Immunomodulators in the treatment of cutaneous lymphoma

Journal of the European Academy of Dermatology and Venereology 13 (1999) 83±90

Review article

www.elsevier.com/locate/jeadv

Immunomodulators in the treatment of cutaneous lymphoma Christina Rogalski, Reinhard Dummer, GuÈnter Burg* Clinic of Dermatology, University Hospital of ZuÈrich, Gloriastr. 31, CH-8091 Zurich, Switzerland

Abstract Background Cutaneous lymphoma involves clonal proliferation of immunocompetent cells. Immunointerventional strategies are a rational approach to the treatment of cutaneous lymphoma given the pathophysiological aspects of the disease. Objective Immunomodulatory therapies in cutaneous lymphoma are reviewed, including interferons, interleukin-2, cyclosporin A, monoclonal antibodies, autologous bone marrow transplantation, fusion toxins, thymopentin and extracorporeal photopheresis as well as recently reported methods such as vaccination therapy, mycophenolate, and new retinoids. Results/Conclusion Cutaneous lymphoma is sensitive to immunointerventions. This approach should be used in early stages of the disease when it is more susceptible and bene®ts better from immunomodulatory treatment modalities. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Immunointervention; Immunomodulators; Cutaneous lymphoma; Interferon; Interleukin

1. Introduction Cutaneous lymphomas are clonal proliferations of immunocompetent cells. In cutaneous T cell lymphoma (CTCL) a proliferation of helper T cells with an initially strong af®nity to the epidermis takes place whereas cutaneous B cell lymphoma (CBCL) involves clonal proliferation of B lymphocytes at a certain point in the normal differentiation pathway from stem cell to plasma cell or to memory cell. The distinct homing behavior of lymphomatoid cells can be explained by the functional properties of various adhesion moelcules like lymphocyte function-associated antigen (LFA)-1/intercellular adhesion molecule (ICAM)-1, very late activation antigen (VLA)-4/vascular cell adhesion molecule (VCAM)-1, cutaneous lymphocyte antigen (CLA)/E

* Corresponding author. Tel.: 141-1-255-2550; fax: 141-1-2554403. E-mail address: [email protected] (G. Burg)

selectin and their action on lymphocytes, keratinocytes, endothelial cells, and other structures [1,2]. Keratinocytes themselves produce a broad spectrum of cytokines, like interleukin-1(IL-1), a costimulator of T and B cells and stem cells, IL-3, IL-6, IL-7 that might be important for the proliferation of lymphoid cells in CTCL, IL-8, IL-10, tumor necrosis factor (TNF)-a , granulocyte-macrophage colonystimulating factor (GM-CSF), transforming growth factor (TGF), and others [2]. The neoplastic lymphocytic clone(s) in most CTCL are fully differentatiated T helper memory or, less frequently, cytotoxic T cells that predominantly display TH2 cytokines, such as IL-4, IL-5, IL-10, IL-15. Interferon (IFN)-g production is restricted to exceptional cases [3]. In CTCL patients, the neoplastic cells have an impact on the immune condition of the host presenting reduced natural killer cell activity, alterations in serum immunoglobulins, diminished delayed type hypersensitivity reaction against recall

0926-9959/99/$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. PII: S 0926-995 9(99)00081-1

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antigens and an increased incidence for second malignancies and infections. In this special situation, immune interventions may target the neoplastic cells directly using approaches commonly applied for immunosuppression, such as cyclosporin A that interferes with signal transduction in T cells, fusion toxins binding to the high af®nity IL2 receptor, and chemotherapeutics agents like methotrexate or cyclophosphamid. Other agents like interferons, interleukin-2, and thymopentin support the growth and activity of reactive anti-tumoral pathways involving natural killer cells, cytotoxic killer T cells, macrophages, etc. Interferons are proteins acting as cytostatic, antiviral, and immunomodulatory agents. Structural, biologic, and physicochemical differences separate the interferons into three main groups: IFN-a , IFN-b , and IFN-g that are divided into different subtypes. We have studied the expression of interferong receptors on cell lines derived from cutaneous T cell lymphomas and in leukemic cells of patients with SeÂzary Syndrome. CTCL cell lines as well as clonal T cells from SeÂzary subjects express both interferon-g receptor chains. However, the tumor cells cannot be induced to upregulate typically interferoninduced surface molecules such as HLA-DR or ICAM-1. Preliminary investigations have demonstrated that tumor cells in CTCL are de®cient in interferon-g signaling. Since interferon-g fails to induce an increased STAT binding in electromobility band

