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CAR-T cell engineered with TCR-like antibody specific for HBV surface antigen epitope E183-91/HLA-A *0201 exhibit
Fengling Wang1, Jiaqian Li1, Yong Huang1
1Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
Abstract:
CAR-T cell therapy demonstrates significant efficacy in hematologic malignancies, with target selection critically determining therapeutic outcomes. However, the available tumor surface antigens are limited, especially in the treatment of solid tumors. A potential solution to overcome this limitation entails employing antibodies recognizing peptide-major histocompatibility complex (pMHC) structures, enabling CAR-T cell to detect intracellular tumor antigens through a T cell receptor (TCR)-like recognition mechanism. This study focuses on HBV-associated hepatocellular carcinoma (HBV-HCC), where HBV DNA integration into the host genome generates specific viral antigen epitopes presented by MHC class I molecules, representing attractive targets for CAR-T cell therapy. We engineered CAR-T cells with a TCR-like antibody (HBs183 CAR-T) specific for the immunodominant HBV envelope epitope Env183-191 presented by HLA-A *0201, and evaluated the antigen-specific cytotoxicity and safety profile of the CAR-T cells through in vitro functional assays and in vivo evaluation in heterogenous tumor models (subcutaneous and intraperitoneal xenografts). Our research provides a reference for CAR-T cell therapy targeting intracellular antigens, particularly specific antigens derived from viral infections, as targets for CAR-T treatment, and offers a preliminary concept validation for the CAR-T treatment of HBV-HCC tumors.
Insights
This study engineered chimeric antigen receptor T cells (CAR-T) to target intracellular HBV antigens in liver cancer. The novel approach demonstrated antigen-specific killing in preclinical models, validating CAR-T therapy for viral-associated tumors.
Area of Science:
- Immunology
- Oncology
- Virology
Background:
- Chimeric antigen receptor T cell (CAR-T) therapy shows promise in hematologic cancers but faces challenges in solid tumors due to limited surface antigens.
- Targeting intracellular antigens via peptide-major histocompatibility complex (pMHC) structures offers a strategy to broaden CAR-T applicability.
- Hepatocellular carcinoma (HCC) associated with Hepatitis B virus (HBV) presents unique intracellular targets from integrated viral DNA.
Purpose of the Study:
- To engineer and evaluate CAR-T cells targeting a specific intracellular HBV antigen (Env183-191) presented by HLA-A*0201.
- To assess the in vitro and in vivo efficacy and safety of these engineered CAR-T cells against HBV-associated HCC.
- To provide a proof-of-concept for targeting viral-derived intracellular antigens in cancer therapy.
Main Methods:
- Development of CAR-T cells (HBs183 CAR-T) utilizing a T cell receptor (TCR)-like antibody against the HBV Env183-191 epitope.
- In vitro assessment of antigen-specific cytotoxicity and effector functions.
- In vivo evaluation in subcutaneous and intraperitoneal xenograft models of HBV-HCC.
Main Results:
- Engineered HBs183 CAR-T cells exhibited specific recognition and killing of target cells presenting the HBV Env183-191 epitope.
- Demonstrated potent anti-tumor activity in both subcutaneous and intraperitoneal preclinical models.
- Preliminary safety profile was evaluated in vivo.
Conclusions:
- CAR-T cells engineered to target intracellular viral antigens (HBV Env183-191) are effective against HBV-associated HCC in preclinical settings.
- This approach validates targeting intracellular antigens, particularly viral epitopes, for CAR-T therapy.
- Presents a potential therapeutic strategy for HBV-HCC and other virally driven cancers.
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