← Back to Search
Development Of Ipilimumab: Contribution To A New Paradigm For Cancer Immunotherapy.
A. Hoos, R. Ibrahim, A. Korman, K. Abdallah, D. Berman, V. Shahabi, K. Chin, R. Canetta, R. Humphrey
Published 2010 · Medicine
Download PDFAnalyze on Scholarcy
Identification of cytotoxic T-lymphocyte antigen-4 (CTLA-4) as a key negative regulator of T-cell activity led to development of the fully human, monoclonal antibody ipilimumab to block CTLA-4 and potentiate antitumor T-cell responses. Animal studies first provided insight into the ability of an anti-CTLA-4 antibody to cause tumor regression, particularly in combination regimens. Early clinical studies defined ipilimumab pharmacokinetics and possibilities for combinability. Phase II trials of ipilimumab in advanced melanoma showed objective responses, but a greater number of patients had disease stabilization. In a phase III trial, ipilimumab was the first agent to demonstrate an improvement in overall survival in patients with previously treated, advanced melanoma. The adverse event profile associated with ipilimumab was primarily immune-related. Adverse events can be severe and life-threatening, but most were reversible using treatment guidelines. Ipilimumab monotherapy exhibits conventional and new patterns of activity in advanced melanoma, with a delayed separation of Kaplan-Meier survival curves. The observation of some new response patterns with ipilimumab, which are not captured by standard response criteria, led to novel criteria for the evaluation of immunotherapy in solid tumors. Overall, lessons from the development of ipilimumab contributed to a new clinical paradigm for cancer immunotherapy evolved by the Cancer Immunotherapy Consortium.
This paper references
CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma.
A. Hurwitz (1998)
Activity and Safety of CTLA-4 Blockade Combined with Vaccines in Cynomolgus Macaques
T. Keler (2003)
Regulatory T Cells: Overcoming Suppression of T-Cell Immunity
T. Golovina (2010)
Association of peripheral blood absolute lymphocyte count (ALC) and clinical activity in patients (pts) with advanced melanoma treated with ipilimumab.
D. Berman (2009)
Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients
F. S. Hodi (2008)
Potentiating endogenous antitumor immunity to prostate cancer through combination immunotherapy with CTLA4 blockade and GM-CSF.
L. Fong (2009)
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)
Impact of HLA-A2 Status on Ipilimumab Efficacy and Safety: Pooled Data from Four Phase II Trials in Advanced Melanoma
Jedd D. Wolchok (2010)
Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4.
P. Attia (2005)
Enhancement of Antitumor Immunity by CTLA-4 Blockade
D. Leach (1996)
Novel immunotherapies as potential therapeutic partners for traditional or targeted agents: cytotoxic T-lymphocyte antigen-4 blockade in advanced melanoma
S. Agarwala (2010)
Association of baseline and on-study tumor biopsy markers with clinical activity in patients (pts) with advanced melanoma treated with ipilimumab.
O. Hamid (2009)
Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.
L. Zhang (2003)
Preoperative CTLA-4 Blockade: Tolerability and Immune Monitoring in the Setting of a Presurgical Clinical Trial
B. Carthon (2010)
Improved survival with ipilimumab in patients with metastatic melanoma.
F. S. Hodi (2010)
Improved Endpoints for Cancer Immunotherapy Trials
A. Hoos (2010)
Estrogen-progestagen menopausal hormone therapy and breast cancer: does delay from menopause onset to treatment initiation influence risks?
A. Fournier (2009)
Immunological aspects of local radiotherapy: clinical relevance.
S. Formenti (2010)
Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients
F. S. Hodi (2003)
CTLA-4 blockade with ipilimumab induces significant clinical benefit in a female with melanoma metastases to the CNS
F. S. Hodi (2008)
Immunotherapy: past, present and future
T. Waldmann (2003)
Complete regression of a previously untreated melanoma brain metastasis with ipilimumab
N. Schartz (2010)
Manipulation of T cell costimulatory and inhibitory signals for immunotherapy of prostate cancer.
E. Kwon (1997)
A phase II multicenter study of ipilimumab with or without dacarbazine in chemotherapy-naïve patients with advanced melanoma
E. Hersh (2009)
Technology evaluation: ipilimumab, Medarex/Bristol-Myers Squibb.
M. Morse (2005)
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)
Induction of indoleamine 2, 3-dioxygenase by death receptor activation contributes to apoptosis of melanoma cells via mitochondrial damage-dependent ROS accumulation.
