Immunotherapy for Cutaneous T-Cell Lymphoma: Current Landscape and Future Developments

Abstract

Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic, progressive primary cutaneous T-cell lymphomas (CTCLs) for which there are no curative treatments. Skin-directed therapies, such as phototherapy, radiation therapy, or topical nitrogen mustard, provide only short-term remissions. Numerous attempts with different chemotherapeutic regimes failed to achieve meaningful clinical responses. Immunotherapy seems to be a promising avenue to achieve long-term disease control in CTCL. There is compelling evidence indicating that MF and SS are immunogenic lymphomas, which can be recognized by the patient’s immune system. However, CTCL uses different strategies to impair host’s immunity, eg, via repolarizing the T-cell differentiation from type I to type II, recruiting immunosuppressive regulatory T-cells, and limiting the repertoire of lymphocytes in the circulation. Many currently used therapies, such as interferon-α, imiquimod, extracorporeal phototherapy, and allogeneic bone marrow transplant, seem to exert their therapeutic effect via activation of the antitumor cytotoxic response and reconstitution of the host’s immune system. It is likely that novel immunotherapies such as immune checkpoint inhibitors, cancer vaccines, and chimeric antigen receptor-T cells will help to manage CTCL more efficiently. We also discuss how current genomic techniques, such as estimating the mutational load by whole genome sequencing and neoantigen calling, are likely to provide clinically useful information facilitating personalized immunotherapy of CTCL.

The neoantigen landscape of mycosis fungoides

“…There is robust evidence that MF is an immunogenic tumour and that the immune system is an essential factor limiting its progression (reviewed in ref. (6)). It has been well documented that iatrogenic immunosuppression causes a catastrophic dissemination of MF (7,8).…”

“…Many current therapies (interferons, imiquimod, extracorporeal photopheresis and allogeneic stem cell transplant) are considered to act primarily via stimulation of the antitumour immunity (9)(10)(11)(12). However, the experience with immune checkpoint inhibitors has been disappointing in MF (6). The literature comprising approximately 50 cases of MF treated with various immune checkpoint inhibitors reports response rates ranging from 9% to 56% with only a few documented complete remissions (13)(14)(15)(16)(17).…”

Rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for sézary syndrome

“…The rationale relies on the fact that genetic alterations occurring in the microenvironment of lymphomas specifically in the programmed death ligand receptor (PD-L1/PD-L2) loci can lead to overexpression of PD-L1/2 on malignant cells, which helps tumor cells to evade the effective antitumor immune response [4]. Similarly, CTCL such as Mycosis Fungoides (MF) and Sézary Syndrome (SS) can debilitate the immune response against malignant cells in the tumor microenvironment and thus could be considered a target for therapies that can restore immune surveillance [5]. However, there is a concern for the use of immune checkpoint inhibitors in patients with lymphoma who undergo allogenic hematopoietic cell transplantation due to the possibility of triggering or aggravating graft versus host disease.…”

Cutaneous T‐cell lymphomas and sleep quality: a bidirectional relationship?

“…We suggest that sleep disturbance, through its immunomodulating effects, can lead to impaired skin integrity and prejudice cutaneous regeneration resulting in the lesions worsening and the establishment of a negative circular relationship between poor sleep and the disease. A review study has provided evidence that the progression of CTCL is related to an immunosuppressive state, loss of T‐cell diversity, as well as changes in the inflammatory tumor microenvironment . Malignant CD4 + T cells establish the immune system balance TH1/TH2 response.…”

“…Malignant CD4 + T cells establish the immune system balance TH1/TH2 response. Chronic TH2‐biased inflammation facilitates an immunosuppressive state and ultimately favors tumor survival, through extra production of inflammatory cytokines like interleukin (IL)‐4, IL‐5, and IL‐10 in addition to suppression of IL‐2 and IFN‐γ …”