Extracorporeal Photochemotherapy (Photopheresis)

Mechanism of Action—Extracorporeal Photopheresis

Although the precise mechanism of ECP has yet to be fully elucidated, crucial components of ECP have been identified from clinical studies and laboratory models ( Box 24.1 ). Mechanisms of action have been best studied for ECP in the treatment of CTCL, which likely have some relevance for therapeutic responses observed in the T-cell-mediated autoimmune diseases (such as scleroderma) for which ECP has also been used. ECP has also been used with some success in graft-versus-host disease (GVHD) and solid organ transplant rejection. In these conditions, ECP is thought to cause immune tolerance through induction of regulatory T cells (Treg).

Cutaneous T-Cell Lymphoma

Q24.3 An immunological mechanism for ECP has been hypothesized. In support of this, there were clinically significant persistent responses in CTCL patients in the original phase I/II study, despite the fact that only about 5% of the body’s circulating malignant T cells were extracorporeally exposed to activated 8-MOP/UVA. Furthermore, the effects of ECP on circulating leukocytes appears to selectively target lymphoma cells. CTCL patients treated with ECP maintain their absolute number of normal T cells with a disproportionately greater decrease in their total body burden of malignant T cells. Completely responding patients selectively exhibit loss of all detectable signs of malignant cells. Lastly, response to ECP is improved in individuals with normal or near normal natural killer (NK) and CD8+ cytotoxic T lymphocyte (CTL) numbers and function. Taken together, these findings suggest that a potential mechanism of action of ECP may be the stimulation of NK and CTL-mediated antitumor responses.

As a possible explanation for its immunological effects, treatment with photopheresis induces large numbers of monocytes to express dendritic cell (DC) differentiation markers by flow cytometry as well as by deoxyribonucleic acid (DNA) microarray analysis. Furthermore, these induced DC are functional, with the capacity in vitro to stimulate allogeneic CD4+ T cells to proliferate as well as differentiate CD8+ T cells into cytotoxic cells. During ECP, isolated leukocytes are passaged through the exposure plate that is coated with the patient’s plasma proteins and platelets. Monocytes transiently adhering to the surface are activated and a portion of these will undergo monocyte-to-dendritic cell maturation. Simultaneously, lymphocytes from CTCL patients undergo programmed cell death (i.e., apoptosis) during ECP caused by the exposure to UVA in the presence of 8-MOP. ECP-generated DC therefore have the ability and the opportunity to ingest the pathogenic apoptotic T cells, ultimately leading to the potential production and reinfusion of putative T-cell-loaded antigen-presenting cells (APC) capable of stimulating immunity against CTCL cells. The recent development and study of a miniature ECP device in a mouse tumor model demonstrated that monocyte-to-dendritic cell differentiation and the resulting tumor-loaded DC were important for the selective antitumor effects of ECP.

Alternative mechanisms reviewed elsewhere emphasize that the primary effect of ECP is to induce apoptosis in the target pathogenic cell, such as the circulating CTCL malignant cells, or to induce cytokine shifts from increased T-helper type (Th) 2 cytokines (e.g., interleukin [IL]-4, IL-5, IL-13, IL-31) and T-regulatory cytokines (e.g., TGFβ), to increased Th1 cytokines that favor an antitumor milieu including interferon (IFN)-γ.

Autoimmune Dermatoses

Q24.4 The reinfusion of syngeneic apoptotic cells by photopheresis appears to induce tolerogenic effects, which may explain the utility of ECP in autoimmune disease, GVHD, and organ transplant rejection. Based on animal models and clinical experience, this effect appears to be orchestrated by DC and Treg as well as immunomodulatory cytokines. In a mouse model of contact hypersensitivity, the extracorporeal treatment of splenocytes and lymph node cells led to the induction of tolerance mediated by CD4+ CD25+ T cells, the putative regulatory T-cell population, in an antigen-specific manner. Underscoring the importance of DC, the tolerance was lost with depletion of CD11c+ cells during reinfusion. Similar tolerizing effects of ECP were seen in mouse models of lupus-like GVHD and skin transplant. In line with this, the use of prophylactic ECP in lethal murine GVHD models resulted in immune tolerance in the host, as measured by reduced DC activation and increased Treg cells. How and why ECP seems to induce stimulatory DC, such as in the setting of CTCL, and inhibitory DC, such as in the setting of chronic GVHD (cGVHD), remain unclear.

Studies performed in human patients further supports the importance of Treg cells to the success of ECP in treating these diseases. In patients with lung transplantation, graft survival after ECP was correlated with increasing levels of circulating CD4+ CD25+ cells induced by ECP. In addition, in patients with cGVHD, a clinically significant cutaneous response was seen exclusively in patients who developed clonal populations of alloreactive T lymphocytes; because these cells expanded in the absence of clinical disease, these cells presumably represent Treg. Similar studies have shown normalization of inverted ratios of CD4 to CD8 cells after ECP treatment, suggesting a reduction in cytotoxic effector cells and potentially the expansion of the CD4+ regulatory T-cell component.

In addition, several studies have demonstrated that ECP has the ability to influence leukocyte cytokine production, including the production of tumor necrosis factor-α (TNF-α) and IL-6 after ECP along with increased IFN-γ and decreased IL-4 from peripheral blood mononuclear cells. Such shifts in T-helper cytokine profiles may have a definite role in the pathogenesis of autoimmune diseases, and therefore may partially explain the beneficial responses observed in patients treated for autoimmune disease with ECP.

US Food and Drug Administration-Approved Indications