Pembrolizumab in systemic and cutaneous T-cell lymphoma

Introduction

Programmed death-1 (PD-1) is a critical pathway that regulates T-cell over-activation by attenuating the immune response and maintaining self-tolerance. Tumors can exploit this intrinsic immune checkpoint to escape immune surveillance and selectively block antitumor immune responses. High expression of PD-1 ligands (PD-L1 and, to a lesser extent, PD-L2) on tumor cells has been found to correlate with poor prognosis in various cancer types, suggesting that the PD-1 pathway plays a critical role in tumor immune evasion. PD-L1 expression can be found in T cell lymphomas, and translocations of both PD-L1 and PD-L2 have been observed in cutaneous T cell lymphoma (CTCL) (1-3). Moreover, the lesional skin and circulating Sézary cells in CTCL often exhibit PD-1 expressing T-cells representing either malignant or non-neoplastic T cells (3-5). Therefore, PD-1 and its ligands may be viable targets for therapeutic intervention in PTCL and CTCL, allowing for reversal of tumor-induced T-cell suppression, thereby augmenting antitumor immune activity. Pembrolizumab is a highly selective humanized monoclonal antibody of the immunoglobulin G4/kappa isotype designed to block interaction between PD-1 and its ligands.

Unique among cancers, it is important to highlight that the malignant cells in T-cell lymphomas can express PD-1, most notably angioimmunoblastic T cell lymphoma, certain subtypes of peripheral T-cell lymphoma (PTCL) and CTCL (5,6). Therefore, there does exist a theoretical concern that PD-1 blockade could directly activate the cancerous cells and accelerate tumor growth, as proposed in early murine studies (7).

Clinical studies in PTCL and CTCL

Clinical activity

Limited published data is available for pembrolizumab in the treatment of PTCL and CTCL. In a phase 2, single-arm study coordinated by the Cancer Immunotherapy Trials Network (CITN) (Table 1), pembrolizumab demonstrated significant clinical activity in pretreated patients with mycosis fungoides (MF) and Sézary syndrome (SS) (8). Overall response rate (ORR) was 38% in 24 evaluable patients. Median time to response was 11 weeks. Responses were durable, with 89% of responses ongoing at a median of 32 weeks duration. In this small sample size, there was no apparent correlation of CD8⁺ T cells, PD-1, PD-L1, and PD-L2 expression levels in the skin or blood compartments with clinical responses.

Nivolumab, a PD-1 inhibitor with a similar efficacy and toxicity profile to pembrolizumab, has demonstrated efficacy in T-cell lymphoma, as seen in a phase I, open-label, dose-escalation study in patients with relapsed or refractory hematologic malignancies (1). Of 16 CTCL and 5 PTCL patients evaluable, ORR was 13% and 40%, respectively.

Safety

In the phase 2 study of MF/SS, pembrolizumab was generally well-tolerated but immune-mediated toxicities were observed at rates similar to those seen in the treatment of other malignancies. Of the 24 patients treated with pembrolizumab, immune-related serious adverse events included a case of grade 2 pneumonitis and a grade 3 steroid-refractory duodenitis. Notably patients with SS frequently experienced an immune-mediated skin flare reaction (six patients, two grade 2 and four grade 3) that improved with additional treatment.

In the phase 1b trial with nivolumab, 79 patients with various hematology malignancies were treated with nivolumab monotherapy (1). The majority of the drug-related adverse events were grade 1 or 2, and the incidence of severe or life-threatening events attributable to nivolumab was low across all disease cohorts. Immune-mediated toxicities were limited to anticipated events and were mostly manageable.

Summary and future studies

The promising findings of pembrolizumab in MF/SS support further investigation of PD-1 blockade in the treatment of PTCL and CTCL. Preliminary data suggest synergistic effects of PD-1 inhibitors used in combination with immunomodulatory agents. A phase 2 study of pembrolizumab in combination with gamma interferon, a key antitumor cytokine that strengthens cytotoxic effector responses, is under development (NCT03063632). Similarly, other combined approaches are being studied: pembrolizumab with romidepsin (NCT03278782), pembrolizumab with decitabine and pralatrexate (NCT03240211), nivolumab with brentuximab vedotin (NCT02581631), and nivolumab with ipilimumab (NCT01592370). Translational correlative studies are highly encouraged in these clinical trials to identify biomarkers of clinical outcome and to optimize the combination strategies with checkpoint inhibitors. These studies will guide use of PD-1 blockade within the landscape of PTCL and CTCL therapy.

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Michinori Ogura and Pier Luigi Zinzani) for the series “The Development New Agents in T-cell Lymphoma” published in Annals of Lymphoma. The article has undergone external peer review.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aol.2018.03.02). The series “The Development New Agents in T-cell Lymphoma” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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