Natural Receptor- and Ligand-Based Chimeric Antigen Receptors: Strategies Using Natural Ligands and Receptors for Targeted Cell Killing

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has been widely successful in the treatment of B-cell malignancies, including B-cell lymphoma, mantle cell lymphoma, and multiple myeloma; and three generations of CAR designs have led to effective FDA approved therapeutics. Traditionally, CAR antigen specificity is derived from a monoclonal antibody where the variable heavy (VH) and variable light (VL) chains are connected by a peptide linker to form a single-chain variable fragment (scFv). While this provides a level of antigen specificity parallel to that of an antibody and has shown great success in the clinic, this design is not universally successful. For instance, issues of stability, immunogenicity, and antigen escape hinder the translational application of some CARs. As an alternative, natural receptor- or ligand-based designs may prove advantageous in some circumstances compared to scFv-based designs. Herein, the advantages and disadvantages of scFv-based and natural receptor- or ligand-based CAR designs are discussed. In addition, several translational aspects of natural receptor- and ligand-based CAR approaches that are being investigated in preclinical and clinical studies will be examined.

Natural killer cells in clinical development as non-engineered, engineered, and combination therapies

“…Selection of the right affinity for the antigen epitope is necessary to achieve optimal binding to the target TAA and to avoid on-target off-tumor toxicities for antigens expressed on both tumor and healthy cells [175]. It has been reported that the variable domains from the scFv can interact with each other through a phenomenon known as domain swapping, which can lead to CAR oligomerization [176] and might translate into inferior clinical efficacy [177].…”

“…Selection of the right affinity for the antigen epitope is necessary to achieve optimal binding to the target TAA and to avoid on-target off-tumor toxicities for antigens expressed on both tumor and healthy cells [ 175 ]. It has been reported that the variable domains from the scFv can interact with each other through a phenomenon known as domain swapping, which can lead to CAR oligomerization [ 176 ] and might translate into inferior clinical efficacy [ 177 ]. Additionally, hydrophobic interactions with receptors cause antigen-independent activation, resulting in the so-called tonic signaling [ 175 , 178 ], and can be a cause of poor anti-tumor efficacy, impaired survival, and reduced persistence in vivo [ 179 ].…”

Genetic Modification of T Cells for the Immunotherapy of Cancer

“…CARs are considered chimeric because they are constructed from molecules that provide various levels of functionality to the receptor. The most basic CAR, known as a first-generation CAR ( Figure 2 B), is made up of a single chain variable fragment (scFv) that contains the heavy and light chain antigen binding regions isolated from an immunoglobulin molecule that is fused to a CD3ζ signaling chain via a hinge and transmembrane domain ( Figure 3 ) [ 97 , 98 , 99 , 100 ]. Early CAR molecules used Fc receptor γ (FcRγ) signaling domains, rather than CD3ζ [ 101 ].…”

“…As a result, first generation CARs have since been modified to include costimulatory cassettes to improve the functionality of CAR T cells in vivo [ 103 , 104 , 109 , 110 , 111 ]. The most common costimulatory cassettes included in CAR constructs are CD28, 4-1BB, ICOS, or OX40 ( Figure 2 C) [ 100 , 104 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 ]. Third generation CARs include two distinct costimulatory cassettes, such as 4-1BB and CD28 together ( Figure 2 D) [ 117 , 118 , 119 , 120 ].…”

“…Despite their success, there are still a number of challenges that prevent these therapies from achieving their maximum potential. Hostile tumor microenvironments, antigen escape, and tumor heterogeneity can inhibit proper engraftment and long-term function of engineered T cells [ 100 ]. As a result, new methods of treatment have been sought out to enhance anti-tumor effects of adoptive T cell therapy to improve the frequency of clinical success.…”