Abnormal vascular structure and function within brain metastases is linked to pembrolizumab resistance

Abstract

Background: We recently conducted a phase 2 trial (NCT028865685) evaluating intracranial efficacy of pembrolizumab for brain metastases (BM) of diverse histologies. Our study met its primary efficacy endpoint and illustrates that pembrolizumab exerts promising activity in a select group of patients with BM. Given the importance of aberrant vasculature in mediating immunosuppression, we explored the relationship between immune checkpoint inhibitor (ICI) efficacy and vascular architecture in the hopes of identifying potential mechanisms of intracranial ICI response or resistance for BM.

Methods: Using Vessel Architectural Imaging, a histologically validated quantitative metric for in vivo tumor vascular physiology, we analyzed dual-echo DSC/DCE MRI for 44 patients on trial. Tumor and peri-tumor cerebral blood volume/flow, vessel size, arterial and venous dominance, and vascular permeability were measured before and after treatment with pembrolizumab.

Results: BM that progressed on ICI were characterized by a highly aberrant vasculature dominated by large-caliber vessels. In contrast, ICI-responsive BM possessed a more structurally balanced vasculature consisting of both small and large vessels, and there was a trend toward a decrease in under-perfused tissue, suggesting a reversal of the negative effects of hypoxia. In the peri-tumor region, the development of smaller blood vessels, consistent with neo-angiogenesis, was associated with tumor growth before radiographic evidence of contrast enhancement on anatomical MRI.

Conclusions: This study, one of the largest functional imaging studies for BM, suggests that vascular architecture is linked with ICI efficacy. Studies identifying modulators of vascular architecture, and effects on immune activity, are warranted and may inform future combination treatments.

Keywords: brain metastases; checkpoint inhibition; functional imaging; vascular efficiency.

Figure 1.

Study schema. 58 enrolled patients, while on treatment with pembrolizumab, obtained perfusion MRI due to available funding. 44 patients had evaluable MRI data. Intracranial response was defined on the metastasis-level using Response Assessment for Neuro-Oncology (RANO) criteria. These brain metastases were then used in Vessel Architectural Imaging analysis.

Figure 2.

Intracranial response is associated with a structurally balanced vascular architecture. BM that responded to ICI had a significantly higher proportion of microvasculature within the contrast-enhancing area of the tumor, compared to SD or PD for both pretreatment (P = .04; P = .007, respectively) and posttreatment (P = .01; P = .04). Similarly, PR/CR BM displayed a trend towards a longitudinal decrease in under-perfused tissue (P = .13). In addition, BM that responded to ICI had a nonsignificant trend toward a higher degree of under-perfusion compared to SD or PD for both pretreatment (P = .06, P = .10) and posttreatment (P = .08, P = .08).

Figure 3.

Pembrolizumab exerts differential effects on vessel size within BM depending on response. Blood vessels within ICI-responsive BM had smaller vessel sizes, compared to BM that did not respond to ICI. Median posttreatment vessel sizes were significantly larger for BM with SD (P = .0004) and PD (P = .002), compared with PR/CR. The median vessel size increased during treatment with pembrolizumab for patients with SD (P = .0006) and PD (P = .02). No change was noted for PR (P = .43) in the same interval.

Figure 4.

Schematic illustration of pretreatment vasculature in ICI-responsive BM (left), compared with dysfunctional vasculature observed in ICI-resistant BM (right). A “therapeutically favorable” vasculature harbors a more normal-functioning vascular architecture and stable blood flow, which may augment immune activity and the therapeutic impact of ICI. A “therapeutically unfavorable” vasculature possesses abnormal vascular structures and increased vascular permeability, resulting in decreased vascular efficiency (eg, vessel leakiness, unstable blood flow, hypoxia, acidity)—thus potentially reducing immune activity and the therapeutic impact of ICI.

Figure 5.

DSC-MRI peri-tumor analysis may detect early tumor progression before development of contrast enhancement. For both perfusion parameters, there were significant interactions between ICI response and visit. BM with PD had highly significant increases over time (P < .0001) for both parameters, with no significant changes noted for PR or SD. Furthermore, the rates of change from baseline to 6 weeks were different for PR versus PD (P = .008—microvasculature; P = .008—under-perfused tissue).