Neoadjuvant And Adjuvant Anti-Pd-1 Based Combination Immunotherapy With A Novel Axl Inhibitor, Ski-G-801 In Syngeneic Tumor Model: A Combined Analysis Of Immune Profiling

Introduction: Neoadjuvant therapy suggests the systemic treatment of cancer prior to surgical therapy. The main purpose of neoadjuvant therapy is to improve surgical outcomes in patients for whom a primary surgical approach is difficult to practice. Recently, Anti-PD-1 has been applied to neoadjuvant and adjuvant therapy, but the anti-cancer responses are not sufficient to prevent tumor recurrence. According to our previous study, a novel AXL inhibitor, SKI-G-801 strongly inhibits metastasis of syngeneic tumor with immune responses. The primary goal of this study is to overcome limitation of anti-PD-1 based neoadjuvant and adjuvant therapy with SKI-G-801. Methods: 4T1 cancer bearing mouse models were established for neoadjuvant or adjuvant treatment. Mice were treated with single anti-PD-1 (BIW), SKI-G-801 (QD) or a combination for 6 days, followed by the surgical dissection of tumor tissue in a subcutaneous xenograft model. In five mice per group, their survival rates were monitored for 50 days. We used flow cytometry and immunohistochemistry for comprehensive immune profiling and tumor-infiltrating lymphocytes (TILs) from three mice per group surgically removed tumor tissues. Three tumors per group were stained, and CD3-positive cells per unit area (mm2) were analyzed using Vectra Polaris. Results: According to results, the median survival of control group (only surgical operation without treatment) was 16 days (N=5), whereas, the longest survival group was neoadjuvant-combination (median survival = 37 days). Two out of five mice were survived until end of experiment (D-50). Most of the groups had similar outcomes excluding neoadjuvant-combination group. The median survival of adjuvant-anti-PD-1 group was 30 days, and adjuvant-SKI-G-801 and neoadjuvant-anti-PD-1 group were 25 days. The Neoadjuvant-SKI-G-801 was recorded 23.5 days. Statistically, survival rate of neoadjuvant-combination therapy was significantly higher than of neoadjuvant-anti-PD-1 and neoadjuvant-SKI-G-801 (log-rank test, p Conclusion: This study confirmed that a potential combination with aPD-1 and SKI-G-801 applies to neoadjuvant therapy, as evidenced by increased T cell infiltration and function. Our findings provide a rationale for further clinical investigations. Keywords: Axl inhibitor, Neoadjuvant therapy, Adjuvant therapy, Immunotherapy, Anti-PD-1 Citation Format: Ha Ni Jo, Wongeun Lee, Chun-Bong Synn, Hee Kyu Lee, Jae-Hwan Kim, Yeongseon Byeon, Sung Eun Kim, Ji Min Lee, Do Hee Kim, Jung-Ho Kim, Beung-Chul Ahn, Min Hee Hong, Hye Ryun Kim, Kyoung-Ho Pyo, Byoung Chul Cho. Neoadjuvant and adjuvant anti-PD-1 based combination immunotherapy with a novel AXL inhibitor, SKI-G-801 in syngeneic tumor model: A combined analysis of immune profiling [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5189.