Description

Dual-Specific Engineered T Cells Targeting Hepatocellular Carcinoma and the Immunosuppressive Microenvironment

Dual-Specific Engineered T Cells Targeting Hepatocellular Carcinoma and the Immunosuppressive Microenvironment

Global Impact and Challenge of Hepatocellular Carcinoma (HCC)

HCC accounts for most primary liver cancers, which are the fourth most common causes of cancer-related death worldwide,and China has a high incidence of liver cancer. In 2020, new cases and deaths from liver cancer in China accounted for approximately half of the global total. For patients with HCC, conventional treatments, including surgery, liver transplantation, and local ablative and intra-arterial therapies, often have a certain incidence of tumor recurrence and poor prognosis.Therefore, novel treatments with favorable prognosis are still required.

Immunotherapy’s Frontier: Navigating the Unique Challenges of Solid Tumors

In the realm of hematologic malignancies, T cell immunotherapy, including Chimeric Antigen Receptor T cells (CAR-T) and T Cell Receptor T cells (TCR-T), has witnessed remarkable advancements. However, solid tumors like HCC present a distinct challenge due to their immunosuppressive microenvironment, a critical factor that enables tumor immune escape and sets.

Innovating with the “Bispecific T-cell Leaper”: Targeting HCC and CAFs to Disrupt Immunosuppression

Recognizing the pivotal role of Cancer-Associated Fibroblasts (CAFs) in orchestrating the immunosuppressive microenvironment that promotes HCC immune escape, this project introduces the “Bispecific T-cell Leaper”. Engineered to specifically target both HCC cells and CAFs, this dual-specific T cell therapy aims to dismantle the immunosuppressive milieu and restore the body’s natural defenses against HCC, marking a significant stride towards more effective cancer treatments.

Our Aims

  1. Bioinformatics database analysis of candidate markers for CAFs.

  2. Collection of tumor tissues from HCC patients and mouse models to validate the expression of candidate markers.

  3. Construction of TRuC/TCR recombinant lentiviral vectors.

  4. Lentiviral infection of human primary T cells to generate TRuC/TCR T cells.

Our Methods

Methods

Result

Bispecial engineered T cells targeting HCC and TME were constructed based on TRuC platform

FAP was proved to be a critical molecule on CAFs associated with tumor progression. The effectiveness of FAP as a target protein was corroborated by the close relationship between FAPhi CAFs and HCC patient survival. FAPhiCAFs exclude tumor-specific T cells from infiltrating into the tumor. Based TRuC T-cell platform, we design a dual-specific engineered T cell named “Bispecific T-cell Leaper” , consisting of FAP-TRuC/AFP-TCR expressing on T cella, which can target FAPpos CAFs and AFPpos HCC cells, thus inhibiting tumor microenvironment formation. Its efficiency of clearing FAPpos CAFs and promoting intratumoral infiltration of CD8+TCR+TIL was confirmed by intratumoral cell analysis.

Conclusions

FAP-TRuC/AFP-TCR-T, bispecific engineered T cells targeting HCC and immunosuppressive microenvironment, can delay the progression and improve the prognosis of HCC.

Reference:

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