This is an exploratory project that seeks to investigate the role and potential for therapeutic targeting of CD11c- expressing cells that include conventional dendritic cells, plasmacytoid dendritic cells, and age-associated B cells using a switchable chimeric antigen (sCAR) T cell system. This novel strategy differs from the conventional CAR T cell approach by having a ternary antigen recognition complex instead of the CAR directly binding the target antigen. Accordingly, target antigen recognition, is mediated by a soluble ?switch? Fab, and therfore, dependence on the switch for sCAR T cell-target cell recognition allows for a controllable system that can be activated or made quiescent. This is a collaborative project that brings together a PI who has extensive experience in animal models of lupus and a consortium PI who developed the sCAR T cell system. This proposal consists of two aims.
In aim 1, we will first generate a small library of anti-CD11c switches and then characterize switches in vitro and in vivo for their ability to promote sCAR T cell activation, survival, and killing of CD11c cell populations.
In aim 2, an anti-CD11c switch will be used in combination with sCAR T cells to determine if CD11c+ cells are required for maintaining established disease in lupus-prone mice and the effect of modifying switch dosing schedule on CD11c+ cell numbers and autoimmune disease. This application will provide new insights into the basic and therapeutic aspects of CD11c-expressing cells in lupus and more broadly, has the potential for advancing a new powerful methodological approach that: a) will be able to define the significance of cell populations in normal and disease conditions, b) will be universally and directly applicable to virtually any mouse model, and c) can be moved to the clinic.
Despite significant advances in defining the basic underlying immunological, genetic, and cellular processes contributing to the development of systemic lupus erythematosus (SLE), a major deficiency is the lack of mechanisms to readily translate these findings to the clinic. In this proposal, we will use a novel ?switchable? chimeric antigen receptor (sCAR) T cell approach to investigate the contribution and therapeutic potential of certain CD11c-expressing cells known to play essential roles in lupus. By introducing and demonstrating the utility of this new approach in advancing understanding of pathogenesis and treatment possibilities for lupus, this project should have a major impact on both the basic and clinical aspects of this disease as well as provide the impetus for a major advance in how specific cell types based on cell surface markers can be temporally eliminated in vivo for research and for therapy.
