CARs: Beyond T Cells and T Cell-Derived Signaling Domains.

Jan Dörrie,Nico M. Sievers,Niels Schaft

doi:10.3390/ijms21103525

Abstract

When optimizing chimeric antigen receptor (CAR) therapy in terms of efficacy, safety, and broadening its application to new malignancies, there are two main clusters of topics to be addressed: the CAR design and the choice of transfected cells. The former focuses on the CAR construct itself. The utilized transmembrane and intracellular domains determine the signaling pathways induced by antigen binding and thereby the cell-specific effector functions triggered. The main part of this review summarizes our understanding of common signaling domains employed in CARs, their interactions among another, and their effects on different cell types. It will, moreover, highlight several less common extracellular and intracellular domains that might permit unique new opportunities. Different antibody-based extracellular antigen-binding domains have been pursued and optimized to strike a balance between specificity, affinity, and toxicity, but these have been reviewed elsewhere. The second cluster of topics is about the cellular vessels expressing the CAR. It is essential to understand the specific attributes of each cell type influencing anti-tumor efficacy, persistence, and safety, and how CAR cells crosstalk with each other and bystander cells. The first part of this review focuses on the progress achieved in adopting different leukocytes for CAR therapy.

Highlights

T cells are characterized by the possession of a T cell receptor (TCR), in most T cells, consisting of the α and β TCR chains
The main part of this review summarizes our understanding of common signaling domains employed in chimeric antigen receptor (CAR), their interactions among another, and their effects on different cell types
Of CD4 and CD8, T cells can differentiate from a naïve state (TN) towards an effector (TE) or a memory (TM) phenotype, which is further subdivided in the central memory (TCM) and the effector memory (TEM) compartment, which differ in their self-renewal capacity and effector functions [1,2,3,4,5,6,7]

Summary

Alternative Cell Types Suitable for CAR Cell Therapy

While having proven their potential in the treatment of hematological cancers [27,28,29,30], CAR therapies have not yet been successfully translated to solid cancers [31,32]. The intrinsic features and unique anti-tumor capabilities of different immune cells might prove better suitable to overcome current hurdles in both efficacy and safety of CAR therapy This includes abilities to evade suppression by the TME, to drive a broader immune response thanks to cross-interactions among different cell types, to not be restricted to the autologous setting (as conventional α/β T cells are prone to induce graft versus host disease (GvHD), and the reduced tendency towards autoimmunity [36]. Blood circulating γ/δ T cells were shown to, under certain conditions, act as antigen-presenting cells (APCs) stimulating conventional α/β T cells [49] These launch a poly-antigen targeting attack on the tumor incorporating diverse α/β TCRs [50]. Neither of them has shared details on their CAR constructs and no results have been published yet

NKT Cells

NK Cells

Notes Completed Suspended

Myeloid Cells

Neutrophils

Monocytes

Macrophages

Myeloid Dendritic Cells

Alternative Extracellular and Intracellular Domains Used in CARs

Classical Signaling Domains

Non-Classical Extracellular and Signaling Domains

Findings