Hi-TCR-T Cell Therapy

High-Affinity T-Cell Receptor Engineered T-Cell Therapy (Hi-TCR-T) is an advanced T-cell receptor (TCR) retargeting technology based on genetic engineering. This platform integrates natural TCR activation and regulatory mechanisms with the multi-targeting characteristics of fourth-generation CAR-T cells, inducing a controllable anti-tumor immune response that rapidly migrates to the tumor site. It exhibits multi-targeting capabilities and can improve the tumor microenvironment by secreting immunomodulatory factors, effectively killing tumor cells while maintaining good response durability. Simultaneously, it releases lower levels of cytokines, leading to effective tumor cell clearance with fewer toxic side effects.

Therapeutic Mechanism

1. High-Affinity TCR Screening and Engineering Optimization
   Through protein engineering and affinity enhancement technologies, natural TCRs are optimized to make them more stable, efficient, and improve their ability to recognize target tumor antigens.
2. Genetic Redirection of T Cells
   The optimized TCR gene is introduced into the patient's T cells, giving them new anti-tumor targeting functions.
3. Ex Vivo Expansion
   The modified T cells are expanded in large quantities in vitro and subjected to functional and safety testing.
4. Cell Infusion
   After Hi-TCR-T cell infusion, an immune response can be initiated in the patient to precisely recognize and kill tumor cells.

Fig.1 Schematic diagram of TCR-T cell construction preparation for clinical applications. (Zhang et al., 2022).

Key Advantages

Broader Tumor Antigen Recognition

Engineered high-affinity TCRs can recognize intracellular and surface tumor antigens, including neoantigens generated by tumor-specific mutations.

Enhanced Sensitivity

High-affinity TCRs allow T cells to detect and respond to low levels of tumor antigen, improving efficacy in tumors with heterogeneous or low antigen expression.

High Specificity

The engineering and optimization of T-cell receptors enhance the recognition of tumor antigens while minimizing cross-reactivity with normal tissues, thereby reducing the risk of off-target toxicity and improving safety.

Potential for Personalized Therapy

TCRs can be matched to patient HLA types and tumor antigen profiles, enabling precision immunotherapy tailored to individual patients.

Clinical Evidence

Preliminary clinical trials of super-potent Hi-TCR-T cell therapy targeting BCMA/NKG2DL/FAP in patients with relapsed/refractory multiple myeloma have shown excellent efficacy.

• Efficacy in treated patients: In the treatment group of 10 patients, the complete remission rate reached 100%, with sustained remission. At the last follow-up, one patient remained in complete remission, eight patients achieved partial remission, and one patient maintained stable disease.
• Safety profile: During a follow-up period of 32 to 66 months, the only observed adverse event was fever, indicating a favorable safety profile.
• Broad applicability: Follow-up of 8 to 32 months demonstrated efficacy across different disease types.
• Recognition and presentation: These research results were publicly presented as a Late-breaking Abstract (LBA) at the 39th annual meeting of the Society for Immunotherapy of Cancer.

In summary, multi-target super-potent Hi-TCR-T cells show highly promising efficacy against relapsed/refractory advanced tumors, including solid tumors.

Potential Therapeutic Applications

Hi-TCR-T cell therapy aims to address several key challenges in cancer treatment, including tumor heterogeneity, immune evasion, and limited response to existing therapies. With its high-affinity TCR engineering, multi-target antigen recognition capabilities, and adaptability to the solid tumor immune microenvironment, Hi-TCR-T's therapeutic indications primarily focus on relapsed/refractory solid tumors (especially hepatocellular carcinoma) and certain hematological malignancies.

Solid Tumors

Solid tumors present unique challenges to cellular immunotherapy, including antigen heterogeneity, physical barriers limiting T cell infiltration, and an immunosuppressive tumor microenvironment. Hi-TCR-T cell therapy is specifically designed to overcome these obstacles.

Potential solid tumor indications include:

Hepatocellular Carcinoma (HCC)

Other advanced or metastatic solid tumors with limited treatment options

Through multi-target antigen recognition and modulation of the tumor immune microenvironment, Hi-TCR-T cells can enhance tumor infiltration, in vivo persistence, and anti-tumor activity in solid tumors, providing a new treatment option for patients with advanced and refractory cancers.

Hematological Malignancies

Hi-TCR-T is particularly suitable for patients with relapsed or refractory hematological malignancies who have developed resistance to standard treatments or experienced disease recurrence.

Potential indications include, but are not limited to:

Relapsed/Refractory Multiple Myeloma (R/R MM)

Other plasma cell or lymphoid malignancies expressing specific tumor-associated antigens

Through multi-target design, Hi-TCR-T is expected to reduce antigen escape and improve the durability of clinical responses in patients who have previously received multiple lines of treatment.

• Hi-TCR-T Treatment for Solid Tumors
• Multi-Target Hi-TCR-T for Hepatocellular Carcinoma