Extracorporeal Photopheresis: A Case of Immunotherapy Ahead of Its Time

Abstract

Extracorporeal photopheresis (ECP) is a cell-based immunotherapy that involves the reinfusion of autologous leukocytes after exposure to psoralen and UVA. The treatment has been used for over 30 years, at first on patients with cutaneous T-cell lymphoma (CTCL) and later for the management of patients with graft-versus-host disease (GvHD), sclerosing disorders, atopic dermatitis, and other diseases that may share the common driving factor of a pathogenic T-cell clone or clones in blood circulation. Patients with clinical improvement mount an antigen-specific immune response that may have tolerance traits in the case of GvHD or anticlonal cytotoxic characteristics in the case of CTCL. The exact mechanisms that dictate one response or the other are not fully understood, but the evidence accumulated so far indicates that multiple events occur simultaneously and consequentially contribute to the end result. These include contact of cells with the outside (plastics and tubing of the ECP apparatus), exposure to psoralen and UVA that activates platelets, monocytes, and other myeloid cells, the release of damage-associated molecular patterns, differentiation of monocytes into dendritic cells, and generation and successive presentation of numerous antigens after the phagocytosis of apoptotic cells. Once reintroduced, the ECP product increases the frequency and activity of regulatory T cells (Tregs), shifts the systemic cytokine balance, and promotes extravasation of immune cells that together shape the effects of this treatment. In this review, we summarize the seminal work and most recent literature of the therapeutic mechanisms and reflect on future avenues of improvements and applications of ECP.

Keywords: Cutaneous T-cell lymphoma; Extracorporeal photopheresis; Immunotherapy.

Fig. 1

Cell cycle arrest and commitment to apoptosis of ECP-exposed cells. Upon exposure to ECP cells that suffer extensive DNA damage, fail to repair it or bear severe mitochondrial alterations initiate a gradual process of apoptosis. Severely affected cells have an immediate flip-flow of phosphatidylserine, others halt cell cycle via activation of p21 and p53, and apoptotic bodies appear as early as 72 h after treatment as a result of activation of both intrinsic and extrinsic apoptosis pathways.

Fig. 2

Activated platelets contribute to APC activation. In parallel to the induction of apoptosis, the exposure to 8-MOP/UVA and the contact with tubing and plastics of the ECP apparatus induce changes in multiple blood components. Platelets are activated, adhere to the walls of the irradiation chamber, and express p-selecting. Extracellular ATP, IL-1β, HGMB1, and other DAMP are secreted and collectively promote monocyte differentiation into DC. A prolonged incubation in the irradiation chamber seems to promote phagocytosis of apoptotic cells and presentation of new antigens in a process referred as transimmunization.

Fig. 3

Dual effect of ECP on antigen-specific immune and clinical responses. Upon reintroduction of treated cells, patients experience a shift in Th1 and Th2 balance closely associated with the type of disease. Whereas CTCL frequently respond to ECP with a shift toward a Th1 type response and cytotoxic CD8 T cells are primed by cross-presentation, GvHD patients often transit to a Th2 type response with immunomodulatory cytokines such as IL-10 and TGF-β closely related to the upregulation of PD1 and expression of GILZ in APC.