responses are enhanced in CTLA‐4‐deficient CD8+ T cells
C. Chambers (1998)
Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma
G. Phan (2003)
Melan-A–specific Cytotoxic T Cells Are Associated with Tumor Regression and Autoimmunity Following Treatment with Anti-CTLA-4
O. Klein (2009)
Specific blockade of CTLA-4/B7 interactions results in exacerbated clinical and histologic disease in an actively-induced model of experimental allergic encephalomyelitis
A. Hurwitz (1997)
Enhancement of vaccine-mediated antitumor immunity in cancer patients after depletion of regulatory T cells.
J. Dannull (2005)
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)
Generation of antitumor immunity by cytotoxic T lymphocyte epitope peptide vaccination, CpG-oligodeoxynucleotide adjuvant, and CTLA-4 blockade.
E. Davila (2003)
CTLA-4 Blockade Confers Lymphocyte Resistance to Regulatory T-Cells in Advanced Melanoma: Surrogate Marker of Efficacy of Tremelimumab?
C. Ménard (2008)
Immunization of Patients with Metastatic Melanoma Using Both Class I- and Class II-Restricted Peptides from Melanoma-Associated Antigens
G. Phan (2003)
TH17 cells in tumour immunity and immunotherapy
W. Zou (2010)
Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25+Cd4+ Regulatory Cells That Control Intestinal Inflammation
S. Read (2000)
Accumulation of Foxp3+ T Regulatory Cells in Draining Lymph Nodes Correlates with Disease Progression and Immune Suppression in Colorectal Cancer Patients
Liufu Deng (2010)
CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion.
B. Kavanagh (2008)
Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with ipilimumab (MDX-010).
J. Weber (2008)
Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF.
L. Fong (2009)
Autoimmunity in a phase I trial of a fully human anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody with multiple melanoma peptides and Montanide ISA 51 for patients with resected stages III and IV melanoma.
Kristin M. Sanderson (2005)
Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blockade: the effect is manifested only at the restricted tumor-bearing stages.
Y. Yang (1997)
CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism.
P. Shrikant (1999)
CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation
M. Krummel (1995)
Effect of low dose cyclophosphamide on the immune system of cancer patients: depletion of CD4+, 2H4+ suppressor-inducer T-cells.
D. Berd (1988)
Development, regulation and functional capacities of Th17 cells
K. Hirota (2009)
CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance
R. Friedline (2009)
Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses.
C. A. Chambers (1999)
Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Regulates the Unfolding of Autoimmune Diabetes
F. Lühder (1998)
ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28
A. Hutloff (1999)
Regulatory T cells, tumour immunity and immunotherapy
W. Zou (2006)
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)
Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade.
A. Hurwitz (2000)
Checkpoint blockade in cancer immunotherapy.
A. Korman (2006)
Cutting Edge: CTLA-4–B7 Interaction Suppresses Th17 Cell Differentiation
H. Ying (2010)
Ipilimumab: controversies in its development, utility and autoimmune adverse events
J. Weber (2008)
Antigen-dependent clonal expansion of a trace population of antigen-specific CD4+ T cells in vivo is dependent on CD28 costimulation and inhibited by CTLA-4.
E. Kearney (1995)
CTLA-4 can function as a negative regulator of T cell activation.
T. Walunas (1994)
Re-establishing Peripheral Tolerance in the Absence of CTLA-4: Complementation by Wild-Type T Cells Points to an Indirect Role for CTLA-41
E. Tivol (2002)
Prognostic Factors That Determine the Long-Term Survival of Patients with Unresectable Metastatic Melanoma
Agop Y. Bedikian (2008)
Overcoming immunologic tolerance to melanoma: targeting CTLA-4 with tremelimumab (CP-675,206).
A. Ribas (2008)
CTLA-4 regulates induction of anergy in vivo.
R. Greenwald (2001)
Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting
G. Ku (2010)
Anti-CTLA-4 antibody therapy associated autoimmune hypophysitis: serious immune related adverse events across a spectrum of cancer subtypes
T. Dillard (2009)
CTLA‐4 regulates cell cycle progression during a primary immune response
R. Greenwald (2002)
Mechanisms of costimulation
A. Sharpe (2009)
Analysis of the Cellular Mechanism of Antitumor Responses and Autoimmunity in Patients Treated with CTLA-4 Blockade
A. Maker (2005)
Tremelimumab in Combination with Exemestane in Patients with Advanced Breast Cancer and Treatment-Associated Modulation of Inducible Costimulator Expression on Patient T Cells
R. Vonderheide (2010)
Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study.
C. Willett (2009)
T helper 17 T cells do good for cancer immunotherapy.
Glenda Canderan (2010)
The interaction properties of costimulatory molecules revisited.
A. V. Collins (2002)
Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4.
Kimberly E. Beck (2006)
Manipulation of costimulatory signals to enhance antitumor T-cell responses.
J. Allison (1995)
A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Comparing the Tolerability and Efficacy of Ipilimumab Administered with or without Prophylactic Budesonide in Patients with Unresectable Stage III or IV Melanoma
J. Weber (2009)
Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multi-peptide vaccine for resected stages IIIC and IV melanoma.
J. Weber (2006)
The immunobiology of cancer immunosurveillance and immunoediting.
Gavin P Dunn (2004)
Prognostic factors in metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy.
