Abstract PR4: Modulation of integrin CD11b as a novel therapeutic strategy against lung cancer

Abstract

Lung cancer is the leading cause of cancer-related deaths in the United States. With a 5-year survival rate at 19%, lung cancer patients are urgently in need of new therapeutic options. A major problem facing cancer therapy is the immune suppression by the tumor and its subsequent escape from the immune response, which is mediated by the tumor microenvironment. Tumors have large numbers of myeloid-derived suppressor cells (MDSCs), which suppress the adaptive immune response, increase neovascularization of the tumor, and promote tumor survival. Integrin heterodimer CD11b/CD18 (aka Mac-1 or αMβ2) is highly expressed on MDSCs and plays an important role in innate cell recruitment and other biologic functions. GB1275 (previously known as ADH503) is a novel small-molecule CD11b allosteric modulator. In experimental models of pancreatic cancer, GB1275 reduces MDSC infiltration and M2 macrophage polarization leading to tumor growth inhibition. GB1275 is currently in phase 1/2 clinical development in patients with pancreatic, esophageal, gastric/GEJ, triple-negative breast, castration-resistant prostate, or microsatellite stable colorectal cancer. To investigate the impact of CD11b modulation in the context of lung cancer, GB1275 treatment effects on tumor growth and immune infiltrates were assessed in the Lewis Lung Carcinoma (LLC) syngeneic tumor model, propagated in C57BL/6 wild-type (WT) mice. Additionally, we developed a transgenic CD11b knockin (KI) mouse that renders CD11b in a partially active state. CD11b KI mice were engineered to express partially active CD11b by introducing a point mutation at position 332 causing an isoleucine to glycine switch (I332G). We studied LLC tumor growth in CD11b KI mice as an orthogonal approach to test the mechanism of action. We will present data showing that pharmacologic modulation of CD11b with GB1275 significantly reduces LLC tumor growth. Concomitantly, we will present our studies with the CD11b KI mice that show a significant reduction in both the size and the rate of LLC tumor growth, as compared to the WT mice, mimicking treatment effects with GB1275. Our comprehensive pharmacologic and genetic studies show that CD11b activation reprograms MDSCs to enhance the adaptive immune response and is a novel strategy against lung cancer. This abstract is also being presented as Poster B71. Citation Format: Terese D. Geraghty, Anugraha Rajagopalan, Rabail Aslam, Vineet Gupta. Modulation of integrin CD11b as a novel therapeutic strategy against lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr PR4.