CAN WE PROGRAM TUMOURS TO KILL EACH OTHER? | TUMOUR-SELECTIVE SYSTEMIC DELIVERY OF TRAIL USING A HYBRID PHAGE VECTOR FOR MELANOMA BRAIN METASTASIS

Can we program tumours to kill each other?
Brain metastases are the most common intracranial tumours in adults and arise from the secondary spread of systemic cancer to the brain and remain largely incurable with very poor prognoses. Melanoma is one of the leading causes of brain metastases. There is a major unmet clinical need for systemically delivered therapies that can cross the blood-brain-barrier and selectively target tumours while sparing healthy brain tissue.
Here, we investigate TPA (transmorphic phage/adeno-associated virus, AAV), a hybrid gene vector designed for tumour-selective treatment of brain metastases. TPA can be administered intravenously, subcutaneously, or intraperitoneally, enabling systemic delivery. Our vector builds on a previously established bacteriophage-based gene delivery platform with demonstrated tumour selectivity following systemic administration.
Tumour specificity is achieved via dual targeting:
i) binding to αvβ3 or αvβ5 integrin receptors via the RGD4C peptide; and
ii) delivery of TRAIL (tumour-necrosis-factor-related apoptosis inducing ligand) which activates the death receptors (DR4/DR5) on cancer cells to induce apoptosis, without harming healthy cells. This TRAIL-mediated apoptosis can spread to neighbouring tumour cells via a bystander effect.
We evaluate this strategy in vivo in a mouse model of metastatic melanoma using histopathology, biodistribution analyses, and quantitative imaging.