Abstract 4692: Multimodal cancer therapy consisting of antibody-drug conjugates and radiotherapy in cancer treatment

Abstract Targeting tumor associated antigens (TAA) with highly potent cytotoxic payloads by Antibody Drug Conjugates (ADC) technology is revolutionizing cancer treatment. Whether ADC could replace current chemotherapy as the standard partner of radiotherapy (RT) remain elusive. We sought to systematically decipher the impact of different payload classes and ADC combinations on tumor response to RT. A broad matrix of frequently targeted TAAs including EGFR, HER2, HER3, TROP2, Nectin4 and CEACAM in prototypic cancer cell lines representing different entities, including squamous cell carcinoma (A431), breast cancer (AU565, BT474, MDA-MB-361 and 231, MCF-7), lung cancer (NCI-H1975, A549), gastric cancer (NCI-N87) and pancreatic cancer (BxPC3) were evaluated. Moreover, representative payloads classes, i.e., tubulin inhibitors (MMAE and DM1/4), topoisomerase I inhibitors (DXd and SN-38), and the alkylating agent duocarmycin were examined. Accordingly, combination of RT with ADCs targeting HER2: trastuzumab emtansine/deruxtecan/duocarmazine (T-DM1/T-DXd/T-Duo) and disitamab vedotin, TROP2: datopotamab deruxtecan and sacituzumab govitecan, EGFR: depatuxizumab MMAE, HER3: patritumab deruxtecan, Nectin4: enfortumab vedotin and CEACAM5: tusamitamab ravtansine were evaluated. A broad heterogeneity in sensitivity to payload classes was found e.g., for topoisomerase inhibitor Deruxtecan a low nM (3, 3 nM) IC50 was observed in sensitive A431. In contrast, 1 µM Deruxtecan led to only 20% loss of viability in resistant BT474 cells. In line, BT474 showed resistance to HER2 targeting ADC with topoisomerase inhibitor payload (T-DXd) but was sensitive to the same antibody conjugated with tubulin inhibitor payloads (T-DM1). These data indicate that not only TAA presence and density but also intrinsic payload sensitivity maybe relevant for assessment of ADC efficacy. Consequently, in tumors sensitive to both tubulin and topoisomerase inhibitors like AU565 breast cancer cell line similar ∼ 65% cytotoxicity was found at 1 nM to both T-DM1 and T-DXd, regardless of the payload substance class. The relevance of TAA targeting, payload and drug antibody ratio (DAR) was further demonstrated by comparing different ADCs vs. antibody vs. payload alone. Enhanced radiosensitivity was exploited for different ADC and substance classes e.g., MMAE and SN-38 IC50 concentrations led to >2-Fold reduction of the survival fraction (SF) of A431 cells when combined with 2Gy RT. Together, this study demonstrates that inherent sensitivity of tumor cells to different payload classes, DAR and TAA dynamic are of relevance for the efficacy of ADC. Informed selection of ADC exhibited synergistic effects with RT providing a novel multimodal and promising strategy for efficient cancer eradication. Citation Format: Allegra Gerharz, Julian Schlegel, Christiane Rutenberg, Claudia Rittmüller, Mahmoud Moustafa, Ivana Dokic, Jürgen Debus, Amir Abdollahi. Multimodal cancer therapy consisting of antibody-drug conjugates and radiotherapy in cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4692.