BiTE‐Secreting CAR‐γδT as a Dual Targeting Strategy for the Treatment of Solid Tumors

Author:

Huang Shi‐Wei12ORCID,Pan Chih‐Ming1,Lin Yu‐Chuan1,Chen Mei‐Chih1,Chen Yeh2,Jan Chia‐Ing3,Wu Chung‐Chun1,Lin Fang‐Yu1,Wang Sin‐Ting45,Lin Chen‐Yu1,Lin Pei‐Ying1,Huang Wei‐Hsaing1,Chiang Yu‐Ting1,Tsai Wan‐Chen1,Chiu Ya‐Hsu1,Lin Ting‐Hsun1,Chiu Shao‐Chih16,Cho Der‐Yang167ORCID

Affiliation:

1. Translational Cell Therapy Center Department of Medical Research China Medical University Hospital Taichung 40447 Taiwan

2. Institute of New Drug Development China Medical University Taichung 40447 Taiwan

3. Department of Pathology Kaohsiung Veterans General Hospital Kaohsiung 813414 Taiwan

4. Department of Dermatology Taichung Veterans General Hospital Taichung 40447 Taiwan

5. Department of Gastroenterology Taichung Veterans General Hospital Taichung 40447 Taiwan

6. Graduate Institute of Biomedical Sciences China Medical University Taichung 40447 Taiwan

7. Department of Neurosurgery China Medical University Hospital Taichung 40447 Taiwan

Abstract

AbstractHLA‐G is considered as an immune checkpoint protein and a tumor‐associated antigen. In the previous work, it is reported that CAR‐NK targeting of HLA‐G can be used to treat certain solid tumors. However, the frequent co‐expression of PD‐L1 and HLA‐G) and up‐regulation of PD‐L1 after adoptive immunotherapy may decrease the effectiveness of HLA‐G‐CAR. Therefore, simultaneous targeting of HLA‐G and PD‐L1 by multi‐specific CAR could represent an appropriate solution. Furthermore, gamma‐delta T (γδT) cells exhibit MHC‐independent cytotoxicity against tumor cells and possess allogeneic potential. The utilization of nanobodies offers flexibility for CAR engineering and the ability to recognize novel epitopes. In this study, Vδ2 γδT cells are used as effector cells and electroporated with an mRNA‐driven, nanobody‐based HLA‐G‐CAR with a secreted PD‐L1/CD3ε Bispecific T‐cell engager (BiTE) construct (Nb‐CAR.BiTE). Both in vivo and in vitro experiments reveal that the Nb‐CAR.BiTE‐γδT cells could effectively eliminate PD‐L1 and/or HLA‐G‐positive solid tumors. The secreted PD‐L1/CD3ε Nb‐BiTE can not only redirect Nb‐CAR‐γδT but also recruit un‐transduced bystander T cells against tumor cells expressing PD‐L1, thereby enhancing the activity of Nb‐CAR‐γδT therapy. Furthermore, evidence is provided that Nb‐CAR.BiTE redirectes γδT into tumor‐implanted tissues and that the secreted Nb‐BiTE is restricted to the tumor site without apparent toxicity.

Funder

China Medical University Hospital

Ministry of Education

Ministry of Science and Technology, Taiwan

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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