Building on Synthetic Immunology and T Cell Engineering: A Brief Journey Through the History of Chimeric Antigen Receptors

Abstract

Advancement in our understanding of immune cell recognition and emerging cellular engineering technologies during the last decades made active manipulation of the T cell response possible. Synthetic immunology is providing us with an expanding set of composite receptor molecules capable to reprogram immune cell function in a predefined fashion. Since the first prototypes in the late 1980s, the design of chimeric antigen receptors (CARs; T-bodies, immunoreceptors), has followed a clear line of stepwise improvements from antigen-redirected targeting to designed “living factories” delivering transgenic products on demand. Building on basic research and creative clinical exploration, CAR T cell therapy has been achieving spectacular success in the treatment of hematologic malignancies, now beginning to improve the outcome of cancer patients. In this study, we briefly review the history of CARs and outline how the progress in the basic understanding of T cell recognition and of cell engineering technologies made novel therapies possible.

Combining Radiation- with Immunotherapy in Prostate Cancer: Influence of Radiation on T Cells

“…Both targeting strategies are based on the formation of synapses between the T cell and the target cell [ 45 , 46 ]. The interaction leads to the activation of the immune cell, release of pro-inflammatory cytokines and finally the killing of the target cell (e.g., [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ] introduction). Therefore, we wanted to learn how radiation may influence the capability of redirected immune cells.…”

“…Over the past decades diverse strategies were developed for retargeting of immune cells to tumor cells using conventional antibodies (Abs) or recombinant derivatives e.g., bispecific antibodies (bsAbs) or immune cells genetically modified to express Chimeric Antigen Receptors (CARs) (e.g., [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]). While these humoral and cellular immunotherapy options are highly efficient in B-cell leukemias, their application is limited for the treatment of solid tumors which may be due to mechanical barriers, the lack of expression of suitable homing receptors and adhesion molecules which interferes with an efficient infiltration of immune cells into tumor tissues.…”

Apheresis for chimeric antigen receptor T‐cell production in adult lymphoma patients

“…1 T cells genetically modified to express a synthetic chimeric antigen-receptor (CAR) are capable of detecting and destroying malignant cells. 1 The CAR is a hybrid molecule consisting of an antibody-derived single chain fragment variable (scFv) fused to intracellular signaling domains, such as CD3ζ, CD28, and 4-1BB. 2,3 Antigen-specific binding to surface molecules on tumor cells is mediated by the extracellular scFv resulting in subsequent T-cell activation triggered by the intracellular signaling moieties.…”

“…Driven by encouraging clinical results, adoptive T‐cell therapy is gaining increasing significance in anti‐cancer therapy 1 . T cells genetically modified to express a synthetic chimeric antigen‐receptor (CAR) are capable of detecting and destroying malignant cells 1 .…”

“…Driven by encouraging clinical results, adoptive T‐cell therapy is gaining increasing significance in anti‐cancer therapy 1 . T cells genetically modified to express a synthetic chimeric antigen‐receptor (CAR) are capable of detecting and destroying malignant cells 1 . The CAR is a hybrid molecule consisting of an antibody‐derived single chain fragment variable (scFv) fused to intracellular signaling domains, such as CD3ζ, CD28, and 4‐1BB 2,3 .…”