Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy

Semin Oncol. 2010 Oct;37(5):533-46. doi: 10.1053/j.seminoncol.2010.09.015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / therapeutic use*
  • Antigens, CD / immunology*
  • Antineoplastic Agents / adverse effects
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers
  • CTLA-4 Antigen
  • Drug Evaluation
  • Drug-Related Side Effects and Adverse Reactions
  • Humans
  • Immune System Diseases / chemically induced
  • Immune System Diseases / therapy
  • Ipilimumab
  • Melanoma / drug therapy*
  • Melanoma / immunology
  • Monitoring, Immunologic
  • Practice Guidelines as Topic
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / immunology
  • Survival Analysis

Substances

  • Antibodies, Monoclonal
  • Antigens, CD
  • Antineoplastic Agents
  • Biomarkers
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • Ipilimumab