shift assays (EMSAs), the defect is proposed to be at the receptor level, the associated kinases, or on the level of the STAT-1 protein [4]. 1.1. Interferon-a (IFN-a ) Interferon-a production is induced by viruses, B cell mitogens, foreign and tumor cells and produced by leukocytes and lymphoblastoid cells. Interferon-a activates macrophages/monocytes, T cells, natural killer cells and modulates antibody production. The mechanism of action relies on the direct cytotoxicity and interference with enzymes involved in cell proliferation. It also enhances cell surface antigens like class I molecules on lymphocytes. IL-4 and IL-5 production by T cells is inhibited [5]. Exposure of cells to interferon-a downregulates IFN receptors that are determined by chromosome 21 for a cell surface structure necessary for interferon response [6]. Recombinant interferon-a was the ®rst to be studied in CTCL and it is now the most used in combination or monotherapy. The maximal tolerated dose was 50 MU/m 2 three times a week for at least 3 months and resulted in a partial response in 45% of CTCL subjects [7]. There are several studies about interferon-a treatment in CTCL. An overview of the literature shows that lower doses (3±9 MU/m 2) are just as effective, but less toxic [5] (see Table 1). In our subjects (n ˆ 43) suffering from CTCL, Sezary syndrome and mycosis fungoides in various

Table 1 Ef®cacy of immunomodulators for the treatment of cutaneous lymphomas

IFN-a IFN-b IFN-g IL-2 Cyclosporin A Autologous BMT Fusion toxins Thymopentin Retinoids Extracorporal photopheresis

References

No. a

RR (%)

No. a CR

No. a PR

[7±9,11,13,14] [17] [5,18,19] [20,21] [22] [27±30] [31±35] [36±38] [39±41] [42,43]

174 15 16 12 11 23 39 28 25 38

75 33 50 58 18 74 54 64 44 40

40 3 0 25 0 13 7 8 12 3

91 2 8 33 2 4 14 10 32 37

a Number of patients based on the references cited in this article and treated in our department. RR: objective response rate. BMT: bone marrow transplantation.

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stages 40% showed at least partial response after application of interferon-a (2±3 £ 3±9 Mio IE/week £ 0.1±5.1 years). Cyclic pulse treatment with interferon-a and increasing doses do not seem to show better results than continuous treatment with equivalent doses [8]. The lowest ef®cient dose tested was 3 MU/m 2 which was well tolerated. Some subjects who did not show a complete response on low dose IFN-a experienced remission induced with dose escalation. Whether daily IFN-a has any bene®t over application three times a week is not clear, but the advantage lies in compliance. An objective response is generally seen by 3±5 months of treatment, but maximum response may take much longer [9]. Different tumors have different threshold levels of sensitivity for IFN. For example, hairy cell leukemia is sensitive to much lower doses of IFN-a than CTCL [9]. Early stages seem to bene®t better from immunomodulatory treatment modalities than advanced stages of CTCL [10]. The side effects with IFN-a during initial exposure to the drug are fever, chills, myalgias, and malaise which are easily controlled with acetaminophen. Dose related side-effects are gastrointestinal complaints, metallic taste, anorexia, leukopenia, decrease in platelet count, elevation of liver function tests as well as stupor, psychosis and peripheral neuropathy [5]. One patient with CTCL developed a reversible nephrotic syndrome with IFN-a [11]. Cardiac toxicity of IFN is known but not reported in application of lower doses [7]. Telogen ef¯uvium and fatigue may also occur. As with other immunomodulatory drugs, concomitant autoimmune thyroiditis or vitiligo may occur [12]. In general, elderly subjects tolerate a lower maximum dose than younger patients. Intralesional IFN may be given safely and has a bene®cial effect, both locally and systemically [13,14]. The development of neutralizing or binding interferon antibodies presents an important problem. The intracutaneous or subcutaneous route is more likely to induce antibody formation than the intravenous route, as do higher doses and more frequent injections, with an incidence of 3±30% [15]. Incidences are reported from 3 to 30%. The presence of IFN antibodies (binding and neutralizing) may have impact on the outcome of CTCL treatment with IFN-a therapies. We have investigated the incidence of neutralizing and binding interferon-a antibodies in patients with

