Immune checkpoint inhibitors to treat cutaneous malignancies

Abstract

As the incidence of cutaneous malignancies continues to rise and their treatment with immunotherapy expands, dermatologists and their patients are more likely to encounter immune checkpoint inhibitors. While the blockade of immune checkpoint target proteins (cytotoxic T-lymphocyte-associated protein-4, programmed cell death-1, and programmed cell death ligand-1) generates an antitumor response in a substantial fraction of patients, there is a critical need for reliable predictive biomarkers and approaches to address refractory disease. The first article of this Continuing Medical Education series reviews the indications, efficacy, safety profile, and evidence supporting checkpoint inhibition as therapeutics for metastatic melanoma, cutaneous squamous cell carcinoma, and Merkel cell carcinoma. Pivotal studies resulting in the approval of ipilimumab, pembrolizumab, nivolumab, cemiplimab, and avelumab by regulatory agencies for various cutaneous malignancies, as well as ongoing clinical research trials, are discussed.

Keywords: CTLA-4 inhibitor; Kaposi sarcoma; Merkel cell carcinoma; PD-1 inhibitor; PD-L1 inhibitor; basal cell carcinoma; checkpoint inhibitor; cutaneous lymphomas; cutaneous malignancies; cutaneous squamous cell carcinoma; immunotherapy; melanoma; skin cancer.

Figure 1.

Immune checkpoint inhibitors reinvigorate antitumor immune responses.(A) Cytotoxic T cells in the tumor microenvironments express high level of inhibitory receptors such as CTLA-4 and PD-1. In the absence of immune checkpoint inhibitors, ligation of CTLA-4 and PD-1 by B7 or PD-L1 expressed by antigen presenting cells or tumor cells dampens the cytotoxic functions of T cells and inhibits their antitumor activity. (B) Anti-CTLA-4, anti-PD-1, and anti-PD-L1 can bind CTLA-4, PD-1, and PD-L1 and prevent the PD-1/PD-L1 and CTLA-4/B7 interactions, which restore the antitumor functions of cytotoxic T cells. Abbreviations: APC, antigen presenting cell; MHC, major histocompatibility complex; TCR, T-cell receptor; CTLA-4, cytotoxic T-lymphocyte-associated protein-4; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1; B7, B7 protein.

Figure 2.

Timeline history of approved immune-checkpoint inhibitors to treat melanoma Level IA evidence includes evidence from meta-analysis of randomized controlled trials. level IB evidence includes evidence from at least one randomized controlled trial. Level IIA evidence includes evidence from at least one controlled study without randomization. Level IIB evidence includes evidence from at least one other type of experimental study. Level III evidence includes evidence from nonexperimental descriptive studies (i.e. comparative, correlation & case-control). Level IV evidence includes evidence from expert committee reports or opinions or clinical experience of respected authorities, or both.

Figure 3.

Timeline history of approved immune-checkpoint inhibitors to treat cutaneous squamous cell carcinoma and Merkel cell carcinoma Level IA evidence includes evidence from meta-analysis of randomized controlled trials. level IB evidence includes evidence from at least one randomized controlled trial. Level IIA evidence includes evidence from at least one controlled study without randomization. Level IIB evidence includes evidence from at least one other type of experimental study. Level III evidence includes evidence from nonexperimental descriptive studies (i.e. comparative, correlation & case-control). Level IV evidence includes evidence from expert committee reports or opinions or clinical experience of respected authorities, or both.

Figure 4.

Durable antitumor response after treatment with ipilimumab and nivolumab in a patient with BRAF wildtype melanoma, metastatic to the lungs. (A) February 2016 (B) May 2016 (C) January 2018. Adverse events affecting multiple organs were observed and successfully managed with corticosteroids.

Figure 5.

(A, B) Complete clinicopathologic response at three weeks after the first dose of pembrolizumab in a patient with Merkel cell carcinoma. (C) Findings on histopathology reveal dermal fibrosis and mixed lymphocytic inflammation with negative synaptophysin and chromogranin stains (not shown), both of which were expressed at pre-treatment with pembrolizumab.