The last 20 years have signalled a dramatic change in the clinical landscape of cancer therapeutics. Since the early 1990s, when interleukin (IL)-2, a T cell growth factor, first gained US Food and Drug Administration approval for the treatment of kidney cancer and melanoma, there has been a rising tide of immunotherapy. The field continues to attract vast scientific, clinical, patient and public attention; a Google search of ‘cancer immunotherapy’ yields over 2 million results, and there are thousands of ongoing clinical trials worldwide.
Undoubtedly the biggest change in this field in recent years has been the advent of immune checkpoint inhibitors (ICPIs). The immune checkpoints are a network of stimulatory and inhibitory receptors and ligands that are attractive as therapeutic targets because of their role in the regulation of the immune response. The upregulation of immune checkpoints such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) normally act to downregulate the immune response to chronic antigenic exposure.1 These pathways may be exploited by cancer cells as they develop mechanisms to evade host immunity and thrive. The theory that blocking elements of these pathways has the potential to reverse tumour-induced immunosuppression and stimulate the immune system to eliminate cancer cells has led to a flood of scientific and clinical research.
In 2010, Hodi et al.2 published a pivotal phase III trial demonstrating efficacy of the first ICPI in advanced melanoma. The agent was ipilimumab, an immunoglobulin G1 monoclonal antibody targeting CTLA-4. Ipilimumab was shown to prolong overall survival (OS) (10.1 vs 6.4 months, HR 0.68, p<0.001) in patients with pretreated advanced melanoma, achieving an overall response rate of 10.9%. Response was seen to be independent of common predictors of outcome (age, sex, stage, lactate dehydrogenase [LDH] level, prior high-dose IL-2).2
Despite the low and unpredictable response rate and significant toxicity (grades 3–4 in 10–15% of patients), the demonstration of a survival advantage signalled a revolution in the treatment of advanced melanoma.2 A pooled analysis of long-term survival data showed a proportion of durable responses to treatment, with around 20% of patients surviving 3 years:3 a striking contrast to the historically poor prognosis of these patients.
Since this seminal study, research into checkpoint-targeted immunotherapeutic agents has grown exponentially in a variety of cancer types. In what is often termed a ‘gold rush’ approach to clinical research, the efficacy of these targeted agents has been assessed across a broad range of solid and haematological malignancies in recent years. The rate of change and volume of research in this field are astounding, and any attempt to comprehensively summarize them would risk becoming rapidly obsolete. This chapter reviews recent research and highlights some key developments and emerging patterns of response.
Many indications and agents have shown significant promise. In 2015, the KEYNOTE-006 study in patients with advanced melanoma achieved better results on all counts with the anti-PD-1 receptor agent pembrolizumab compared with single-agent ipilimumab: response rates were higher (34% vs 11.9%), 12 month survival ...