T Cell-Activating Mesenchymal Stem Cells as a Biotherapeutic for HCC

Area of Science:

• Oncology
• Immunotherapy
• Cancer Biology

Background:

• Advanced hepatocellular carcinoma (HCC) has a poor prognosis, necessitating innovative therapeutic strategies.
• Mesenchymal stem cells (MSCs) possess inherent tumor-homing capabilities, making them attractive candidates for targeted cancer therapies.
• Glypican-3 (GPC3) is a validated target antigen for HCC immunotherapy.

Purpose of the Study:

• To engineer MSCs to express a GPC3/CD3 bispecific T cell engager (GPC3-ENG) for redirecting T cells to GPC3+ HCC.
• To evaluate the impact of co-stimulatory molecules (CD80 and 41BBL) on the efficacy of GPC3-ENG MSCs.
• To assess the in vitro and in vivo anti-tumor activity of modified MSCs in HCC models.

Main Methods:

• Genetic modification of MSCs using viral vectors to encode GPC3-ENG, an irrelevant antigen engager (EGFRvIII), and/or co-stimulatory molecules.
• In vitro co-culture assays with GPC3+ HCC cells, T cells, and engineered MSCs to measure T cell activation (IFNγ, IL-2 production) and tumor cell killing.
• In vivo studies using a HUH7 HCC xenograft mouse model to evaluate the anti-tumor efficacy and survival benefit of GPC3-ENG MSCs.

Main Results:

• Co-culture of GPC3-ENG MSCs with T cells and GPC3+ HCC cells led to T cell activation and tumor cell lysis.
• Co-expression of CD80 and 41BBL on GPC3-ENG MSCs enhanced antigen-dependent IL-2 production and accelerated tumor cell killing.
• In vivo administration of GPC3-ENG MSCs, with or without co-stimulatory molecules, demonstrated significant anti-tumor activity and improved survival in the HCC xenograft model.

Conclusions:

• MSCs engineered to express GPC3-ENG, particularly with co-stimulatory molecules, effectively redirect T cells to target GPC3+ HCC.
• This MSC-based immunotherapy approach exhibits potent anti-tumor activity in preclinical models.
• Further investigation of this modified MSC-based GPC3-targeted immunotherapy for HCC is warranted.