The primary objective of this project is to examine the feasibility, safety, and potential therapeutic efficacy of autologous antigen-specific Treg therapy in patients with pemphigus vulgaris (PV). To accomplish this objective, we will conduct a phase I-II development program. PV is an excellent model disease for these investigations because the autoantigens are well-defined, and mechanistic analyses can readily be performed with peripheral blood and with diseased tissue. This program is designed to complement the primary project by comparing enriched antigen-specific Treg therapy with polyclonal Treg therapy in the treatment of a severe autoimmune disease.
The specific aims are:
Specific Aim #1 : Conduct a phase I dose-escalation study of Treg therapy in patients with PV. By so doing, we seek to: (1) generate sufficient preliminary safety data on Treg infusion in patients with PV to enable us to move to a phase II efficacy trial during the course of the 5-year ACE cycle; (2) demonstrate the presence, and assess the persistence, of transferred Tregs in blood and in target tissue (skin); (3) assess disease-specific and immunologic biomarkers in blood and skin; and (4) generate preliminary efficacy data using the Pemphigus Disease Activity Index (PDAl).
Specific Aim #2 : Conduct a phase II trial of Treg therapy in patients with PV based on the results of the phase I studies. In its simplest form, the phase II trial would have three groups - a control group, a group that receives polyclonal Tregs, and a group that receives antigen-specific Tregs. However, there are other design options to consider depending on the results of phase I and new data that may become available including (1) multiple dose groups; (2) additional treatment groups to assess the impact of simultaneous administration of low-dose interleukin 2 (IL-2) in an effort to enhance Treg activity; and (3) additional experimental groups utilizing IVIG as the background therapy, as this modality does not suppress T cell function. In addition to the primary clinical outcomes, molecular mechanisms described above will be included in this phase II trial.
This project explores a novel approach to PV that is based on Tregs; the body's own regulatory mechanisms to control autoimmunity; rather than traditional toxic therapies. As PV is a well characterized; antigen-specific disease; it provides a unique opportunity to compare the therapeutic efficacy of antigen-specific versus polyclonal Tregs. This approach is particularly relevant to the goals of the ACE program because it involves a strategy that may have broad applicability across diverse autoimmune diseases.