To address on-target, off-tumor toxicity with CAR T cell therapy, Castellarin et al. developed a model in which hHER2 was stably expressed at high (hHER2-high) or low (hHER2-low) levels on normal hepatocytes to mimic clinical situations. High-affinity (HA) and low-affinity (LA) HER2 CAR T cells (CARTs) caused lethal liver toxicity in mice with hHER-high livers, but in hHER2-low mice, LA-CARTs resulted in less liver damage and lower circulating IFNγ. LA-CARTs exhibited superior antitumor efficacy against hHER2+ xenografts compared to HA-CARTs, partly due to faster trafficking from the liver into the tumor.
Contributed by Katherine Turner
ABSTRACT: Off-tumor targeting of human antigens is difficult to predict in preclinical animal studies and can lead to serious adverse effects in patients. To address this, we developed a mouse model with stable and tunable human HER2 (hHER2) expression on normal hepatic tissue and compared toxicity between affinity-tuned HER2 CAR T cells (CARTs). In mice with hHER2-high livers, both the high-affinity (HA) and low-affinity (LA) CARTs caused lethal liver damage due to immunotoxicity. Mice with hHER2-low livers, LA-CARTs exhibited less liver damage and lower systemic levels of IFN-gamma than HA-CARTs. We then compared affinity-tuned CARTs for their ability to control a hHER2-positive tumor xenograft in our model. Surprisingly, the LA-CARTs outperformed the HA-CARTs with superior antitumor efficacy in vivo. We hypothesized that this was due in part to T cell trafficking differences between LA and HA-CARTs and found that the LA-CARTs migrated out of the liver and infiltrated the tumor sooner than the HA-CARTs. These findings highlight the importance of T cell targeting in reducing toxicity of normal tissue and also in preventing off-tumor sequestration of CARTs, which reduces their therapeutic potency. Our model may be useful to evaluate various CARTs that have conditional expression of more than one scFv.
Author Info: (1) Center for Cellular Immunotherapies, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (2) Center for Cel
Author Info: (1) Center for Cellular Immunotherapies, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (2) Center for Cellular Immunotherapies, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (3) Center for Cellular Immunotherapies, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (4) Center for Cellular Immunotherapies, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (5) Center for Cellular Immunotherapies, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (6) Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, United States of America. (7) Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (8) Center for Cellular Immunotherapies, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America. (9) Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States of America.