D. Minor (2009)
Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients
F. Ghiringhelli (2006)
Detailed analysis of immunologic effects of the cytotoxic T lymphocyte-associated antigen 4-blocking monoclonal antibody tremelimumab in peripheral blood of patients with melanoma
B. Comin-Anduix (2008)
Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates.
J. Brahmer (2010)
Enhancement of Antitumor Immunity by CTLA-4 Blockade
D. Leach (1996)
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)
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.
J. Wolchok (2010)
Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival
T. Curiel (2004)
CTLA-4 blockade in combination with xenogeneic DNA vaccines enhances T-cell responses, tumor immunity and autoimmunity to self antigens in animal and cellular model systems.
P. Gregor (2004)
Recent Advances Using Anti-CTLA-4 for the Treatment of Melanoma
A. Sarnaik (2009)
In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance.
E. Sotomayor (1999)
Phase I/II study of ipilimumab for patients with metastatic melanoma.
J. Weber (2008)
Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study.
S. O’Day (2010)
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria
J. Wolchok (2009)
Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients
F. S. Hodi (2008)
CTLA4 blockade increases Th17 cells in patients with metastatic melanoma
E. V. von Euw (2009)
Lymphoproliferation in CTLA-4-deficient mice is mediated by costimulation-dependent activation of CD4+ T cells.
Cynthia A Chambers (1997)

This paper is referenced by
Checkpoint‐Inhibitoren in der Immuntherapie: Ein Meilenstein in der Behandlung des malignen Melanoms
S. Wilden (2016)
Ipilimumab and Cancer Immunotherapy: A New Hope for Advanced Stage Melanoma
M. Mansh (2011)
In Situ Activation of Pituitary-Infiltrating T Lymphocytes in Autoimmune Hypophysitis
Han-Huei Lin (2017)
The Immune Response to Tumors as a Tool toward Immunotherapy
F. Pandolfi (2011)
Rapid complete response of metastatic melanoma in a patient undergoing ipilimumab immunotherapy in the setting of active ulcerative colitis
A. Bostwick (2015)
Erratum to: Evolution of the B7 family: co-evolution of B7H6 and Nkp30, identification of a new B7 family member, B7H7, and of B7's historical relationship with the MHC
M. Flajnik (2012)
Novel immunotherapeutic strategies after stem cell transplantation. Boosting graft-versus-tumor immunity by interference with co-inhibitory signaling
Willemijn Hobo (2013)
Advances in the treatment of metastatic melanoma: new immunomodulatory agents.
M. Sznol (2012)
Overcoming immunosuppression in the melanoma microenvironment induced by chronic inflammation
V. Umansky (2011)
Adjuvanted influenza-H1N1 vaccination reveals lymphoid signatures of age-dependent early responses and of clinical adverse events
O. Sobolev (2016)
Immunogenicity of Murine Solid Tumor Models as a Defining Feature of In Vivo Behavior and Response to Immunotherapy
M. G. Lechner (2013)
Cellular heterogeneity map of diverse immune and stromal phenotypes within breast tumor microenvironment
Y. Li (2020)
Interrogating the repertoire: broadening the scope of peptide–MHC multimer analysis
M. Davis (2011)
Baseline laboratory parameters predicting clinical outcome in melanoma patients treated with ipilimumab: a single‐centre analysis
T. Gambichler (2018)
A Review of T-Cell Related Therapy for Osteosarcoma
Kazushige Yoshida (2020)
Enhancing cancer immunotherapy by intracellular delivery of cell-penetrating peptides and stimulation of pattern-recognition receptor signaling.
H. Wang (2012)
Recognition of self and altered self by T cells in autoimmunity and allergy
Lei Yin (2012)
Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types
P. Ascierto (2013)
Epithelial-to-Mesenchymal Transition Contributes to Immunosuppression in Breast Carcinomas.
Anushka Dongre (2017)
Murine regulatory T cells differ from conventional T cells in resisting the CTLA-4 reversal of TCR stop-signal.
Y. Lu (2012)
Coinhibitory molecules in hematologic malignancies: targets for therapeutic intervention.
W. J. Norde (2012)
Immune-suppressive properties of the tumor microenvironment
J. C. Becker (2013)
Hypothesis Testing: CTLA4 Co-stimulatory Pathways Critical in the Pathogenesis of Human and Mouse Alopecia Areata
J. Sundberg (2011)
T cell resistance to activation by dendritic cells requires long-term culture in simulated microgravity.
J. H. Bradley (2017)
Prospects for TIM3-Targeted Antitumor Immunotherapy.
S. Ngiow (2011)
Butyrophilins: an emerging family of immune regulators.
Lucie Abeler-Dörner (2012)
Pre-Clinical Murine Models: Syngeneic Models for Immuno-Oncology
Joseph F. Murphy (2015)
Molecular imaging biomarkers for cell-based immunotherapies
M. Haris (2017)
The Optimal Radiation Dose to Induce Robust Systemic Anti-Tumor Immunity
J. Poleszczuk (2018)
Immunotherapy of melanoma
J. Haanen (2013)
A prospective phase II trial exploring the association between tumor microenvironment biomarkers and clinical activity of ipilimumab in advanced melanoma
O. Hamid (2010)
Chemokines, costimulatory molecules and fusion proteins for the immunotherapy of solid tumors.
M. G. Lechner (2011)
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