Immunologic checkpoints for cancer treatment: From scientific rationale to clinical applicationDevelopment of Ipilimumab: Contribution to a New Paradigm for Cancer Immunotherapy
Section snippets
CTLA-4 is a Key Molecule in Immune Regulatory Pathways
The host immune system plays an essential role in the response to cancer. This requires an orchestrated set of events involving several types of leukocytes to recognize and attempt to eliminate tumor cells.14 However, the clinical effects of the immune system are limited due to powerful regulatory mechanisms that inhibit the immune response to cancer, allowing tumor cells to evade immune surveillance and to grow into a clinical mass through immunoediting. An important component in this process
Generation of Ipilimumab (MDX-010): A Fully Human, Anti–CTLA-4 Antibody
The identification of CTLA-4 as a key molecule in the downregulation of T-cell activation led to the hypothesis that CTLA-4 blockade could promote antitumor immunity mediated by effector CD4+ and CD8+ T cells (Figure 1).14, 15 Antibody blockade of CTLA-4 was evaluated in syngeneic tumor transplant models, including prostate cancer and mammary carcinoma, where it demonstrated an antitumor effect.27, 28, 29, 30 Combination regimens were also tested in animal studies in order to enhance the
Phase I/II Studies of Ipilimumab in Human Cancers
Studies in mouse models of several tumor types and in healthy cynomolgus macaques, particularly pharmacokinetic and safety data, provided the impetus for early clinical testing of ipilimumab activity against human cancers. Early clinical testing of ipilimumab was conducted in Medarex-sponsored studies and in trials performed at the US National Cancer Institute.39, 40, 41, 42 Phase I trials were initiated in several tumor types, including prostate cancer, ovarian carcinoma, renal carcinoma,
Phase II Studies of Ipilimumab Monotherapy in Advanced Melanoma
A phase II clinical trial program was initiated under the sponsorship of Bristol-Myers Squibb in 2006 to evaluate the efficacy and safety of ipilimumab monotherapy in patients with advanced (unresectable stage III or stage IV) melanoma (summarized in Table 1). Three phase II studies were undertaken in this patient population: (1) CA184-008 was an open-label, single-arm study of ipilimumab monotherapy at 10 mg/kg in previously treated patients49; (2) CA184-022 was a dose-ranging study of
Ipilimumab Improves Overall Survival in Patients With Advanced Melanoma
The first completed phase III study to evaluate the efficacy and safety of ipilimumab was MDX010-20, which enrolled patients between September 2004 and August 2008.16 In study MDX010-20, 676 HLA-A*0201–positive patients with previously treated, unresectable stage III or IV melanoma were randomized 3:1:1 to ipilimumab plus a gp100 peptide vaccine (n = 403), ipilimumab alone (n = 137), or gp100 alone (n = 136). Ipilimumab at 3 mg/kg and/or gp100 was administered every 3 weeks for up to four
Immune-Related Adverse Events and Treatment Guidelines
Beginning with preclinical studies, the ability of anti–CTLA-4 antibodies to break peripheral immune tolerance was recognized (as evidenced by the appearance of ‘prostatitis’ and depigmentation in mice treated with an anti–CTLA-4 antibody in combination with a GM-CSF–expressing tumor cell vaccine).32, 59 Early clinical studies documented adverse events that were consistent with ipilimumab breaking tolerance to self antigens.39, 40, 41 The adverse events observed in this study included
Kinetics of Response and Survival: New Response Criteria and Adjusted Statistical Models
In 2004, the Cancer Immunotherapy Consortium (previously the Cancer Vaccine Consortium), a nonprofit organization with the aim to improve the development of cancer immunotherapies, started a community-wide process. This included multiple initiatives over the next 6 years in order to understand the clinical kinetics of immunotherapy drug effects and to integrate them into a new development paradigm. In this context, a wide group of oncologists, immunotherapists, and regulators participated in a
Biomarkers Indicative of Ipilimumab's Mechanism of Action
Several analyses have been conducted to identify potential predictive markers of response to ipilimumab. In parallel with other phase II studies, a Bristol-Myers Squibb–sponsored phase II study (CA184-004) was conducted for the purpose of identifying predictive markers of response and/or toxicity in patients with advanced melanoma. This exploratory study randomized 82 patients to treatment with ipilimumab at 3 mg/kg (n = 40) or 10 mg/kg (n = 42); as in studies 007, 008, and 022, patients were
Conclusions and Future Directions
The development of ipilimumab was accompanied by a number of important lessons for the agent and for cancer immunotherapy as a whole (see Table 2). These lessons have led to a successful clinical trial program for ipilimumab in advanced melanoma. Indeed, ipilimumab is the first agent to demonstrate a statistically significant improvement in overall survival in a phase III trial in patients with previously treated, advanced melanoma.16 The irAEs associated with ipilimumab therapy are well
Acknowledgment
Editorial and writing assistance was provided by StemScientific, funded by Bristol-Myers Squibb Co.
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Financial disclosures: All authors are current employees of Bristol-Myers Squibb Co.