Systemic PD-1/PD-L1 inhibition combined with local vascular-targeted photodynamic therapy (VTP): Effects on primary tumor and prevention of lung metastasis in a preclinical RCC model.

Abstract

477 Background: Immune checkpoint inhibitors targeting the PD-1 pathway have shown activity against advanced renal cell carcinoma in phase 2 clinical trials. The response to PD-1 inhibition is not consistent however and may depend on host factors (ie. PD-L1 expression). Strategies that modulate immune regulation in the tumor microenvironment can impact responses to PD-1 pathway inhibitors. We have previously shown that VTP treatment of primary tumors using the novel photosensitizer WST-11 induces a defined local inflammatory response. We sought to evaluate whether response to PD-1/PD-L1 inhibition could be enhanced with VTP treatment of primary tumors. Methods: Balb/c mice bearing orthotopically implanted Renca kidney tumors were treated with IgG alone, anti-PD-1/anti-PD-L1 monoclonal antibodies (mAbs), VTP alone, or VTP + mAbs. VTP treatment of the primary tumor was performed 10 days (d10) after tumor implantation. Primary tumor response, enumeration of lung metastases and histologic analysis was performed on d21. Results: Treatment of the primary tumor with VTP and systemic PD-1/PD-L1 inhibition (n=15) resulted in regression of primary tumors whereas PD-1/PD-L1 inhibition alone (n=21) or VTP treatment alone (n=16) did not (no gross tumor vs. median tumor size 96mm2 vs 36 mm2 vs 81 mm2for combination vs mAbs alone vs VTP alone vs control, p<0.0001). Significant treatment effect was also observed in the combined treatment group by histologic analysis. Furthermore, growth of lung metastases was prevented with the combined treatment regimen compared to either treatment alone (median number lung mets=3 vs 56 vs 53 vs 23 for combination, mAb alone, VTP alone and control, respectively, p=0.0252). Conclusions: Only the combination of systemic PD-1/PD-L1 inhibition and local VTP provided primary tumor control and prevention of distant metastasis. Modulation of the inflammatory response in the tumor microenvironment with local therapy such as VTP may enhance the effects of systemic PD-1/PD-L1 blockade to provide better local and metastatic tumor control that can be investigated in prospective clinical trials.