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- Titel:
Genetically-modified, redirected T cells target hepatitis B surface antigen-positive hepatocytes and hepatocellular carcinoma lesions in a clinical setting.
- Dokumenttyp:
- Journal Article
- Autor(en):
- Wan, Xueshuai; Wisskirchen, Karin; Jin, Tao; Yang, Lu; Wang, Xiaorui; Wu, Xiang'an; Liu, Fang; Wu, Yu; Ma, Christy; Pang, Yong; Li, Qi; Zhang, Ke; Protzer, Ulrike; Du, Shunda
- Abstract:
- BACKGROUND/AIMS: Hepatitis B virus (HBV)-DNA integration in HBV-related hepatocellular carcinoma (HBV-HCC) can be targeted by HBV-specific T cells. SCG101 is an autologous, HBV-specific T-cell product expressing a T-cell receptor (TCR) after lentiviral transduction recognizing the envelope-derived peptide (S20-28) on HLA-A2. We here validated its safety and efficacy preclinically and applied it to an HBV-related HCC patient (NCT05339321). METHODS: Good Manufacturing Practice-grade manufactured cells were assessed for off-target reactivity and functionality against hepatoma cells. Subsequently, a patient with advanced HBV-HCC (Child-Pugh class A, Barcelona Clinic Liver Cancer stage B, Eastern Cooperative Oncology Group performance status 0, hepatitis B e antigen-, serum hepatitis B surface antigen [HBsAg]+, HBsAg+ hepatocytes 10%) received 7.9×107 cells/kg after lymphodepletion. Safety, T-cell persistence, and antiviral and antitumor efficacy were evaluated. RESULTS: SCG101, produced at high numbers in a closed-bag system, showed HBV-specific functionality against HBV-HCC cells in vitro and in vivo. Clinically, treatment was well tolerated, and all adverse events, including transient hepatic damage, were reversible. On day 3, ALT levels increased to 1,404 U/L, and concurrently, serum HBsAg started decreasing by 3.84 log10 and remained <1 IU/mL for over six months. HBsAg-expressing hepatocytes in liver biopsies were undetectable after 73 days. The patient achieved a partial response according to modified RECIST with a >70% reduction in target lesion size. Transferred T cells expanded, developed a stem cell-like memory phenotype, and were still detectable after six months in the patient's blood. CONCLUSION: SCG101 T-cell therapy showed encouraging efficacy and safety in preclinical models and in a patient with primary HBV-HCC and concomitant chronic hepatitis B with the capability to eliminate HBsAg+ cells and achieve sustained tumor control after single dosing.
- Zeitschriftentitel:
- Clin Mol Hepatol
- Jahr:
- 2024
- Band / Volume:
- 30
- Heft / Issue:
- 4
- Seitenangaben Beitrag:
- 735-755
- Volltext / DOI:
- doi:10.3350/cmh.2024.0058
- PubMed:
- http://view.ncbi.nlm.nih.gov/pubmed/38808361
- Print-ISSN:
- 2287-2728
- TUM Einrichtung:
- Institut für Virologie (Prof. Protzer)
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