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In vivo therapeutic effects of affinity-improved-TCR engineered T-cells on HBV-related hepatocellular carcinoma
Qi Liu 1 2 , Ye Tian 1 , Yanyan Li 1 , Wei Zhang 3 , Wenxuan Cai 1 , Yaju Liu 3 , Yuefei Ren 1 4 , Zhaoduan Liang 1 , Peipei Zhou 1 5 , Yajing Zhang 1 2 , Yifeng Bao 1 , Yi Li 6 2
Affiliations
Affiliations
1
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China.
2
University of the Chinese Academy of Sciences, Beijing, China.
3
Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Hefei, Anhui, China.
4
School of Life Sciences, University of Science and Technology of China, Hefei, Anhui, China.
5
Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, China.
6
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Guangzhou, China [email protected].
PMID: 33323464 DOI: 10.1136/jitc-2020-001748
Abstract
Background: In patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), virus-specific cytotoxic T lymphocytes (CTLs) fail to eliminate HCC cells expressing HBV antigens. As the expression of viral antigen in HBV-associated HCC may decrease to allow tumor to escape immune attacks, we hypothesized that an HBV surface antigen (HBsAg)-specific affinity-improved-T-cell receptor (TCR) will enable T cells to target HCC more effectively than corresponding wild-type-TCR. We also postulated that TCR promiscuity can be exploited to efficiently capture HBV variants that can hinder CTL-based therapeutics.
Methods: We applied flexi-panning to isolate affinity-improved TCRs binding to a variant antigen, the human leukocyte antigen (HLA)-A*02:01-restricted nonapeptide HBs371-379-ILSPFLPLL, from libraries constructed with a TCR cloned using the decapeptide HBs370-379-SIVSPFIPLL. The potency and safety of the affinity-improved-TCR engineered T-cells (Ai-TCR-T) were verified with potentially cross-reactive human and HBV-variant peptides, tumor and normal cells, and xenograft mouse models.
Results: Ai-TCR-T cells retained cognate HBV antigen specificity and recognized a wide range of HBV genotypic variants with improved sensitivity and cytotoxicity. Cell infusions produced complete elimination of HCC without recurrence in the xenograft mouse models. Elevated accumulation of CD8+ Ai-TCR-T cells in tumors correlated with tumor shrinkage.
Conclusion: The in vitro and in vivo studies demonstrated that HBsAg-specific Ai-TCR-T cells had safety profiles similar to those of their wild-type counterparts and significantly enhanced potency. This study presents an approach to develop new therapeutic strategies for HBV-related HCC.
Keywords: CD8-Positive T-lymphocytes; adoptive; cell engineering; immunohistochemistry; immunotherapy; liver neoplasms.
© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. |
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