Abstract 6732: Immunomodulatory and anti-tumor effect of a CCR2-targeted STING agonist iADC in human lung cancer

Abstract Introduction: Antibody drug conjugates (ADCs) targeting cancer-cell antigens can improve therapeutic index and show prominent clinical impact. Limited studies have used ADCs to target antigens present in non-malignant cells in the tumor microenvironment or to deliver immunomodulatory agents. We developed an immune-cell directed antibody drug conjugate (iADC) TAK-500 that selectively activates STING in C-C chemokine receptor type 2 (CCR2) expressing cells to achieve enhanced efficacy over non-targeted STING agonists. Here, we spatially mapped CCR2 protein in human NSCLC and studied the immunomodulatory role and anti-tumor effect of the novel iADC TAK-500 on human lung cancer tumor explants ex vivo. Methods: Using multiplexed quantitative immunofluorescence (mQIF) panels we measured the levels of CCR2 protein, myeloid cell populations and tumor infiltrating lymphocyte (TIL) subsets in 411 primary NSCLC carcinomas from treatment-naïve patients in 2 independent cohorts and determined their clinical significance. In addition, we longitudinally studied CCR2 levels, myeloid cells (DAPI/CCR2/CD68/CD11b), TILs (DAPI/CK/CD4/CD8/CD20), T-cell functional markers (DAPI/CK/CD3/Ki-67/GZMB [Granzyme B]) and cancer-cell death/proliferation markers (DAPI/CK/TFR1/Ki-67/CC3 [Cleaved Caspase 3]) in 314 primary cultured tissue fragments from paired tumor and non-tumor specimens resected from 11 lung cancer patients at Yale New Haven Hospital between 2021-2023 (8 adenocarcinomas, 2 small cell carcinomas, and 1 squamous cell carcinoma). Each biopsy was divided into 4-mm2 fragments, cultured in extracellular matrix for 5 days with or without TAK-500 treatment. Samples were processed into FFPE tissue and stained with mQIF panels using a tissue microarray format. Results: CCR2 protein was detected in 386 of 411 (94%) NSCLCs from 2 independent cohorts predominantly localized in CD11b+ intratumor myeloid cells and CD68+ tumor-associated macrophages (TAMs). Elevated CCR2 was associated with adenocarcinoma histology, increased PD-L1, activating KRAS mutations and longer survival. Treatment with TAK-500 for 5 days reduced CCR2 levels in myeloid cells and CD68+ TAMs, without significant changes in TIL or T-cell GZMB/Ki-67 levels. TAK-500 also significantly reduced tumor proliferation (Ki-67 expression) and increased tumor cell apoptosis (CC3 levels) after 5 days of treatment. Notably, these TAK-500-induced changes were observed only in tumor specimens with high baseline CCR2 levels above the median in retrospective NSCLC cohorts. No significant effect was observed in the paired non-tumor fragments. Conclusion: Our results reveal prominent myeloid CCR2 expression in a subset of human NSCLCs with distinct clinicopathologic/molecular characteristics. Using a novel lung cancer explant ex vivo system, we demonstrate a CCR2-dependent immunomodulatory and anti-tumor effect of TAK-500 iADC. Citation Format: Angelo Porciuncula, Vicky A. Appleman, Alex Parent, Jeff Raizer, Richard C. Gregory, Neil Lineberry, Adnan O. Abu-Yousif, Kurt A. Schalper. Immunomodulatory and anti-tumor effect of a CCR2-targeted STING agonist iADC in human lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6732.