Permeabilization of tumor margins in brain macrometastases using a type-1 receptor selective tumor necrosis factor mutein.

BACKGROUND

Brain metastasis remains a major clinical challenge. The blood-brain barrier, which persists in the margins even in late-stage macrometastases, is a major impediment to effective drug delivery, surgery, or radiotherapy. The aim of this study was to determine whether a mutein of human tumor necrosis factor (TNF) that is selective for the TNFR1 receptor could increase permeabilization in the margins of brain metastases, enabling better delineation and more complete treatment.

METHODS

Intracerebral xenograft mouse models of breast cancer (MDA231Br-GFP), melanoma (H1_DL2), and lung cancer (SEBTA) brain metastasis were used to test the efficacy of the TNF mutein (mutTNF) in permeabilizing the margins of well-established macrometastases. Changes in tumor permeabilization were assessed in vivo by gadolinium-enhanced magnetic resonance imaging (MRI) and ex vivo by IgG immunohistochemistry.

RESULTS

Tumor margin permeabilization was increased following mutTNF treatment in all 3 models. The MDA231Br-GFP model showed a significant increase in the extent of both gadolinium enhancement (P < 0.01) and IgG extravasation (P < 0.05), whilst significant effects were detected by MRI alone in the SEBTA (P < 0.01) and H1_DL2 (P < 0.05) models. Although a strong trend toward increased IgG extravasation was found in the SEBTA model (P = 0.076). Consistent with these findings, the models showed differing degrees of both infiltration and vascular TNFR1 expression at the margins (MDA231Br-GFP > SEBTA > H1_DL2), suggesting a greater sensitivity to mutTNF with increasing marginal invasiveness.

CONCLUSIONS

This work demonstrates the potential of TNFR1-selective mutTNF as an adjuvant strategy to improve tumor margin delineation and enhance therapeutic access in brain metastases.