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CTCL treated with interferon-a combined with retinoid or PUVA. Of the subjects treated with interferona 2a, 41% developed binding interferon antibodies. Only 11% had neutralizing antibodies. Interferon antibody formation was more frequent in subjects with normal CD4/CD8 ratios and high tumor burden index and was also observed in subjects treated simultaneously with PUVA. Responses were more frequently seen in interferon-a antibody negative subjects [16]. 1.2. Interferon-b (IFN-b ) Beta-interferon is produced by ®broblasts and epithelial cells after stimulation by viruses or foreign nucleic acids. IFN-b is coded on chromosome 9 and shares the same interferon cell surface receptors (type 1) as IFN-a ; it is species-speci®c in terms of antiviral activity. IFN-b is involved in the regulation of nonspeci®c humoral immune responses, increases the expression of HLA class I and reduces the expression of HLA class II antigens, that are stimulated by IFN-g . IFN-b also stimulates natural killer cells and suppressor cells. It shows antiproliferative activity against tumor cells. IFN-b was well tolerated in dosages of 150±500 MU/m 2 in phase one studies. In dermatology IFN-b is mostly used for topical treatment of condylomata acuminata. It is not commonly used in the treatment of cutaneous lymphoma and there are only a few reports regarding such use with excellent results on local application and partial response in intramuscular treatment (Table 1) [17]. 1.3. Interferon-g (IFN-g ) IFN-g is produced by activated T cells or natural killer cells on stimulation by T-cell mitogens, speci®c antigens, or interleukin-2. IFN-g binds to a separate (type 2) IFN receptor and induces class I and II histocompatibility molecules. Some studies have shown that IFN-g has more potent anticellular activity than IFN-a or IFN-b , a good reason to study IFN-g in CTCL. Sixteen patients with CTCL (Stage Ib±IVa) received 0.5 mg/m 2 for at least 8 weeks. There was an overall response rate of 31% with a median duration of response of 10 months [18]. Intralesional administration has also been described [19]. Objective

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response rate (complete and partial response) of IFNg in CTCL is about 50%, with a complete response rate of less than 10% when the results of the few studies done are reviewed all together [5]. The toxicity's seen with IFN-g were similar to those observed with IFN-a but perhaps more frequent and more severe. Flu-like symptoms, fever, transient elevations of hepatic enzymes and weight loss occurred as well as reversible neutropenia, urticaria, and nephrotic syndrome. 1.4. Interleukin-2 (IL-2) IL-2 (lymphocyte proliferation factor, T cell growth factor, TCGF, thymocyte-stimulating factor) is secreted by CD41 T lymphocytes after antigen recognition. In high concentrations IL-2 stimulates the cytotoxicity of T Lymphocytes, natural killer cells, and macrophages. Treatment strategies are based on the fact that different effector cells of the immune system are activated by varying concentrations of IL-2, depending on differences in expression of IL-2 receptors. Low-dose IL-2 exhibits immunomodulatory activities by inducing secretion of other soluble mediators, such as TNF-a , TNF-b , and IFNg . Marolleau et al.[20] tested high-dose recombinant interleukin-2 in advanced cutaneous T cell lymphoma of seven patients. Continuous infusion, 20 £ 10 [7] IU/m 2/day were administered during three fortnightly induction cycles and ®ve monthly consolidation cycles. Three complete and two partial responses were received. Sequential immunophenotypic studies showed an increase of the CD11 cells in dermal in®ltrates and no signi®cant modi®cation of natural killer cells or cytotoxic T lymphocytes. Cutaneous lymphoma can be treated by local injection of recombinant IL-2 [21]. After six injections four nodules out of ®ve disappeared and a bigger one diminished in size, with complete remission for 13 months. These studies and our own experiences in four cases of advanced CTCL indicate that high dose rIL-2 may be an alternative treatment approach in subjects who do not respond to other treatments. 1.5. Cyclosporin A Cyclosporin A prolongs the survival of transplanted organs by reducing the transcriptions of cytokines, especially IL-2, that are thought to mediate T-cell

