Immunotherapy of advanced melanoma with immune checkpoint inhibition
- Jeffrey A Sosman, MD
Jeffrey A Sosman, MD
- Professor of Medicine
- Robert H. Lurie Comprehensive Cancer Center of Northwestern
Although the incidence of melanoma is increasing, most cases are diagnosed at an early stage. In that setting, surgical excision is curative in most cases, and patients at high risk of developing metastatic disease may benefit from adjuvant immunotherapy. (See "Initial surgical management of melanoma of the skin and unusual sites" and "Adjuvant therapy for cutaneous melanoma".)
The management of patients with disseminated disease is a difficult problem, although recent advances have led to important improvements in patient outcomes. These approaches include immunotherapy (particularly with checkpoint inhibition) and targeted therapy that inhibits the mitogen-activated protein (MAP) kinase pathway. (See "Molecularly targeted therapy for metastatic melanoma".)
This topic reviews the efficacy and role of immune checkpoint inhibitors in the treatment of advanced melanoma (algorithm 1). The toxicity associated with these agents is discussed separately, as is an overview of the management of patients with advanced melanoma. (See "Toxicities associated with checkpoint inhibitor immunotherapy" and "Overview of the management of advanced cutaneous melanoma".)
Activation of cellular immunity begins when T cells recognize peptide fragments of intracellular proteins that are expressed on the surface of antigen-presenting cells (APCs) bound to specific mixed histocompatibility complex (MHC) molecules. This interaction requires the presence of a costimulatory molecule (B7), and this activation results in upregulation of cytotoxic T-lymphocyte antigen 4 (CTLA-4). The CTLA-4 receptor on T lymphocytes is a negative regulator of T cell activation that outcompetes cluster of differentiation 28 (CD28) for binding to B7 on APCs. CTLA-4 thereby serves as a physiologic "brake" on the activated immune system. (See "Principles of cancer immunotherapy".)
A second co-inhibitory pathway uses the programmed cell death receptor 1 (PD-1), which is an inhibitory receptor present on activated T cells. When PD-1 binds to its ligand (PD-L1), which is often present on activated tumor cells, the ability of the T cell to produce an effective immune response is downmodulated. Antibodies directed against PD-1 (nivolumab, pembrolizumab) or PD-L1 thus may restore or augment an antitumor immune response and produce tumor regressions in patients with advanced melanoma. (See 'Anti-PD-1 monoclonal antibodies' below.)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
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- RESPONSE TO CHECKPOINT INHIBITION
- Patterns of response
- ANTI-PD-1 MONOCLONAL ANTIBODIES
- - Ipilimumab-refractory disease
- - No prior immunotherapy
- - Previously untreated patients
- - Prior anti-CTLA-4 therapy
- Adjuvant therapy
- - Dose and schedule
- - Adjuvant therapy
- ANTI-PD-1 VERSUS ANTI-CTLA-4: TOXICITY
- COMBINED ANTI-CTLA-4 AND ANTI-PD-1 IMMUNOTHERAPY
- Ipilimumab plus nivolumab
- - Efficacy
- - Toxicity
- Ipilimumab plus pembrolizumab
- OTHER IMMUNOTHERAPY COMBINATIONS
- Checkpoint inhibition plus intralesional T-VEC
- Sequential therapy
- GM-CSF combinations
- BRAIN METASTASES
- NONCUTANEOUS MELANOMA
- OTHER IMMUNE REGULATORY CHECKPOINTS
- SUMMARY AND RECOMMENDATIONS