Immune checkpoints normally stop the body from mounting an immune response against healthy cells.Some cancers can acquire these checkpoints so that the tumour cells are not recognised by the immune system.Inhibiting the checkpoints therefore enables the tumour cells to be recognised and allows an immune response to be activated against them.Immune checkpoint inhibitors can improve the survival of some patients with advanced malignancies.These include malignant melanoma, renal cell carcinoma, urothelial bladder cancer and non-small cell lung cancer.Trials have shown that immune checkpoint inhibitors have significant benefits over conventional therapies so they are increasingly being used in routine clinical practice.However, a significant proportion of patients will not respond to immune checkpoint inhibitors and retain a poor prognosis.The optimal use of these drugs requires further study.Immune-related adverse events commonly include pneumonitis, hepatitis, nephritis, colitis and endocrinopathies.However, nearly any organ system can be affected.These toxicities present clinicians with a new challenge of recognising them early and acting promptly.the immune response is highly precise, as the receptor on the T cell is specific for one particular antigen.In addition to this antigen-specific binding, a 'second signal' is needed for T-cell activation.This involves co-stimulatory receptors such as CD28.The two-step process acts as a fail-safe, to prevent an inappropriate immune response causing damage to healthy tissues.If a second signal is not received, the T cells become anergic.Two pathways are central to the immune process:• cytotoxic T-lymphocyte associated antigen 4 (CTLA-4)• programmed cell death 1 (PD-1) molecule.The CTLA-4 pathway is the best studied and its predominant role is as an immune dampener to prevent the initial activation of T cells in lymph nodes.PD-1 regulates the interaction of already activated T cells in extra-lymphatic tissues (see Fig.).2Highly mutant tumours are commonly able to acquire, or 'hijack' the immune checkpoints.This allows tumour cells to be inappropriately recognised as self tissues and so they restrain the T cell's ability to mount an effective antitumour response.The immune checkpoint inhibitors stop the inhibitory effects of tumour cells on T cells.By inhibiting the immune checkpoints, immune-mediated antitumour activity is restored.
Introduction Metastatic uveal melanoma (mUM) has historically been associated with short survival and limited effective treatments. Immune checkpoint inhibitors (ICIs) have been trialed in mUM; however, robust conclusions regarding their efficacy are difficult to draw given small study sizes and heterogeneous patient populations. Methods Five databases were searched using a combination of ‘ICI’ and ‘mUM’ headings, and data on patient demographics, objective response rate (ORR), overall survival (OS) and progression-free survival (PFS) were extracted. Pooled ORR was calculated using a random effects model and the inverse variance method. Available Kaplan–Meier OS and PFS curves were used to construct summary OS and PFS plots, from which median values were derived. Results Pooled ORR was 9.2% overall (95% CI 7.2–11.8) [4.1% for anti-CTLA4 (95% CI 2.1–7.7), 7.1% for anti-PD(L)1 (95% CI 4.5–10.9) and 13.5% for anti-CTLA4 plus anti-PD1 (95% CI 10.0–18.0)]. Median OS was 11.5 months overall (95% CI 9.5–13.8) [8.0 months for anti-CTLA4 (95% CI 5.5–9.9), 11.7 months for anti-PD(L)1 (95% CI 9.0–14.0) and 16.0 months for ipilimumab plus anti-PD1 (95% CI 11.5–17.7) ( P < 0.001)]. Median PFS was 3.0 months overall (95% CI 2.9–3.1). Discussion ICIs have limited efficacy in mUM and a recommendation for their use must consider the balance of benefit and risk for individual patients if no other options are available. Further biomarker profiling studies may be helpful in assessing which patients will benefit from ICIs, in particular the addition of ipilimumab to anti-PD1 therapy.
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