Thompson, Houston R.

458 Background: Immune checkpoint inhibitors (ICI) targeting PD-1/PD-L1 axis has revolutionized the therapeutic landscape of patients with advanced and locally advanced renal cell carcinoma (RCC). However, complete response rates remain low and there is a need for novel therapeutic options for ICI-resistant and refractory RCC. Our group has generated a novel humanized anti-PD-L1 antibody, called H1A, that induces PD-L1 degradation preventing not only its interaction with PD-1 but also inhibiting pro-tumorigenic intracellular signaling. In this study, we compared the antitumor activity of H1A with FDA-approved ICI using patient-derived immune cells and humanized mouse tumor models. Methods: In vivo antitumor activity of H1A and atezolizumab (ATZ) was compared in three humanized PD-1/PD-L1 mouse tumor models with different immunogenicity (E0771:high, MC38:moderate, B16-F10:poor). Peripheral blood mononuclear cells (PBMC) were isolated from 14 RCC patients undergoing with nephrectomy. PBMC were treated with H1A, nivolumab (NIV), atezolizumab (ATZ) and pembrolizumab (PEM) to evaluate their efficacy in inducing tumor cell death in an ex-vivo cytotoxicity assay. Mass cytometry was employed to determine the impact of H1A and atezolizumab on the PBMC profile. Results: MC38 tumors showed moderate response to both H1A and ATZ which was abrogated by CD8 T cell depletion. In E0771 tumors, higher percentage of complete responders was observed with H1A compared to ATZ and E0771 rechallenge revealed memory antitumor immunity with complete rejection of tumors. Patient-derived PBMC treated with H1A showed superior tumor cell killing compared to NIV, PEM and ATZ (p<0.01). While H1A treatment of PBMC induced expansion of effector NK and CD8 T cells (GZMB+ T-bet+), ATZ treatment led to enrichment of Tregs (CD25+,Foxp3+) expressing inhibitory markers PD-1 and LAG-3. Conclusions: H1A demonstrated superior antitumor activity compared to FDA-approved ICI which lays the ground for clinical testing of H1A as a next-generation immune checkpoint inhibitor for the treatment of renal cell carcinoma.

381 Background: Venous tumor thrombus (VTT) is associated with worse oncologic outcomes in clear cell renal cell carcinoma (ccRCC). It is unknown if VTT and pulmonary embolism (PE) predispose patients to pulmonary metastasis. Methods: We queried our institutional registry for ccRCC patients undergoing radical nephrectomy (1970-2019). Cox proportional hazards regression models, adjusting for factors associated with ccRCC progression, were used to determine if VTT and PE were associated with pulmonary metastasis. Results: Of 3,410 patients studied, 1,025 (30%) had VTT, and patients with VTT were more likely to present with pulmonary metastasis at nephrectomy (20% vs 7%, p<0.001). Within the VTT subset, level of VTT was not significantly associated with pulmonary metastasis at nephrectomy (p=0.3). For all patients who had metastatic disease at nephrectomy (n=643), pulmonary metastasis was more common in those with VTT versus those without VTT (68% vs 51%, p<0.001). Excluding patients with pulmonary metastasis at nephrectomy, on multivariable analysis, VTT remained associated with post-nephrectomy pulmonary metastasis (hazard ratio (HR) 1.31, p<0.001) without a notable difference in HRs between renal vein (1.27) and caval (1.38) VTT. Presence of PE in the setting of VTT was associated with increased pulmonary metastasis post-nephrectomy (HR 2.31, p<0.001). Conclusions: VTT is associated with disproportionately increased pulmonary metastasis at presentation and post-nephrectomy in ccRCC patients. Further, the presence of PE at nephrectomy for VTT was associated with increased pulmonary metastasis post-nephrectomy. These results support a metastatic predilection of ccRCC with VTT to the lungs.