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T Cells Directed against the Metastatic Driver Chondromodulin-1 in Ewing Sarcoma: Comparative Engineering with CRISPR/Cas9 vs. Retroviral Gene Transfer for Adoptive Transfer.
Xue, Busheng; von Heyking, Kristina; Gassmann, Hendrik; Poorebrahim, Mansour; Thiede, Melanie; Schober, Kilian; Mautner, Josef; Hauer, Julia; Ruland, Jürgen; Busch, Dirk H; Thiel, Uwe; Burdach, Stefan E G.
  • Xue B; Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany.
  • von Heyking K; Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany.
  • Gassmann H; Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany.
  • Poorebrahim M; Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany.
  • Thiede M; Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany.
  • Schober K; Institute for Medical Microbiology, Immunology and Hygiene, School of Medicine, Technical University of Munich, 81674 Munich, Germany.
  • Mautner J; Department of Gene Vectors, Helmholtz Centre Munich, 81377 Munich, Germany.
  • Hauer J; DZIF, German Center for Infection Research, Partner Site Munich, Germany Institute of Clinical, 81675 Munich, Germany.
  • Ruland J; Department of Pediatrics, Children's Cancer Research Center, Kinderklinik München Schwabing, School of Medicine, Technical University of Munich, 80804 Munich, Germany.
  • Busch DH; Munich Childhood Health Alliance (CHANCE) e.V, 80337 Munich, Germany.
  • Thiel U; DZIF, German Center for Infection Research, Partner Site Munich, Germany Institute of Clinical, 81675 Munich, Germany.
  • Burdach SEG; DKTK German Cancer Consortium, Partner Site Munich, 81675 Munich, Germany.
Cancers (Basel) ; 14(22)2022 Nov 08.
Article in English | MEDLINE | ID: covidwho-2287314
ABSTRACT
Ewing sarcoma (EwS) is a highly malignant sarcoma of bone and soft tissue with early metastatic spread and an age peak in early puberty. The prognosis in advanced stages is still dismal, and the long-term effects of established therapies are severe. Efficacious targeted therapies are urgently needed. Our previous work has provided preliminary safety and efficacy data utilizing T cell receptor (TCR) transgenic T cells, generated by retroviral gene transfer, targeting HLA-restricted peptides on the tumor cell derived from metastatic drivers. Here, we compared T cells engineered with either CRISPR/Cas9 or retroviral gene transfer. Firstly, we confirmed the feasibility of the orthotopic replacement of the endogenous TCR by CRISPR/Cas9 with a TCR targeting our canonical metastatic driver chondromodulin-1 (CHM1). CRISPR/Cas9-engineered T cell products specifically recognized and killed HLA-A*0201+ EwS cell lines. The efficiency of retroviral transduction was higher compared to CRISPR/Cas9 gene editing. Both engineered T cell products specifically recognized tumor cells and elicited cytotoxicity, with CRISPR/Cas9 engineered T cells providing prolonged cytotoxic activity. In conclusion, T cells engineered with CRISPR/Cas9 could be feasible for immunotherapy of EwS and may have the advantage of more prolonged cytotoxic activity, as compared to T cells engineered with retroviral gene transfer.
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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Year: 2022 Document Type: Article Affiliation country: Cancers14225485

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Full text: Available Collection: International databases Database: MEDLINE Type of study: Prognostic study Language: English Year: 2022 Document Type: Article Affiliation country: Cancers14225485