Generation of neoantigen-specific T cells for adoptive cell transfer for treating head and neck squamous cell carcinoma

Wei，Teng1,2; Leisegang，Matthias3,4,5,6; Xia，Ming1; Kiyotani，Kazuma7; Li，Ning1; Zeng，Chenquan1; Deng，Chunyan1; Jiang，Jinxing1; Harada，Makiko7; Agrawal，Nishant8; Li，Liangping2; Qi，Hui1; Nakamura，Yusuke7; Ren，Lili1

2021

10.1080/2162402X.2021.1929726

OncoImmunology   影响因子和分区

2162-4011

2162-402X

Adoptive cell therapy using TCR-engineered T cells (TCR-T cells) represents a promising strategy for treating relapsed and metastatic cancers. We previously established methods to identify neoantigen-specific TCRs based on patients’ PBMCs. However, in clinical practice isolation of PBMCs from advanced-stage cancer patients proves to be difficult. In this study, we substituted blood-derived T cells for tumor-infiltrating lymphocytes (TILs) and used an HLA-matched cell line of antigen-presenting cells (APCs) to replace autologous dendritic cells. Somatic mutations were determined in head and neck squamous cell carcinoma resected from two patients. HLA-A*02:01-restricted neoantigen libraries were constructed and transferred into HLA-matched APCs for stimulation of patient TILs. TCRs were isolated from reactive TIL cultures and functionality was tested using TCR- T cells in vitro and in vivo. To exemplify the screening approach, we identified the targeted neoantigen leading to recognition of the minigene construct that stimulated the strongest TIL response. Neoantigen peptides were used to load MHC-tetramers for T cell isolation and a TCR was identified targeting the KIAA1429 mutation. TCR-T cells were activated, exhibited cytotoxicity, and secreted cytokines in a dose-dependent manner, and only when stimulated with the mutant peptide. Furthermore, comparable to a neoantigen-specific TCR that was isolated from the patient’s PBMCs, KIAA1429-specific TCR T cells destroyed human tumors in mice. The established protocol provides the required flexibility to methods striving to identify neoantigen-specific TCRs. By using an MHC-matched APC cell line and neoantigen-encoding minigene libraries, autologous TILs can be stimulated and screened when patient PBMCs and/or tumor material are not available anymore. Abbreviations: Head and neck squamous cell carcinoma (HNSCC); adoptive T cell therapy (ACT); T cell receptor (TCR); tumor-infiltrating lymphocytes (TIL); cytotoxic T lymphocyte (CTL); peripheral blood mononuclear cell (PBMC); dendritic cell (DC); antigen-presenting cells (APC).

adoptive T cell therapy Head and neck squamous cell carcinoma neoantigen T cell receptor engineered T cells tumor-infiltrating lymphocytes

SCI

英语

第一 ; 通讯

WOS:000653994300001

2-s2.0-85106963628

Scopus

1.Cytotherapy Laboratory,Shenzhen People’s Hospital,The Second Clinical Medical College,Jinan University,First Affiliated Hospital,Southern University of Science and Technology),Shenzhen,China
2.Institute of Clinical Oncology,The First Affiliated Hospital,Jinan University,Guangzhou,China
3.Institute of Immunology,Charité - Universitätsmedizin Berlin,Berlin,Germany
4.David and Etta Jonas Center for Cellular Therapy,the University of Chicago,Chicago,United States
5.German Cancer Consortium (DKTK),Partner Site Berlin,Berlin,Germany
6.German Cancer Research Center (DKFZ),Heidelberg,Germany
7.Cancer Precision Medicine Center,Japanese Foundation for Cancer Research,Tokyo,Japan
8.Department of Surgery,The University of Chicago,Chicago,United States

Wei，Teng,Leisegang，Matthias,Xia，Ming,et al. Generation of neoantigen-specific T cells for adoptive cell transfer for treating head and neck squamous cell carcinoma[J]. OncoImmunology,2021,10(1).

Wei，Teng.,Leisegang，Matthias.,Xia，Ming.,Kiyotani，Kazuma.,Li，Ning.,...&Ren，Lili.(2021).Generation of neoantigen-specific T cells for adoptive cell transfer for treating head and neck squamous cell carcinoma.OncoImmunology,10(1).

Wei，Teng,et al."Generation of neoantigen-specific T cells for adoptive cell transfer for treating head and neck squamous cell carcinoma".OncoImmunology 10.1(2021).