expansion and subsequent graft rejection. Cyclosporin has been suggested as an effective agent in the therapy of T cell lymphoma. In a phase II trial CTCL subjects with at least one prior therapy and disease progression could participate. Cyclosporin A was administered orally 7.5 mg/kg twice daily. Only two of 11 CTCL subjects responded to the therapy but experienced recurrence, disease progression and renal toxicity. So Cyclosporin was cytostatic rather than cytocidal or the clinical remissions were due to the anti-in¯ammatory effects of the drug [22]. For this reason Cyclosporin A alone is not an appropriate treatment in CTCL. 1.6. Mycophenolate Mycophenolate mofetil (MMF, CellCept w) is a novel immunosuppressant for the treatment of acute rejection after renal transplantation and also holds great promise towards producing successful outcomes in the treatment of cutaneous lymphoma. MMF, the morpholinoethyl ester of the active compound mycophenolic acid, is a new immunosuppressive agent that blocks de novo synthesis of guanine nucleotids. As this is essential for the purine synthesis of both T and B lymphocytes, the blocking effect on cell division is lymphocyte selective with little effect on the division of other cell types. The toxicity pro®le is comparable with that of azathioprine but mycophenolate is signi®cantly more effective [23]. This mode of action could also be useful in the treatment of cutaneous lymphoma, but as far as we know no attempts have been made, yet. 1.7. Monoclonal antibodies Monoclonal antibodies targeting the CD5 or IL-2 receptor, for example, seem to be the ideal substances to in¯uence biological response modi®cation. Several studies with a monoclonal murine antibody targeting CD5 (T101) were performed [24,25]. Immuno¯uorescence techniques con®rmed that circulating cells did bind the antibody in vivo and were subsequently removed from the circulation. Response ranged from 3 weeks to 3 months after infusion of T101 with regression of skin lesions. This therapy is limited by cell-mediated toxicity at tissue level, myelodepression, and the formation of human anti-mouse antibodies.

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Another approach might be the treatment of CTCL with anti-Tac, a human anti-IL-2 receptor monocloal antibody (Simulect w, Zenapax w), mainly used in renal transplantation to prevent transplant rejection [26]. A speci®c immune suppression is produced through targeting lymphocytes expressing cell surface interleukin-2 receptors to inhibit IL-2 dependent human T cell production. The IL-2 receptor is a useful target for immunosuppressive therapy. Therefore investigations of dosages and methods to reduce the immunogenicity of anti-IL-2 receptor agents may be bene®cial. The a chain of the human IL-2 receptor is expressed mainly on high-grade large cell T cell lymphomas in the skin that are mostly CD30-positive. Therefore the use of these anti-tac antibodies should be investigated in these special types of CTCL. 1.8. Autologous bone marrow transplantation The prognosis of advanced stage cutaneous lymphoma is very poor in case of recurrence after conventional polychemotherapy. In this setting, autologous bone marrow transplantation (BMT) has rarely been evaluated. There are four studies about BMT in cutaneous lymphoma [27±30]. Twenty-three subjects underwent BMT after total body irradiation and/or chemotherapy resulting in 13 complete remissions lasting from 3 to 51 months. These studies demonstrate that patients with cutaneous lymphoma having a poor prognosis can achieve prolonged complete remissions by intensi®cation of therapy using autologous bone marrow transplantation after total body irradiation, but since the disease will relapse this treatment option cannot be recommended. 1.9. Fusion toxins Immune-receptor-directed therapy is mainly performed with unmodi®ed murine monoclonal antibodies. These antibodies are immunogenic and elicit a human immune response, are not cytocidal against human cells, and in most cases not directed against a cell surface structure required for proliferation and survival. Recently therapy with monoclonal antibodies has been revolutionized by the de®nition of cell surface structures as targets for effective monoclonal antibody action by creating less immunogenic and more effective monoclonal antibodies, and by the

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arming of such antibodies with toxins and radionucleides. Fusion of the IL-2 gene with the diphtheria toxin A chain gene resulted in a fusion toxin called DAB 486 IL-2 that binds to the high af®nity IL-2 receptor, is internalized by receptor-mediated endocytosis, and subsequently inhibits protein synthesis of neoplastic lymphocytes bearing the high af®nity IL2 receptor by diphtheria toxin. Studies with DAB 486 IL-2 showed some toxicity's: transaminase elevation, hypotension, ¯uid retention, edema, fever, and even adrenal failure with bilateral adrenal hemorrhage and necrosis [31,32]. The biologic activity and toxicity of DAB 486 IL-2 was tested 20 subjects with IL-2R expressing hematologic malignancies there were no complete responses, only two partial responses and dose-dependent toxicity [31]. Another study including ®ve subjects revealed one complete response, two partial responses, and three signi®cant improvements [33]. Fourteen subjects with CTCL received infusions of DAB 486 IL-2; there were no complete responses, one partial response, two major biologic effects, three stable disease, and eight progressive disease. It was concluded that the expression of IL-2 receptors is a prerequisite for response but is not suf®cient to predict it [34]. The toxicity observed with the DAB 486 IL-2 lead to the design of a new fusion toxin, the DAB 389 IL-2 with fewer side effects. A study of subjects with lymphomas expressing IL-2R has been conducted. Most adverse reactions were transient and mild. Assessment of response indicated ®ve complete responses (4±20 months), seven partial responses in the 35 patients with CTCL, and two partial responses (2 and 9 months) in 17 patients with B-cell NHL [35]. The development of different modalities of receptor speci®c therapy are providing new perspectives for the treatment of cutaneous lymphoma. 1.10. Thymopentin Thymopentin is a synthetic pentapeptide hormone carrying the full hormone activity of thymopoietin despite its short half-life (30 s). Immunoregulatory in vitro effects of thymopentin include enhanced Tcell proliferation in response to alloantigens and mitogens and induction and increase of mitogen-induced IFN-g secretion. There are several reports that thymopentin application may have immunomodulatory

