Abstract 5548: PB101 simultaneously targets tumor angiogenesis and immunity and enhances the efficacy of PD-L1 immune checkpoint blockade

Abstract

Abstract Introduction: Tumor vasculature plays an important role in promoting tumor progression and immune evasion. Previously, we developed PB101, a novel glycosylated decoy receptor that can neutralize VEGF-A, VEGF-B, and PlGF, and demonstrated that it potently inhibits tumor angiogenesis, thereby retarding tumor growth and metastasis. However, its impact on tumor microenvironment (TME), especially anti-cancer immunity, has not been fully elucidated. Here, we investigated distinct modes of immune modulation by PB101 compared with other anti-angiogenic agents, and evaluated its immunotherapeutic potential when combined with immune checkpoint inhibitors (ICIs). Methods: MC38 colon or Hepa-V liver cancer-bearing mice were treated with PB101 or other anti-angiogenic agents with or without various ICIs. The TME was evaluated by histologic, flow cytometric, and Nanostring immune profiling analyses. Results: PB101 markedly suppressed MC38 colon and Hepa-V liver cancer growth in vivo. It simultaneously inhibited both VEGF and PlGF signaling within the TME, thus suppressing tumor angiogenesis. PB101 also induced extensive immune remodeling of the TME. PB101 enhanced intratumoral dendritic cells, but reduced M2-like tumor-associated macrophages. Moreover, PB101 resulted in high influx of activated CD8+, but not CD4+, T cells into the TME. PB101 exhibited the most prominent immune-modulating effect compared with other vascular targeting agents. When combined with various ICIs, PB101 had the greatest synergism with anti-PD-L1 antibody, inducing complete tumor regression and long-term survival. Furthermore, PB101-based combination immunotherapy induced a durable and protective immunity against subcutaneous tumor re-challenge and hematogenous lung metastasis. Conclusion: PB101 elicited strong anti-tumor immunity more effectively than other anti-angiogenic agents. PB101 can strengthen the immunotherapeutic efficacy of PD-L1 inhibitor by establishing a potent and durable immune memory. The combination of PB101 and PD-LI needs to be further validated in clinical trials. Citation Format: Hannah Yang, Seung Joon Lee, Hyun-Gul Yang, Won Suk Lee, Jaekyung Cheon, Beodeul Kang, Sung-Eun Kim, Hyeseong Lim, Hong Jae Chon, Chan Kim. PB101 simultaneously targets tumor angiogenesis and immunity and enhances the efficacy of PD-L1 immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5548.