The T-Body Approach: Redirecting T Cells with Antibody Specificity

Abstract

"T-bodies" are genetically engineered T cells armed with chimeric receptors whose extracellular recognition unit is comprised of an antibody-derived recognition domain and whose intracellular region is derived from lymphocyte stimulating moiety(ies). The structure of the prototypic chimeric receptor, also known as a chimeric immune receptor, is modular, designed to accomodate various functional domains and thereby to enable choice of specificity and controlled activation of T cells. The preferred antibody-derived recognition unit is a single chain variable fragment (scFv) that combines the specificity and binding residues of both the heavy and light chain variable regions of a monoclonal antibody. The most common lymphocyte activation moieties include a T-cell costimulatory (e.g. CD28) domain in tandem with a T-cell triggering (e.g. CD3zeta) moiety. By arming effector lymphocytes (such as T cells and natural killer cells) with such chimeric receptors, the engineered cell is redirected with a predefined specificity to any desired target antigen, in a non-HLA restricted manner. Chimeric receptor (CR) constructs are introduced ex vivo into T cells from peripheral lymphocytes of a given patient using retroviral vectors. Following infusion of the resulting T-bodies back into the patient, they traffic, reach their target site, and upon interaction with their target cell or tissue, they undergo activation and perform their predefined effector function. Therapeutic targets for the T-body approach include cancer and HIV-infected cells, or autoimmune effector cells. To date, the most investigated area is cancer therapy. Here, the T-bodies are advantageous because their tumor recognition is not HLA-specific and, therefore, the same constructs can be used for a wide spectrum of patients and cancers.

Adoptive immunotherapy with genetically engineered T cells: modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response

“…In contrast to recombinant T-cell receptors, CARs consist of a single polypeptide chain with an antibody-derived single chain fragment (scFv) in the extracellular moiety for binding and the CD3z or combined CD28-CD3z signalling domain in the intracellular moiety for T-cell activation. 5,6 During the last years, a variety of CARs with different scFv-binding domains have been generated. These CARs harbour binding specificities for cancer-and leukaemia-associated antigens, such as carcinoembryonic antigen (CEA), melanoma-associated antigens, CD30 and CD19, or for virus-infected cells, such as human immunodeficiency virus and hepatitis B.…”

CD28 cosignalling does not affect the activation threshold in a chimeric antigen receptor-redirected T-cell attack

“…1 The binding domain consists of a single-chain fragment of variable region (scFv) antibody linked either directly or through an extracellular spacer to the intracellular CD3z chain. Although CD3z signalling alone is sufficient to initiate redirected activation of prestimulated T cells, 2,3 an additional costimulatory signal is required for full T-cell activation, prevention from activation-induced cell death and anergy.…”

The Optimal Antigen Response of Chimeric Antigen Receptors Harboring the CD3ζ Transmembrane Domain Is Dependent upon Incorporation of the Receptor into the Endogenous TCR/CD3 Complex

“…Two basic approaches have been explored to date: first, the expression of a and b TCR chains in the T cell, thereby driving the formation of new TCR complexes with the desired Ag specificity in the gene-modified T cell (3,4); and second, the expression of receptors bearing T cell signaling receptors fused to extracellular domains that bind to defined target Ags (5). The most commonly explored route for this second group of receptors (chimeric Ag receptors [CARs]) involves the fusion of a single-chain Ab fragment (scFv) to the signaling domain(s).…”