Turgut Cetindere (2010)
Review: anti-CTLA-4 antibody ipilimumab: case studies of clinical response and immune-related adverse events.
J. Weber (2007)
Phase I/II study of ipilimumab for patients with metastatic melanoma.
J. Weber (2008)
Initial phase II experience of ipilimumab (IPI) alone and in combination with radiotherapy (XRT) in patients with metastatic castration-resistant prostate cancer (mCRPC).
S. Slovin (2009)
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)
Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting
G. Ku (2010)
The concept of immunological surveillance.
F. Burnet (1970)
Focus on TILs: prognostic significance of tumor infiltrating lymphocytes in human melanoma.
Darryl A. Oble (2009)
Concurrent infiltration by CD8+ T cells and CD4+ T cells is a favourable prognostic factor in non-small-cell lung carcinoma
K. Hiraoka (2006)
Costimulation Blockade With Belatacept in Renal Transplantation
F. Tedla (2006)
Prognostic Factors Related to Clinical Response in Patients with Metastatic Melanoma Treated by CTL-Associated Antigen-4 Blockade
Stephanie G Downey (2007)
Cancer and immune response: old and new evidence for future challenges.
L. de la Cruz-Merino (2008)
Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1
P. Tan (1993)
Potential immune biomarkers of gastrointestinal toxicities and efficacy in patients with advanced melanoma treated with ipilimumab with or without prophylactic budesonide
D. Berman (2008)
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)
Cellular and humoral aspects of the hypersensitive states : a symposium held at the New York academy of medicine
H. Lawrence (1959)
Anti-cytotoxic T-lymphocyte antigen-4 antibody: the first in an emerging class of immunomodulatory antibodies for cancer treatment.
L. Fong (2008)
Immunostimulatory monoclonal antibodies for cancer therapy
I. Melero (2007)
The three Es of cancer immunoediting.
Gavin P Dunn (2004)
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumors: Immune-Related Response Criteria
J. Wolchok (2009)
Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule.
P. Linsley (1992)
Cell intrinsic mechanisms of T‐cell inhibition and application to cancer therapy
K. Peggs (2008)
Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study.
C. Willett (2009)
Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma
G. Phan (2003)
Intrapatient Dose Escalation of Anti–CTLA-4 Antibody in Patients With Metastatic Melanoma
A. Maker (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)
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)
Concurrent infiltration by CD 8 T cells and CD 4 T cells is a favorable prognostic factor in non - small - cell lung carcinoma
K Hiraoka (2006)
CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation
M. Krummel (1995)
Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy.
E. Kwon (1999)
A clinical development paradigm for cancer vaccines and related biologics.
A. Hoos (2007)
CTLA-4 blockade reverses CD8+ T cell tolerance to tumor by a CD4+ T cell- and IL-2-dependent mechanism.
P. Shrikant (1999)
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 can function as a negative regulator of T cell activation.
T. Walunas (1994)
Phase II trial of ipilimumab monotherapy in melanoma patients with brain metastases.
D. Lawrence (2010)
Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4
P. Waterhouse (1995)
Meta-analysis of phase II cooperative group trials in metastatic stage IV melanoma to determine progression-free and overall survival benchmarks for future phase II trials.
E. Korn (2008)
Ipilimumab: controversies in its development, utility and autoimmune adverse events
J. Weber (2008)
Realization of the therapeutic potential of CTLA-4 blockade in low-dose chemotherapy-treated tumor-bearing mice.
M. B. Mokyr (1998)
Immunotherapy for advanced melanoma.
L. Fang (2008)
Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study.
S. O’Day (2010)
Immune therapy for cancer.
M. Dougan (2009)
Phase II trial of ipilimumab (IPI) and paclitaxel/carboplatin (P/C) in first-line stage IIIb/IV non-small cell lung cancer (NSCLC).
T. Lynch (2010)
Lessons from randomized phase III studies with active cancer immunotherapies--outcomes from the 2006 meeting of the Cancer Vaccine Consortium (CVC).
L. Finke (2007)
Association between immune-related adverse events (irAEs) and disease control or overall survival in patients (pts) with advanced melanoma treated with 10 mg/kg ipilimumab in three phase II clinical trials.
J. Lutzky (2009)
Evaluation of the effect of systemic corticosteroids for the treatment of immune-related adverse events (irAEs) on the development or maintenance of ipilimumab clinical activity.
