TY - JOUR
T1 - In Vitro and In Vivo Comparison of Lymphocytes Transduced with a Human CD16 or with a Chimeric Antigen Receptor Reveals Potential Off-Target Interactions due to the IgG2 CH2-CH3 CAR-Spacer
AU - Clémenceau, Béatrice
AU - Valsesia-Wittmann, Sandrine
AU - Jallas, Anne Catherine
AU - Vivien, Régine
AU - Rousseau, Raphaël
AU - Marabelle, Aurélien
AU - Caux, Christophe
AU - Vié, Henri
N1 - Publisher Copyright:
© 2015 Béatrice Clémenceau et al.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - The present work was designed to compare two mechanisms of cellular recognition based on Ab specificity: firstly, when the anti-HER2 mAb trastuzumab bridges target cells and cytotoxic lymphocytes armed with a Fc receptor (ADCC) and, secondly, when HER2 positive target cells are directly recognized by cytotoxic lymphocytes armed with a chimeric antigen receptor (CAR). To compare these two mechanisms, we used the same cellular effector (NK-92) and the same signaling domain (FcεRIγ). The NK-92 cytotoxic cell line was transfected with either a FcγRIIIa-FcεRIγ (NK-92CD16) or a trastuzumab-based scFv-FcεRIγ chimeric receptor (NK-92CAR). In vitro, the cytotoxic activity against HER2 positive target cells after indirect recognition by NK-92CD16 was always inferior to that observed after direct recognition by NK-92CAR. In contrast, and somehow unexpectedly, in vivo, adoptive transfer of NK-92CD16 + trastuzumab but not of NK-92CAR induced tumor regression. Analysis of the in vivo xenogeneic system suggested that the human CH2-CH3 IgG2 used as a spacer in our construct was able to interact with the FcR present at the cell surface of the few NSG-FcR+ remaining immune cells. This interaction, leading to blockage of the NK-92CAR in the periphery of the engrafted tumor cells, stresses the critical role of the composition of the spacer domain.
AB - The present work was designed to compare two mechanisms of cellular recognition based on Ab specificity: firstly, when the anti-HER2 mAb trastuzumab bridges target cells and cytotoxic lymphocytes armed with a Fc receptor (ADCC) and, secondly, when HER2 positive target cells are directly recognized by cytotoxic lymphocytes armed with a chimeric antigen receptor (CAR). To compare these two mechanisms, we used the same cellular effector (NK-92) and the same signaling domain (FcεRIγ). The NK-92 cytotoxic cell line was transfected with either a FcγRIIIa-FcεRIγ (NK-92CD16) or a trastuzumab-based scFv-FcεRIγ chimeric receptor (NK-92CAR). In vitro, the cytotoxic activity against HER2 positive target cells after indirect recognition by NK-92CD16 was always inferior to that observed after direct recognition by NK-92CAR. In contrast, and somehow unexpectedly, in vivo, adoptive transfer of NK-92CD16 + trastuzumab but not of NK-92CAR induced tumor regression. Analysis of the in vivo xenogeneic system suggested that the human CH2-CH3 IgG2 used as a spacer in our construct was able to interact with the FcR present at the cell surface of the few NSG-FcR+ remaining immune cells. This interaction, leading to blockage of the NK-92CAR in the periphery of the engrafted tumor cells, stresses the critical role of the composition of the spacer domain.
UR - http://www.scopus.com/inward/record.url?scp=84948783620&partnerID=8YFLogxK
U2 - 10.1155/2015/482089
DO - 10.1155/2015/482089
M3 - Article
C2 - 26665156
AN - SCOPUS:84948783620
SN - 2314-8861
VL - 2015
JO - Journal of Immunology Research
JF - Journal of Immunology Research
M1 - 482089
ER -