Lung cancer is one of the leading causes of cancer-related deaths in the United States. A major hurdle for improved therapies is immune suppression mediated by the tumor and its microenvironment. The lung tumor microenvironment (TME) contains large numbers of tumor-associated macrophages (TAMs), which suppress the adaptive immune response, increase neo-vascularization of the tumor, and provide pro-tumor factors to promote tumor growth. CD11b is highly expressed on myeloid cells, including TAMs, where it forms a heterodimeric integrin receptor with CD18 (known as CD11b/CD18, Mac-1, CR3, and αMβ2), and plays an important role in recruitment and biological functions of these cells, and is a validated therapeutic target. Here, we describe our pre-clinical studies targeting CD11b in the context of lung cancer, using pharmacologic and genetic approaches that work via positive allosteric modulation of CD11b function. GB1275 is a novel small molecule modulator of CD11b that is currently in Phase 1/2 clinical development. We assess GB1275 treatment effects on tumor growth and immune infiltrates in the murine Lewis Lung Carcinoma (LLC) syngeneic tumor model. Additionally, as an orthogonal approach to determine mechanisms of action, we utilize our recently developed novel CD11b knock-in (KI) mouse that constitutively expresses CD11b containing an activating isoleucine to glycine substitution at residue 332 in the ligand binding CD11b A-domain (I332G) that acts as a positive allosteric modulator of CD11b activity. We report that pharmacologic modulation of CD11b with GB1275 significantly reduces LLC tumor growth. CD11b KI mice similarly show significant reduction in both the size and rate of LLC tumor growth, as compared to WT mice, mimicking our observed treatment effects with GB1275. Tumor profiling revealed a significant reduction in TAM infiltration in GB1275-treated and in CD11b KI mice, increase in the ratio of M1/M2-like TAMs, and concomitant increase in cytotoxic T cells. The profiling also showed a significant decrease in CCL2 levels and a concomitant reduction in Ly6C hi monocytes in circulation in both groups. These findings suggest that positive allosteric modulation of CD11b reduces TAM density and reprograms them to enhance the adaptive immune response and is a novel therapeutic strategy against lung cancer.

Background: Detection rates of early-stage lung cancer are traditionally low, which contributes to inconsistent treatment responses and high rates of annual cancer deaths. Currently, low-dose computed tomography (LDCT) screening produces a high false discovery rate. This limitation has prompted research to identify biomarkers to more clearly define eligible patients for LDCT screening, differentiate indeterminate pulmonary nodules, and select individualized cancer therapy. Biomarkers within the Insulin-like Growth Factor (IGF) family have come to the forefront of this research. Main Body: Multiple biomarkers within the IGF family have been investigated, most notably IGF-I and IGF binding protein 3. However, newer studies seek to expand this search to other molecules within the IGF axis. Certain studies have demonstrated these biomarkers are useful when used in combination with lung cancer screening, but other findings were not as conclusive, possibly owing to measurement bias and non-standardized assay techniques. Research also has suggested IGF biomarkers may be beneficial in the prognostication and subsequent treatment via systemic therapy. Despite these advances, additional knowledge of complex regulatory mechanisms inherent to this system are necessary to more fully harness the potential clinical utility for diagnostic and therapeutic purposes. Conclusions: The IGF system likely plays a role in multiple phases of lung cancer; however, there is a surplus of conflicting data, especially prior to development of the disease and during early stages of detection. IGF biomarkers may be valuable in the screening, prognosis, and treatment of lung cancer, though their exact application requires further study.

Background: Detection rates of early-stage lung cancer are traditionally low, which contributes to inconsistent treatment responses and the highest rates of annual cancer deaths in the U.S. Currently, age and smoking history are the primary factors that qualify patients for low-dose computed tomography (LDCT) screening, which contributes heavily to a high false discovery rate. This limitation to the current screening paradigm has prompted research to identify biomarkers that will help more clearly define eligible patients for LDCT screening, differentiate indeterminate pulmonary nodules, and select individualized cancer therapy. Biomarkers within the Insulin-like Growth Factor (IGF) family have come to the forefront of this research. Methods: Literature available through PubMed and Google Scholar sources was cataloged using keywords: {Lung Cancer} AND {IGF} AND {Risk OR Diagnosis OR Prognosis OR Prognostication OR Treatment}. The results were summarized and provided herein.Results: Multiple biomarkers within the IGF family (or axis) have been investigated, most notably IGF-I and IGF binding protein 3 (IGFBP-3). However, newer studies seek to expand this search to other molecules within the IGF axis. Results have differed, however, due to features such as the pre-disease variable expression of IGF-I and IGFBP-3, likely promoted by factors such as obesity and smoking history. Certain studies have demonstrated these biomarkers are useful as a companion test alongside lung cancer screening, but other findings were not as conclusive, possibly owing to measurement bias from pre-analytical variables and non-standardized assay techniques. Research also has suggested IGF biomarkers may be beneficial in the prognostication and subsequent application of treatment via systemic therapy. Despite these advances, however, additional knowledge as to the intricacies of regulatory mechanisms inherent to this system are necessary to more fully harness the potential clinical utility for diagnostic tests and to identify novel targets for therapeutic intervention. Conclusions: The IGF system likely plays a role in multiple phases of lung cancer; however, there is a surplus of conflicting data, especially prior to development of the disease and during early stages of detection. IGF biomarkers may be valuable in the screening, prognosis, and treatment of lung cancer, though their exact application requires further study.