Shaping Functional Avidity of CAR T Cells: Affinity, Avidity, and Antigen Density That Regulate Response

Abstract

Chimeric antigen receptors (CARs) are immunoreceptors that redirect T cells to selectively kill tumor cells. Given their clinical successes in hematologic malignancies, there is a strong aspiration to advance this immunotherapy for solid cancers; hence, molecular CAR design and careful target choice are crucial for their function. To evaluate the functional significance of the biophysical properties of CAR binding (i.e., affinity, avidity, and antigen density), we generated an experimental system in which these properties are controllable. We constructed and characterized a series of CARs, which target the melanoma tumor–associated antigen Tyr/HLA-A2, and in which the affinity of the single-chain Fv binding domains ranged in KD from 4 to 400 nmol/L. These CARs were transduced into T cells, and each CAR T-cell population was sorted by the level of receptor expression. Finally, the various CAR T cells were encountered with target cells that present different levels of the target antigen. We detected nonmonotonic behaviors of affinity and antigen density, and an interrelation between avidity and antigen density. Antitumor activity measurements in vitro and in vivo corroborated these observations. Our study contributes to the understanding of CAR T-cell function and regulation, having the potential to improve therapies by the rational design of CAR T cells. See related article on p. 946

Fluctuations in TCR and pMHC interactions regulate T cell activation

“…First, a number of experimental studies have reported that the T cell response is maximized at an intermediate affinity [50, 51, 52, 53, 54, 55, 56, 57, 58, 59]. Moreover, some of these studies have shown that an optimal affinity exists for both proximal and distal activation events (i.e.…”

“…The implications of these considerations are perhaps most important for designing the next generation of immunotherapies. For example, identifying the optimal affinity and dose is central to the design of CAR T cell therapies [81, 82, 83, 57, 56, 58, 67, 84, 63, 59] as well as cancer vaccines [53, 54, 55, 56, 60]. Our information-theoretic approach provides a framework to guide the optimization of the T cell response via modification of the affinity or dose of the TCR-pMHC binding dynamics.…”

CAR Density Influences Antitumoral Efficacy of BCMA CAR T cells and Correlates with Clinical Outcome

“…The avidity of the scFv against the antigen plays an important role on the functionality of the CAR T cells and its control may result in more effective therapies (55,56). Moreover, strategies combining the avidity of scFvs and the targeting of two molecules (or epitopes) may represent interesting approaches to increase the antitumoral efficacy and to reduce the toxicity (57,58).…”

Lipid-polymer hybrid nanoparticles utilize B cells and dendritic cells to elicit distinct antigen-specific CD4+and CD8+T cell responses

“…Increasing Ag delivery above this concentration threshold diminishes the regulatory phenotype [58], suggesting Ag dose can be a main design lever for controlling immune phenotype. Clinically relevant chimeric Ag receptors (CARs) and engineered T cell receptors (TCRs) are endowed with specific affinity for their target Ag, and increasing Ag affinity induces biphasic T cell responses [59][60][61]. This suggests that biophysical properties such as binding avidity and Ag density play key roles in overall T cell responses.…”