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effects in vivo. The mechanism of action is unclear, but it may increase the production of IFN-g and decrease the production of IL-4, plasma histamine, histamine releasing factor, and respiratory burst activities of polymorphnuclear leukocytes [24]. Thymopentin has been used in patients with MF and SeÂzary syndrome intravenously or subcutaneously, with minor improvement in some patients [36]. Fifty milligrams three times a week intravenously in patients with SeÂzary syndrome and SeÂzary counts below 2600/mm 3 showed an overall response of 75% [37]. Another study reported minor responses [38]. 1.11. Retinoids Retinoids play critical roles during normal development and physiology by modulating cell growth and differentiation. In a variety of tumor cell lines, they inhibit tumor cell growth, modulate differentiation, and induce apoptosis. Retinoids exert their physiological function by activating speci®c intracellular receptors and, in turn, modulating gene expression. Etretinate and isotretinoin have demonstrated ef®cacy (Table 1) in treating CTCL [39±41]. All clinical responses reported to date, however, have been palliative. Targretin w (capsules and topical gel) is presently being evaluated in phase 2 trials. The active ingredient of the investigational drug is a novel synthetic retinoid analogue identi®ed and developed by Ligand pharmaceutical company. 1.12. Extracorporeal photochemotherapy Extracorporeal photochemotherapy (ECP, photopheresis) involves the removal of leukocytes by leukopheresis after the ingestion of 8-methoxy-psoralen. The cells are exposed to UVA ex vivo and then reinfused. The patients receive treatment on two consecutive days every month for 6 months with tapering if a complete response is reached. Partial responders are given adjuvant chemotherapy. ECP was ®rst described as a treatment for CTCL by Edelson et al. [42]. Although it is relatively new it is already considered standard therapy for erythrodermic variants of CTCL. Subjects with erythroderma seem to respond best, and subjects with CD4/CD8

ratio of less than 5 did signi®cantly better than those with low or no CD81 cells in their skin. The mechanism of action may be due to alteration of the major histocompatibility complex (MHC) class I peptides on the surface of malignant cells. The CD81 cells then recognize the altered MHC class I peptides and assist in destroying the malignant clone. Response rates vary from 50±75%; up to 25% of these having a complete response [43]. The side effects of photopheresis are minimal because the treatment cycles are performed ex vivo. Some patients experience nausea, transient increase of erythema, and fever (10%) after reinfusion of cells [42]. We treated nine patients suffering from SeÂzary syndrome (stage IIIa±IVb) with ECP (3±30 cycles) in combination with IFN-a , IL-2, radiotherapy, PUVA, and retinoids. Survival ranged from 0.4 to 8.3 years with one complete response and ®ve patients with partial response, two stable disease and one progressive disease. 1.13. Vaccination therapy Considering the fact that one or a few clones of neoplastic T cells bearing clone-speci®c T-cell receptors are involved in CTCL, vaccination techniques are an interesting idea for treatment. Dendritic cells are pulsed with the idiotype protein of interest in the speci®c subjects and then administered [44,45]. Addition of adjuvants and cytokines (IL-2, GM-CSF, TNFa , IL-12) might be supportive. The potential of the immune system is thus accelerated, generating large numbers of antigen-speci®c T-cells that target the tumor cell clone. 2. Conclusion Cutaneous lymphoma is susceptible to immunointerventions. This approach should be used in early stages of the disease in order to achieve optimal results due to the more favorable ratio between tumor cells and cytotoxic T cells. Further understanding of the pathogenesis of CTCL with special respect to the transformation of normal T lymphocytes into a neoplastic cell clone should provide information for developing new approaches for speci®c immunointerventional measurements.

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