# An oncolytic vaccinia virus encoding CD47 nanobody potentiates antitumor immunity in multiple myeloma

## TL;DR

A virus that targets cancer cells and boosts the immune system shows promise in treating multiple myeloma.

## Contribution

A new oncolytic virus with an anti-CD47 nanobody is developed to enhance antitumor immunity and overcome drug resistance.

## Key findings

- OVV-αCD47nb suppressed tumor growth and improved survival in mouse models of multiple myeloma.
- The virus reprogrammed macrophages and increased CD8+ T cell activity in the tumor microenvironment.
- OVV-αCD47nb synergized with bortezomib to overcome resistance and improve tumor control.

## Abstract

Multiple myeloma (MM) is an incurable malignancy exhibiting immune evasion and resistance to proteasome inhibitors like bortezomib. We engineered an oncolytic vaccinia virus encoding an anti-mouse CD47 nanobody (OVV-αCD47nb) that combines direct oncolysis with localized CD47-SIRPα axis blockade. OVV-αCD47nb maintained infectivity and secreted anti-CD47 nanobodies that enhanced macrophage phagocytosis of tumor cells. In murine MM models, OVV-αCD47nb suppressed tumor growth, extended survival, and induced durable responses without hematologic toxicity. Mechanistically, OVV-αCD47nb remodeled the tumor microenvironment by polarizing macrophages to M1-like phenotypes and enhancing CD8+ T cell infiltration and function. Transcriptomics revealed enriched pro-inflammatory and phagocytic pathways with downregulated autophagy genes. OVV-αCD47nb synergized with bortezomib to overcome resistance and improve tumor control over monotherapies. This multifunctional viro-immunotherapy strategy, which integrates oncolysis, immune reprogramming, and chemosensitization, offers a promising therapeutic approach for CD47-expressing malignancies.

•An oncolytic virus encoding an anti-CD47 nanobody induces multiple myeloma tumor regression•The therapy reprograms the tumor microenvironment and enhances immune cell activity•This strategy overcomes bortezomib resistance by inhibiting autophagy•Localized viral delivery increases treatment efficacy and limits systemic toxicity

An oncolytic virus encoding an anti-CD47 nanobody induces multiple myeloma tumor regression

The therapy reprograms the tumor microenvironment and enhances immune cell activity

This strategy overcomes bortezomib resistance by inhibiting autophagy

Localized viral delivery increases treatment efficacy and limits systemic toxicity

Immunology; Medical biotechnology; Cancer