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
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.
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.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Lesokhin AM, Ansell SM, Armand P, et al. Nivolumab in Patients With Relapsed or Refractory Hematologic Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol 2016;34:2698-704. [Crossref] [PubMed]
- Ungewickell A, Bhaduri A, Rios E, et al. Genomic analysis of mycosis fungoides and Sézary syndrome identifies recurrent alterations in TNFR2. Nat Genet 2015;47:1056-60. [Crossref] [PubMed]
- Kantekure K, Yang Y, Raghunath P, et al. Expression patterns of the immunosuppressive proteins PD-1/CD279 and PD-L1/CD274 at different stages of cutaneous T-cell lymphoma/mycosis fungoides. Am J Dermatopathol 2012;34:126-8. [Crossref] [PubMed]
- Cetinözman F, Jansen PM, Vermeer MH, et al. Differential expression of programmed death-1 (PD-1) in Sézary syndrome and mycosis fungoides. Arch Dermatol 2012;148:1379-85. [Crossref] [PubMed]
- Samimi S, Benoit B, Evans K, et al. Increased programmed death-1 expression on CD4+ T cells in cutaneous T-cell lymphoma: implications for immune suppression. Arch Dermatol 2010;146:1382-8. [Crossref] [PubMed]
- Wada DA, Wilcox RA, Harrington SM, et al. Programmed death 1 is expressed in cutaneous infiltrates of mycosis fungoides and Sézary syndrome. Am J Hematol 2011;86:325-7. [Crossref] [PubMed]
- Wartewig T, Kurgyis Z, Keppler S, et al. PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis. Nature 2017;552:121-5. [PubMed]
- Khodadoust M, Rook AH, Porcu P, et al. Pembrolizumab for Treatment of Relapsed/Refractory Mycosis Fungoides and Sezary Syndrome: Clinical Efficacy in a Citn Multicenter Phase 2 Study. Blood 2016;128:181.
Cite this article as: Dai J, Almazan T, Kim Y, Khodadoust M. Pembrolizumab in systemic and cutaneous T-cell lymphoma. Ann Lymphoma 2018;2:3.