CD147-CAR-NK cell therapy shows minimal toxicities in human CD147 transgenic mouse model with solid tumors
Youssef Sabha1, Sang Hoon Kim2, Hsiang-Chi Tseng1
1Department of Pathology, Immunology and Laboratory Medicine, Rutgers University New Jersey Medical School, 180 South Orange Avenue, Newark, NJ 07103, USA.
Abstract:
The toxicity of chimeric antigen receptor-natural killer (CAR-NK) therapy has not been tested in solid tumors, compared with CAR-T therapy side by side. To address this, we investigated the CD147-CAR-NK "on-target/off-tumor" toxicity and neurotoxicity in human CD147-transgenic (hCD147TG) mice with hepatocellular carcinoma (HCC). We first tested the in vitro cytotoxicity of CD147-CAR-NK against CD147+ tumor and CD147+ healthy cells. Both CD147-CAR-NK cells and CD147-IL15-CAR-NK (autocrine expressing interleukin [IL]-15) can kill tumor cells specifically but not CD147+ healthy lung and spleen tissue from hCD147TG mice. In vivo assays show minimal systemic toxicities against CD147+ healthy tissues but 1-week-longer persistence times in tumor than non-tumor tissues. To evaluate neurotoxicity, we compared the expression of ionized calcium-binding adaptor protein 1 (IBA1), glial fibrillary acidic protein (GFAP), and inducible nitric oxide synthase (iNOS) between CD147-CAR-T- and CD147-CAR-NK-treated hCD147TG mice with HCC. Both CD147-CAR-T- and CD147-CAR-NK-treated mice exhibited higher GFAP and IBA1 expression than control groups. CD147-CAR-T-treated mice showed an increase in iNOS compared to the control groups. The behavioral studies testing spatial memory showed that mice treated with CD147-CAR-NK exhibit better memory function than CD147-CAR-T-treated mice. This study provides a deeper understanding of the CD147-CAR-NK systemic toxicities and neurotoxicity of CD147-CAR-NK relative to CD147-CAR-T therapy.
Insights
Chimeric antigen receptor-natural killer (CAR-NK) therapy shows promising efficacy against solid tumors with minimal systemic toxicity. Compared to CAR-T therapy, CAR-NK treatment demonstrated better memory function in mice, suggesting reduced neurotoxicity.
Area of Science:
- Immunotherapy
- Oncology
- Toxicology
Background:
- Chimeric antigen receptor-natural killer (CAR-NK) therapy's toxicity in solid tumors remains largely uncharacterized compared to CAR-T therapy.
- Hepatocellular carcinoma (HCC) is a solid tumor where CAR-NK therapy requires thorough toxicity assessment.
- Understanding on-target/off-tumor effects and neurotoxicity is crucial for advancing CAR-NK therapy.
Purpose of the Study:
- To investigate the systemic toxicity and neurotoxicity of CD147-CAR-NK therapy in a preclinical model of HCC.
- To compare the safety profile of CD147-CAR-NK therapy side-by-side with CD147-CAR-T therapy.
- To evaluate the in vitro and in vivo efficacy and toxicity of CD147-CAR-NK cells.
Main Methods:
- Utilized human CD147-transgenic (hCD147TG) mice with HCC to model CD147-targeted therapies.
- Performed in vitro cytotoxicity assays using CD147-CAR-NK cells against tumor and healthy cells.
- Assessed in vivo systemic toxicity, tissue persistence, neurotoxicity markers (IBA1, GFAP, iNOS), and behavioral function (spatial memory).
Main Results:
- CD147-CAR-NK cells demonstrated specific cytotoxicity against CD147+ tumor cells without harming CD147+ healthy tissues in vitro.
- In vivo studies showed minimal systemic toxicity and favorable persistence of CAR-NK cells in tumor tissues.
- Neurotoxicity assessments revealed comparable GFAP and IBA1 expression between CAR-NK and CAR-T groups, but CAR-NK treatment was associated with better spatial memory and lower iNOS expression.
Conclusions:
- CD147-CAR-NK therapy exhibits a favorable safety profile with minimal systemic toxicity in a preclinical HCC model.
- CAR-NK therapy demonstrates potential for reduced neurotoxicity compared to CAR-T therapy, evidenced by improved cognitive function.
- This study provides critical insights into the comparative toxicity of CAR-NK and CAR-T therapies, supporting further clinical investigation of CAR-NK for solid tumors.
