TY - JOUR
T1 - Shaping functional avidity of CAR T Cells
T2 - Affinity, avidity, and antigen density that regulate response
AU - Greenman, Raanan
AU - Pizem, Yoav
AU - Haus-Cohen, Maya
AU - Goor, Alona
AU - Horev, Guy
AU - Denkberg, Galit
AU - Sinik, Keren
AU - Elbaz, Yael
AU - Bronner, Vered
AU - Levin, Anat Globerson
AU - Horn, Galit
AU - Shen-Orr, Shai
AU - Reiter, Yoram
N1 - Publisher Copyright: © 2021 American Association for Cancer Research.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85105270525&partnerID=8YFLogxK
U2 - https://doi.org/10.1158/1535-7163.MCT-19-1109
DO - https://doi.org/10.1158/1535-7163.MCT-19-1109
M3 - مقالة
SN - 1535-7163
VL - 20
SP - 872
EP - 884
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 5
ER -