Oncolytic virus driven T-cell-based combination immunotherapy platform for colorectal cancer

Area of Science:

• Oncolytic virotherapy
• Cancer immunotherapy
• Colorectal cancer therapeutics

Background:

• Colorectal cancer (CRC) is a leading cause of cancer mortality worldwide, necessitating novel therapeutic strategies.
• T cell engagers (TCEs) show promise but face challenges in solid tumors, including poor retention and short half-life.
• Effective anti-tumor immunity requires robust T cell responses, which are often suppressed in the tumor microenvironment.

Purpose of the Study:

• To engineer a novel platform for improved intra-tumoral delivery of T cell engagers (TCEs) for colorectal cancer treatment.
• To evaluate the efficacy of Bispecific Engager Viruses (BEVirs) in enhancing T cell-mediated anti-tumor immunity.
• To establish combination strategies involving BEVirs for aggressive and metastatic colorectal cancer.

Main Methods:

• Development of Bispecific Engager Viruses (BEVirs), a tumor-targeted vaccinia virus platform for intra-tumoral delivery of TCEs.
• In vitro co-culture and spheroid models using colorectal cancer cells, T cells, and patient tumor samples to assess TCE functionality and cytotoxicity.
• In vivo studies in syngeneic and xenograft mouse models to evaluate tumor regression, metastasis reduction, and immune responses following BEVirs treatment.
• HiBiT bioluminescent TCE-tagging technology to assess TCE retention and half-life in vivo.

Main Results:

• TCEs targeting CEACAM5 and CD3 demonstrated robust T cell activation in vitro but limited in vivo efficacy due to poor tumor retention and short half-life.
• Engineered BEVirs successfully delivered and secreted functional TCEs from infected colorectal cancer cells, leading to significant tumor regression in mouse models.
• Combination regimens of BEVirs with immune checkpoint inhibitors showed efficacy against colorectal peritoneal metastases.
• Intravenous delivery of BEVirs resulted in a significant reduction of lung metastases, targeting colorectal tumors and specific microenvironmental cells (FAP-positive stromal cells or CTLA4-positive T cells).

Conclusions:

• Bispecific Engager Viruses (BEVirs) represent a novel oncolytic virus platform for enhanced intra-tumoral delivery of immunomodulatory payloads, overcoming limitations of conventional TCEs.
• BEVirs-mediated T cell-based combination immunotherapy demonstrates significant potential for treating aggressive and metastatic colorectal cancer.
• The study highlights a promising new strategy for boosting T cell responses within tumors to achieve durable anti-tumor immunity and abscopal effects.