Viroimmunotherapy for Brain Cancer

Brain cancers remain among the most lethal malignancies, with survival for patients largely unchanged over the past decades. In this project, we develop a next-generation viroimmunotherapy strategy built on two complementary pillars: (i) newly designed tumor-targeted immune cell engagers and (ii) oncolytic Vaccinia virus as a local delivery platform.

Standard immunotherapeutic approaches largely fail in brain tumors. Three key barriers drive this: the blood-brain barrier restricts access for most therapeutic agents; immune cell infiltration into brain tumors is extremely limited; and tumor cells actively suppress immune recognition through checkpoint ligands and other evasion strategies. Overcoming these barriers requires therapies that can reach the tumor, remodel its immune environment, and direct cytotoxic immune cells to kill residual tumor cells.

A central focus of this project is the development of novel immune cell engagers (ICEs): nanobody-based multispecific proteins designed to bridge Natural Killer (NK) cells to tumor cells and trigger cytotoxicity. Our platform allows flexible targeting and can incorporate immunostimulatory cytokines to simultaneously activate and expand NK cells at the tumor site. Several ICEs have been designed, produced, and purified, and are continuously refined based on functional testing in primary human NK cell co-culture assays. This allows us to systematically optimize engager design for potency, selectivity, and translational potential — both as standalone therapeutics and as encoded payloads within oncolytic Vaccinia virus (OVV).

OVV can cross the blood-brain barrier and selectively replicate in and lyse cancer cells, sparing healthy tissue. Its large and manipulable genome allows us to encode ICEs alongside other immunomodulatory payloads — such as immune checkpoint inhibitors — transforming OVV from a simple oncolytic agent into a self-amplifying, local viroimmunotherapy platform that reshapes the tumor microenvironment from within.

Together, ICEs and OVV form a complementary therapeutic strategy currently validated in medulloblastoma using primary human NK cells, patient-derived tumoroids, and blood-brain barrier models. Ultimately, we aim to translate this platform into a new class of localized brain tumor viroimmunotherapy, with the ambition to expand from medulloblastoma toward broader brain tumor indications and improve outcomes for patients who currently have no effective treatment options.

Selected references

1. Dual targeting of CD155/TIGIT and PD-L1/PD-1 immune checkpoints potentiates NK cell-mediated cytotoxicity in medulloblastoma. Neuro Oncology Advances 2025

2. Cellular immunotherapy for medulloblastoma. Neuro Oncology 2023