Abstract 5189: 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
Authors: Jo Ha Ni , Lee Wongeun , Synn Chun-Bong , Lee Hee Kyu , Kim Jae-Hwan , Byeon Yeongseon , Kim Sung Eun , Lee Ji Min , Kim Do Hee , Kim Jung-Ho , Ahn Beung-Chul , Hong Min Hee , Kim Hye Ryun , Pyo Kyoung-Ho , Cho Byoung Chul 
Published: September 2020

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 &lt;0.01).The reason for neoadjuvant therapy is to improve immune responses before surgical operation. We investigated the effects of SKI-G-801 or anti-PD-1 alone and combination therapy on neoadjuvant treatment in the tumor microenvironment. IHC and flow cytometry were performed to elucidate tumor infiltrating immune cell populations with the tumor obtained by surgery. In IHC result, CD3+ cells population was significantly increased in SKI-G-801 alone and combination of neoadjuvant therapy compared to control group (p&lt;0.05, p &lt; 0.001, respectively), however, anti-PD-1 group was not significant. IFN-γ+ Tc cells, CD3+CD44+ memory Tc, and PD-1+Tc cells were significantly infiltrated into the tumor in the combination of neoadjuvant therapy (p &lt; 0.01).

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.