Vaccination Therapy

Introduction

Vaccination for the treatment of CTCL has the aim to achieve a tumor antigen-specific immune response against malignant T-cells. The specific targeting of tumor cells with activated cytolytic effector cells should ideally destroy tumor cells in the absence of significant side effects. Dendritic cell vaccination is a powerful vaccination approach which has been mainly used in melanoma (53). Recent evidence supports the notion that this approach might also be applicable to CTCL (54). Extracorporeal photopheresis, a well-established therapeutic approach in CTCL, has recently been proposed to be a form of DC vaccination (55).

Mode of Action

Evidence for an involvement of the immune system in disease pathogenesis stems from several lines of evidence. Early ultramorphological studies have demonstrated the close apposition of dendritic antigen presenting cells and CTCL cells. Pautrier microabscesses, a histological hallmark of CTCL, represent a collection of epidermal dendritic cells (Langerhans' cells) and intact/apoptotic/necrotic CTCL cells as well as keratinocytes. Migration of LCs from the epidermis is facilitated by the inflammatory environment of the typical MF lesions with lesional production of chemokines critical for DC migration. Inflamed CTCL lesions provide a constant migratory flow of tumor antigen-loaded DC towards draining lymph nodes and presentation of CTCL tumor antigens to the specific adaptive T-cell mediated immune system and to the generation of CTCL tumor antigen-specific effector cells. It is tempting to speculate that CTCL tumor antigen-specific immune response keeps the development of the disease in check and contributes to the well known slow development of the disease. The often-made observation that chemotherapy leads to short-term response with relapse of a more aggressive transformed tumor might be due to the fact that this type of treatment does not only destroy neoplastic helper T-cells but also tumor immunosurveillance mechanisms operative at the site of the lesion. It has been further demonstrated that CTCL skin lesions contain tumor-infiltrating lymphocytes (TIL) that express an activated phenotype (56). Presence of TILs in lesions of CTCL patients was positively correlated with long-term survival. MHC class I restricted cytotoxic CD4 as well as CD8+ T-cells have been isolated form CTCL lesions and shown to kill CTCL cells in a granzyme/perforin dependent pathway (57). Taken together, there is accumulating evidence about an ongoing immuno-surveillance which keeps CTCL lesions in check, at the same time, immune escape mechanisms present in CTCL lesions might overcome the immunosurveillance system.

There is evidence for immune escape mechanisms operative at the tumor site. Production of the inhibitory cytokine TGF beta by CTCL cells might lead to inhibition of the antitumor response through suppressive effects on the proliferation, differentiation, and activation of CTL responses, specifically through inhibition of IL-12 and its signaling. Recent in vitro data suggest that expression of natural killer cell inhibitory receptors leads to the inhibition of CTCL specific T-cell responses (58). As TGF beta has been shown to increase the expression of NK inhibitory receptors on T-lymphocytes, these mechanisms could act synergistically to decrease the antitumor specific T-cell response in CTCL patients.

Indication

There are few available data regarding DC vaccination for CTCL. Early pilot data suggest that DC vaccination induces immune responses as well as clinical responses in selected CTCL patients (54). Patients with lower tumor burden seem to respond better.

Practical Application

Dendritic cells are generated ex vivo from monocyte precursors in the presence of cytokines such as IL-4, GM-CSF, and further maturation stimuli. Dendritic cells are incubated with autologous tumor lysate, washed extensively, and injected into uninvolved inguinal lymph nodes. Injections are preformed every two weeks; both immune and clinical response is evaluated after eight injections (54).

Comments

Proof of principle studies in CTCL patients suggests that vaccination approaches might be successful in this disease. CTCL generally takes a slow course and can be followed with molecular markers (e.g., TCR gene rearrangement analysis). Furthermore, correlation of vaccine administration with the clinical course is easily established. CTCL might be especially suited for pilot trials in future vaccine approaches.

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