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

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.

Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC).

Sézary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.

Bexarotene blunts malignant T-cell chemotaxis in Sezary syndrome: reduction of chemokine receptor 4-positive lymphocytes and decreased chemotaxis to thymus and activation-regulated chemokine.

The malignant cells in Sezary syndrome express the skin trafficking molecules' cutaneous lymphocyte associated antigen (CLA) and chemokine receptor 4 (CCR4). High levels of the CCR4 ligand, thymus, and activation-regulated chemokine (TARC), have been reported in the blood and skin of patients. The rexinoid X-receptor specific retinoid, bexarotene, has contributed to the resolution of cutaneous disease among patients. To evaluate the effects of bexarotene on skin trafficking molecule expression and chemotaxis, peripheral blood mononuclear cells from Sezary syndrome patients and healthy controls were treated with bexarotene in vitro. CCR4 and CLA expression levels and chemotaxis in response to TARC (6.25 ng/ml) were evaluated among lymphocytes before and after treatment with bexarotene (10 microM). Flow cytometric analysis was performed to evaluate CD4, CD26, CLA, and CCR4 cell surface expression. Transwell migration assays were performed to evaluate chemotaxis to TARC. Prior to treatment, malignant cells exhibited higher CCR4 expression (45-90%) and greater than four times more chemotaxis to TARC compared with healthy controls. After treatment with bexarotene for 36-96 hr, a 28% reduction in CCR4 expression was noted (P < 0.05) among the malignant population with an associated 9% decrease in chemotaxis to TARC (P < 0.05). Our results show that bexarotene may inhibit malignant cell trafficking to the skin through an ability to suppress CCR4 expression among Sezary syndrome lymphocytes.

Cutaneous T-cell lymphoma in a cardiac transplant recipient.

Mycosis fungoides, an uncommon form of cutaneous T-cell lymphoma, arises in the skin and frequently progresses to generalized lymphadenopathy Although the cause of cutaneous T-cell lymphoma is unknown, chronic immunosuppression may play a role. A few cases have been reported in renal transplant recipients; however, ours appears to be the 1st report of cutaneous T-cell lymphoma in a cardiac transplant recipient. In our patient, cutaneous manifestations of the disease were noted less than 1 year after transplantation. Seven years after transplantation, Sézary syndrome, a variant form of mycosis fungoides, was diagnosed by tissue biopsy and flow cytometry analysis. Photopheresis improved symptoms but was not well tolerated because of hemodynamic sequelae. Psoralen and ultraviolet A therapy also improved the patient's skin condition, but a generalized lymphadenopathy developed. The maintenance immunosuppressive regimen was changed from cyclosporine (3 mg/kg/day) and azathioprine to cyclosporine (1.5 mg/kg/day) and cyclophosphamide. Although effective in the short-term, the results of this therapeutic strategy could not be fully evaluated because the patient died of acute myocardial infarction.

Current treatment of Cutaneous T-Cell Lymphoma.

Cutaneous T-cell lymphomas are a heterogeneous group of cutaneous non-Hodgkin's lymphomas. In the United States, the incidence of these diseases is rising faster than any other cancer. Environmental triggers may be important in the evolution of malignancy. Current therapy is reviewed with emphasis on a new retinoid, Targretin.

Sézary T-cell activating factor is a Chlamydia pneumoniae-associated protein.

We previously identified a protein that was stimulatory for malignant Sézary T cells, termed Sézary T-cell activating factor (SAF). However, the identity of this protein has not been fully elucidated, nor has it's role been determined in the pathogenesis of cutaneous T-cell lymphoma (CTCL). The basis for epidermotropism and proliferation of malignant cells in the skin of patients with CTCL is unknown. Using a monoclonal antibody inhibitory for SAF activity, we demonstrated that SAF is present in the skin of 16 of 27 samples from patients with mycosis fungoides, the predominant form of CTCL. In this report, the SAF determinant is demonstrated to be associated with Chlamydia pneumoniae bacteria by immunohistochemistry, immunoelectron microscopy, and culture analysis. Reactivity of antibodies against an outer membrane protein of C. pneumoniae or against the lipopolysaccharide of Chlamydiae spp. demonstrated that these determinants are coexpressed in 90% of the SAF-positive samples. We confirmed the presence of C. pneumoniae DNA and RNA in the skin by PCR and reverse transcription-PCR and by sequence analysis of the PCR products. The expression of the C. pneumoniae antigens and SAF appears to be associated with active disease in that C. pneumoniae antigens were absent or greatly diminished in the skin of three patients examined after Psoralen and long-wave UVA radiation treatment. Our results suggest that SAF is a Chlamydia-associated protein and that further investigation is warranted to determine whether SAF and C. pneumoniae play a role in the pathogenesis of CTCL.

