# An αvβ6-specific virotherapy expressing bispecific immune cell activators induces immune cell activation to mediate tumor cell death

## TL;DR

A new virotherapy targets αvβ6-positive tumors and activates immune cells to kill cancer cells, offering a more precise and effective treatment.

## Contribution

The novel approach combines oncolytic virotherapy with bispecific immune cell activators to enhance tumor-specific immune responses.

## Key findings

- Ad5NULL-A20 BICA activates T cells and NK cells at tumor sites, reducing tumor cell viability.
- Ex vivo studies show significant tumor growth reduction in patient-derived organoids with Ad5NULL-A20-BICA and immune cells.

## Abstract

Ad5NULL-A20 is an adenovirus type 5-based precision virotherapy engineered to selectively target αvβ6-positive tumors. Bispecific immune cell activators (BICAs) bind both an immune cell receptor and tumor cell-associated antigen (TAA) in tandem to induce a tumor-specific immune response. Combining the selectivity and oncolytic properties of Ad5NULL-A20 with the potency of BICA will create a more tolerated, enduring immune cell response limited to tumor sites, reducing off-target effects and dose-limiting toxicities. We developed multiple BICA targeting T cells via CD3, natural killer (NK) cells via CD16/NKG2D receptors, and TAA epidermal growth factor receptor (EGFR) and major histocompatibility complex-related chain A (MICA). In vitro studies establish that Ad5NULL-A20 BICA in αvβ6 tumor cells results in T cell and NK activation at tumor sites and a loss of tumor cell viability. Ex vivo studies validate these findings demonstrating a significant and rapid reduction in growth of patient-derived 3D tumor organoids transduced with oncolytic Ad5NULL-A20-BICA in the presence of T cells or NK cells. Ad5NULL-A20 expressing BICA can produce a potent immune response resulting in tumor eradication. This approach has significant translational potential to develop a novel cancer therapeutic for clinical success.

Virotherapies can deliver anti-cancer therapeutics directly to tumors. Bayliss and colleagues develop a precision virotherapy expressing bispecific immunotherapies from tumor cells resulting in immune cell activation and tumor cell killing. Combination cancer therapy has potential to enhance regression of solid tumors in a targeted manner improving on current approaches.