Pilot Study: Patients With Chronic Active Graft Versus Host Disease That Have Failed or Not Tolerated Standard Therapy.

The occurrence of acute or chronic graft-versus-host disease (GVHD) and its
prevention/treatment induce further immunologic compromise. Graft-versus-host disease (GvHD)
accounts for significant morbidity and mortality in recipients of allogeneic bone marrow
transplants (BMT) or peripheral blood stem cell (PBSC) transplants. The condition occurs as
donor lymphocytes recognize the recipient's tissue as foreign and mount an inflammatory and
destructive response in the recipient. GvHD has a predilection for epithelial tissues,
especially skin, liver, and the mucosa of the gastrointestinal tract. This can lead to
severe skin lesions, gastrointestinal hemorrhage, and liver failure. In addition, people
with GvHD are especially susceptible to infection. Approximately 30-70% of people undergoing
allogeneic HSCT for hematologic malignancies can anticipate experiencing acute and/or
chronic GVHD. The physical consequences depend on the severity of GVHD, but moderate to
severe organ system involvement is associated with substantial medical morbidity and
mortality. The current standard of care treatment for patients with chronic graft-vs-host
disease is steroid treatment with or without a calcineurin inhibitor. This treatment, while
effective for some, does not control the chronic gvhd of all. The use of extracorporeal
photopheresis (ECP) was developed in patients with several inflammatory and autoimmune
diseases, including scleroderma and rheumatoid arthritis. Successful use of ECP has also
been reported in patients with cutaneous T cell lymphoma, the Sezary syndrome variant,
cardiac and lung transplant rejection and other T cell mediated/autoimmune and autoimmune
diseases and even after facial transplantation. More recently, ECP has proven to be a
highly effective useful tool in the treatment of GvHD.

The exact mechanism of action of ECP is unknown, but the principle of the process is to
induce leucocyte apoptosis with UVA radiation after their exposure to psoralens, which are
light sensitizers. These leukocytes are immediately re-infused into the patient, where they
undergo early apoptosis. Following apoptosis, the leukocytes are engulfed by macrophage or
other antigen-presenting cells, such as immature dendritic cells, in an anti-inflammatory
cytokine environment. The anti-inflammatory cytokine secretion pattern, with a switch from
TH1 to TH2 for CD4+ lymphocytes, and the engulfment by immature cells without co-stimulatory
molecules induces anergy, by deleting effector T-cells that responded to the presented
antigens. An increase in regulatory T-cells (T-regs) is also induced after ECP and may
contribute to allograft acceptance by the recipient.

ECP has also been effective in treating solid organ transplant rejection and improving the
course of various autoimmune diseases, such as rheumatoid arthritis, systemic lupus
erythematosis, and pemphigus vulgaris. Since the early 1990s, ECP has been investigated as
a rescue immunotherapy for patients with steroid resistant acute and chronic GVHD. ECP is
generally well tolerated and Phase II data have confirmed activity in more than 250 patients
with steroid-refractory cGVHD.

ECP involves the isolation of peripheral blood buffy coat cells, ex vivo exposure of the
cells to 8-methoxypsoralen (8-MOP) and ultraviolet-A radiation, and subsequent re-infusion
of the treated cells to the patient. The combination of 8-MOP and PUVA results in DNA
crosslinks and causes apoptosis. However, the direct induction of lymphocyte apoptosis is
unlikely to account for the clinical efficacy of ECP given that less than 10% of circulating
leukocytes are exposed to PUVA during ECP.

The mechanism of ECP beyond the effects of apoptosis induction is incompletely understood.
Studies to date suggest that ECP in autoimmune conditions or GVHD stimulates anti-idiotypic
responses against host tissue-reactive T cell clones, attenuates antigen-presenting function
by type 2 dendritic cells, and induces anti-inflammatory cytokine responses. In addition,
an important component of tolerance induction is thought to involve the expansion of Tregs
that suppress alloreactive mechanisms.

ECP therapy has been studied in two well-defined minor MHC incompatible murine models of
CD8+ or CD4+ T cell mediated GVHD. These studies showed that ECP treated cells could
successfully reverse established GVHD by reducing allogeneic responses of donor effector T
cells and generating FOXP3+ Tregs from donor cells that had not been directly exposed to
PUVA, thereby ruling out a mechanistic role for direct apoptosis of effector cells. The
increase in Tregs occurred early after the infusion of ECP treated cells, remained stable
for several weeks, and was required to reduce GVHD and mortality after BMT. Correlative data
in humans is preliminary, but one small case series has shown an increase in the percentage
of functional Tregs after 6 ECP procedures from 8.9% to 29% of the total circulating CD4+
cells (p = .05). UVAR Photopheresis System (Therakos, Inc., Exton, PA, USA) was approved for
ECP treatment of advanced cutaneous T cell lymphoma in 1988 by the Food and Drug
Administration. In 2009 FDA approval was granted for this indication for the new Cellex
machine.

Inclusion Criteria:

- Allogeneic HSCT recipients who have chronic extensive GvHD and who have failed or
have not been able to tolerate conventional therapy

- Platelets ≥ 20,000 without transfusion support

- Weight ≥ 15 kg.

- Stated willingness to use contraception in women of childbearing potential

Exclusion Criteria:

- Patients who may not be able to tolerate ECP

- Patients who have received Rituximab monoclonal antibody therapy in the past 3 months

- Patients with a known hypersensitivity to psoralens

- Pregnant or breastfeeding

- Patients who are unable to sign informed consent or who do not have a representative
to give permission to participate