Costimulation of cutaneous T-cell lymphoma cells by interleukin-7 and interleukin-2: potential autocrine or paracrine effectors in the Sézary syndrome.

PURPOSE: To examine interleukin-7 (IL7)- and interleukin-2 (IL2)-induced proliferation of Sézary lymphoma cells and to consider if an autocrine or paracrine growth-stimulatory circuit involving IL7 exists in the Sézary syndrome (SS). MATERIALS AND METHODS: Fresh Sézary lymphoma cells were maintained in short-term culture in the presence of cytokines, and growth was measured by incorporation of (3H)-thymidine (TdR). Expression of IL7 and IL7 and IL2 receptors (IL7-R and IL2-R, respectively) was assessed by polymerase chain amplification of first-strand complementary DNA (RT-PCR), by affinity cross-linking of radioactive iodine-125-IL7, and by dual-color fluorescence-activated cell analysis. IL-7 production was measured by immunoassay. RESULTS: Sézary lymphoma cells from seven patients showed synergistic (five of seven) or additive (two of seven) proliferation when cultured in the presence of IL2 and IL7, as compared with culture with either cytokine alone. Two patients with evidence of synergistic stimulation of [3H]-TdR incorporation showed IL7-R gene expression by RT-PCR and IL7 affinity cross-linking. Incubation of all seven patients' cells with IL7 induced coexpression to varying degrees of IL7-R and IL2-R. Sézary lymphoma cells from at least three of five patients studied expressed IL7 mRNA, and skin from three of five patients studied, as well as normal skin, expressed IL7 mRNA by RT-PCR. CONCLUSION: Sézary lymphoma cells respond by proliferation to IL7 plus IL2, and in some instances produce IL7. Therapeutic maneuvers should be pursued to take advantage of this potential autocrine or paracrine growth-stimulatory mechanism.

Cutaneous T-cell lymphoma: a review.

Cutaneous T-cell lymphomas define a spectrum of disorders associated with T-lymphocytic proliferation with clinical manifestations occurring in the skin during the course of the disease. This review has dealt with two rather uncommon disorders, namely mycosis fungoides and Sezary syndrome which are indolent malignant lymphomas, occurring primarily in the fifth decade, and affecting males most frequently. Historically, mycosis fungoides and Sezary syndrome have been described for a relatively short time. As witnessed by Table 2, little was known concerning these disorders, other than clinical and pathologic features, until the application of immunologic, cell biologic, and cytogenetic technology which burgeoned a multitude of questions. The discovery of TCGF has allowed for both continuous growth of normal and neoplastic T cells and for the clonal expansion of some malignant clones. The establishment of these continuous cultures allowed for: (1) investigation of the mechanism of TCGF production and stimulation of T-cell growth, and (2) identification of HTLV, a retrovirus found in cell cultures from two patients with CTCL, and subsequently from patients with Japanese adult T-cell lymphoma. In addition, the HTLV has been related to a more virulent form of T-cell malignancy. The exact etiologic role of this virus in the CTCL is presently the subject of intense investigation. Through the use of immunologic methods the malignant cell of CTCL has been pheno-typically and functionally characterized as a "helper/inducer" subtype (E rosette+, anti-T-cell antisera+, T11+, T1+, T3+, 3A1-, T6-, T8-) and usually Ia-, HLADR-. Clinical manifestations of the phenotype may be clinically apparent in the serologic abnormalities present in these disorders. Utilizing these methods to investigate these disorders may provide a key to the understanding of T-cell function and cellular immunity much as myeloma provided a model for the understanding of B cells and immunity. Clinically and pathologically, these disorders behave as malignant indolent lymphomas with spread from localized cutaneous lesions to extracutaneous involvement of the blood, lymph nodes, and viscera culminating in the death of the patient from either organ dysfunction or infectious complications. At autopsy, this extracutaneous involvement is more pronounced than what was expected ante-mortem. Application of prospective staging techniques employing such special procedures as E-rosette cytology, cytogenetics, and electron microscopy in addition to usual light microscopy studies has demonstrated a greater percentage of extracutaneous involvement than otherwise expected.(ABSTRACT TRUNCATED AT 400 WORDS)