A. Amin (2009)
Principles of Cancer Therapy: Oncogene and Non-oncogene Addiction
Ji Luo (2009)
Cancer—A Biological Approach*
M. Burnet (1957)
Cancer—A Biological Approach
M. Burnet (1957)
Ipilimumab monotherapy in patients with pretreated advanced melanoma: a randomised, double-blind, multicentre, phase 2, dose-ranging study.
J. Wolchok (2010)
Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade.
A. Hurwitz (2000)
Next generation of immunotherapy for melanoma.
J. Kirkwood (2008)
Betting on immunotherapy for melanoma
M. Sznol (2009)
Superantigen responses and co-stimulation: CD28 and CTLA-4 have opposing effects on T cell expansion in vitro and in vivo.
M. Krummel (1996)
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)
This paper is referenced by
Real-world impact of education: treating patients with ipilimumab in a community practice setting
B. Ledezma (2013)
Clinical and economic outcomes of treatment sequences for intermediate- to poor-risk advanced renal cell carcinoma.
A. Ambavane (2020)
Ipilimumab: A First-in-Class T-Cell Potentiator for Metastatic Melanoma
B. Chmielowski (2013)
Preclinical Development Regression of Human Prostate Cancer Xenografts inMice by AMG 212 / BAY 2010112 , a Novel PSMA / CD 3-Bispeci fi c BiTE Antibody Cross-Reactive with Non-Human Primate Antigens
M. Friedrich (2012)
Predicting analysis times in randomized clinical trials with cancer immunotherapy
Bristol-Myers Squibb (2016)
Toxicities of New Drugs for Melanoma Treatment and their Management
P. Savoia (2015)
Camouflage and sabotage: tumor escape from the immune system
I. Poschke (2011)
Use of ERC-1671 Vaccine in a Patient with Recurrent Glioblastoma Multiforme after Progression during Bevacizumab Therapy: First Published Report.
D. Bota (2015)
Ipilimumab for advanced melanoma: A pharmacologic perspective
V. Trinh (2013)
Immunotherapy for Non-small Cell Lung Cancer: Novel Approaches to Improve Patient Outcome
F. Shepherd (2011)
Developing Cancer Immunotherapies as Drugs: Setting the Stage Through Methodological Progress
Axel Hoos (2014)
Ipilimumab for advanced melanoma: A pharmacologic perspective
Pharm Practice (2012)
Predictive Biomarkers and Personalized Medicine Speci fi c Lymphocyte Subsets Predict Response to Adoptive Cell Therapy Using Expanded Autologous Tumor-In fi ltrating Lymphocytes in Metastatic Melanoma Patients
Laszlo G. Radvanyi (2012)
Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial.
M. Reck (2013)
Biomarkers for Immunostimulatory Monoclonal Antibodies in Combination Strategies for Melanoma and Other Tumor Types
P. Ascierto (2013)
Nivolumab and ipilimumab: immunotherapy for treatment of malignant melanoma.
N. Carreau (2019)
Efficacy and Safety of Avelumab for Patients With Recurrent or Refractory Ovarian Cancer: Phase 1b Results From the JAVELIN Solid Tumor Trial
M. Disis (2019)
Use of ipilimumab in the treatment of melanoma
U. Acharya (2013)
A case of Stevens–Johnson syndrome in a patient on ipilimumab
M. Pathria (2016)
CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations
L. Camacho (2015)
Evolution of Response Criteria in Immunotherapy
Y. Liu (2020)
Targeted therapy and immunotherapy: Emerging biomarkers in metastatic melanoma
P. LoRusso (2019)
The Analysis of Problem and Creation of Classification of Renal Side Effects During Immunotherapy
Liliia Zrielykh (2019)
Roles of the immune system in skin cancer
S. Rangwala (2011)
Novel cancer therapies: treatments driven by tumour biology
Ramya Ramaswami (2013)
DILI and drug development: a regulatory perspective.
M. Avigan (2014)
Integrating New Therapies in the Treatment of Advanced Melanoma
B. Curti (2012)
Durable response rate as an endpoint in cancer immunotherapy: insights from oncolytic virus clinical trials
H. Kaufman (2017)
Clinical Development of Immunostimulatory Monoclonal Antibodies and Opportunities for Combination
I. Melero (2013)
Uso de ipilimumab en pacientes con melanoma metastásico. Experiencia en el Hospital Médica Sur
Jose Manuel Ruiz-Morales (2014)
Adoptive T-cell transfer in melanoma.
O. Itzhaki (2013)
Rationale for targeting the immune system through checkpoint molecule blockade in the treatment of non-small-cell lung cancer
C. Zielinski (2013)See more