HBV-TCR T cell therapy: Preclinical and clinical insights into specificity, safety and efficacy for treating HBV-related HCC.

Abstract

e14525 Background: LioCyx-M, an autologous T-cell therapy modified with mRNA encoding HBV-specific TCRs, was developed using a TCR selected from a proprietary library of HBV-specific TCRs. LioCyx-M has shown promise in hepatocellular carcinoma (HCC) patients. This study presents preclinical specificity, safety and pharmacological effects of LioCyx-M, further supported by clinical pharmacological data in HBV-related HCC patients who failed standard systemic therapies, including anti-PD-L1 antibodies. Methods: TCR specificity was assessed in vitro using human peptides with identical key recognition sites to the target peptide, identified via alanine scanning, to evaluate cross-reactivity. Cross-reactivity with HLA-A2 subtypes and human primary cells of different tissue origins was evaluated. Comprehensive in vivo safety and efficacy were assessed in NPG tumor-bearing mice treated with multiple LioCyx-M infusions over 14 days (n = 136) and 25 days (n = 200) in a GLP-certified lab. Two HCC patients (NCT04745403) each received 8 bi-weekly LioCyx-M infusions, at doses of up to 5×10 6 cells/kg, without prior lymphodepletion. Immune responses induced by LioCyx-M were evaluated by measuringCXCL9, CXCL10, Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR), and T cell phenotypes in blood. Results: LioCyx-M selectively recognized HBV antigens presented by HLA-A*02:01+ lymphoblastoid cell lines (LCL) but showed no cross-reactivity with peptides sharing the target motif. Moreover, there was minimal cross-reactivity with other HLA-A2 subtypes or primary human cells of different tissue origins from 6 donors with different HLA subtypes. In HCC xenograft mice, tumour inhibition was accompanied by increased blood lymphocytes and IFN-γ with no significant histopathological abnormalities in vital organs. In patients, we observed transient increase in CXCL9, CXCL10, NLR and PLR in responders (4 out of 7 patients) in an earlier clinical study (NCT03899415) 1 . Post-treatment, both patients exhibited an immune reprogramming shift from a naive/central memory T to an effector/effector memory T cell phenotype, mirroring in vivo findings of enhanced tumor killing and immune activation. In one patient, effector T cells (CD45RA+CCR7-) and effector memory (CD45RA-CCR7-) T cells increased 4-fold post treatment, while PD1+Tim3+ and PD1+Tim3- exhausted T cells were halved. Conclusions: Preclinical and clinical data demonstrate the specificity, safety and efficacy of multiple LioCyx-M infusions. LioCyx-M treatment reprograms patient’s immunity from exhausted status to immune active status, implying its potential in cancer immunotherapy. Reference Tan et al. Immunological alterations after immunotherapy with short lived HBV-TCR T cells associates with long-term treatment response in HBV-HCC. Hepatol Commun. 2022. Clinical trial information: NCT04745403 .