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 chimeric antigen receptor 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. In mice with hHer2-low livers, LA-CARTs exhibited less liver damage and lower systemic levels of IFN-γ 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 1 single-chain variable fragment (scFv).
Highlights
Chimeric antigen receptor–modified (CAR-modified) T cell therapy has emerged as an effective treatment for blood malignancies and is currently being developed to treat solid tumor cancers
One method of gene transfer used adeno-associated virus serotype 8 (AAV8) that contained a truncated human Her2 gene and a fluorescent reporter (Katushka), which was transduced into murine hepatocytes by i.v. tail vein injection (Figure 1A)
The expression of the fluorescent reporter in murine hepatocytes was detected by ex vivo imaging of livers, which showed greater fluorescence intensity in the livers of mice that received a higher number of genomic copies (GCs) of AAV8 (Figure 1B)
Summary
Chimeric antigen receptor–modified (CAR-modified) T cell therapy has emerged as an effective treatment for blood malignancies and is currently being developed to treat solid tumor cancers. CART therapy can result in severe adverse effects due to on-target, off-tumor toxicity, which arises in patients who have target antigen expressed on both tumor and healthy tissue This expression pattern is typical for the vast majority of target antigens used in CART therapies. A Her CART therapy based on the trastuzumab sequence was used to treat a patient with colorectal cancer; off-tumor targeting of their cardiopulmonary system caused lethal toxicity [2]. This adverse effect was not foreseen based on clinical studies of trastuzumab or in preclinical animal experiments
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