An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma
Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against...
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Published in | The Journal of clinical investigation Vol. 132; no. 16; pp. 1 - 17 |
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Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Ann Arbor
American Society for Clinical Investigation
01.08.2022
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Abstract | Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma (NB), a lethal extracranial solid tumor of childhood. First, we examined CAR T cell expansion in the presence of targets by digital droplet PCR. Next, using pooled competitive optimization of CAR by cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), termed P-COCC, we simultaneously analyzed protein and transcriptome expression of CAR T cells to identify high-activity CARs. Finally, we performed cytotoxicity assays to identify the most effective CAR against each target and combined the CARs into a bicistronic "OR" CAR (BiCisCAR). BiCisCAR T cells effectively eliminated tumor cells expressing GPC2 or CD276. Furthermore, the BiCisCAR T cells demonstrated prolonged persistence and resistance to exhaustion when compared with CARs targeting a single antigen. This study illustrated that targeting multiple TAAs with BiCisCAR may overcome heterogenous expression of target antigens in solid tumors and identified a potent, clinically relevant CAR against NB. Moreover, our multimodal approach integrating competitive expansion, P-COCC, and cytotoxicity assays is an effective strategy to identify potent CARs among a pool of candidates. |
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AbstractList | Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma (NB), a lethal extracranial solid tumor of childhood. First, we examined CAR T cell expansion in the presence of targets by digital droplet PCR. Next, using pooled competitive optimization of CAR by cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), termed P-COCC, we simultaneously analyzed protein and transcriptome expression of CAR T cells to identify high-activity CARs. Finally, we performed cytotoxicity assays to identify the most effective CAR against each target and combined the CARs into a bicistronic "OR" CAR (BiCisCAR). BiCisCAR T cells effectively eliminated tumor cells expressing GPC2 or CD276. Furthermore, the BiCisCAR T cells demonstrated prolonged persistence and resistance to exhaustion when compared with CARs targeting a single antigen. This study illustrated that targeting multiple TAAs with BiCisCAR may overcome heterogenous expression of target antigens in solid tumors and identified a potent, clinically relevant CAR against NB. Moreover, our multimodal approach integrating competitive expansion, P-COCC, and cytotoxicity assays is an effective strategy to identify potent CARs among a pool of candidates. |
Author | Wei, Jun S St Croix, Brad Badr, Sherif Kim, Yong Yean Kelly, Michael C Li, Nan Wen, Xinyu Song, Young K Wu, Xiaolin Qin, Haiying Ho, Mitchell Dower, Christopher M Benzaoui, Mehdi Khan, Javed Wu, Jerry T Zhang, Zhongmei Abdelmaksoud, Abdalla Chou, Hsien-Chao Taylor, Naomi Masih, Katherine E Cheuk, Adam T Milewski, David Tian, Meijie |
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Copyright | Copyright American Society for Clinical Investigation Aug 2022 |
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DOI | 10.1172/JCI162322 |
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SubjectTerms | Antigen (tumor-associated) Antigens Biomedical research Cell adhesion & migration Children Chimeric antigen receptors Clinical trials Cytotoxicity Epitopes Heparan sulfate proteoglycans Immunotherapy Kinases Lymphocytes Lymphocytes T Lymphoma Medical prognosis Metastasis Neuroblastoma Pediatrics Protein expression Proteins Solid tumors Transcriptomes Tumor cells Tumors |
Title | An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma |
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