Abstract B009: Enhancing Antitumor Immune Responses: Trastuzumab Deruxtecan (T- DXd) Induces Immunogenic Cell Death and Phagocytosis, Synergizing with CD47/SIRPα Checkpoint Blockade
Tsao, L-C; Wang, JS; Ma, X; Sodhi, S; Lyerly, HK; Hartman, ZC
Published in: Cancer Immunology Research
Trastuzumab deruxtecan (T-DXd), or fam-trastuzumab-deruxtecan-nxki, is a novel antibody-drug conjugate (ADC) targeting HER2 that has demonstrated profound clinical efficacy across HER2-positive breast cancers (BC) and other cancers. However, the precise mechanisms underlying its superiority over traditional ADCs, such as trastuzumab emtansine (T-DM1), remain poorly understood. In this study, we investigated the immune activation mechanisms mediated by T-DXd cytotoxicity in HER2-positive BC. We found that the T-DXd payload, Deruxtecan (DXd), induces a stronger tumor immunogenic cell death (ICD) phenotype compared to T-DM1. This is evidenced by the elevated release of multiple Damage-Associated Molecular Patterns (DAMPs) and the activation of nearby myeloid immune cells through TLR4 and STING pathways. Additionally, T-DXd’s antibody backbone engages with Fcγ-receptors to stimulate Antibody-Dependent Cellular Phagocytosis (ADCP), similar to trastuzumab. Coupled with DXd-induced ICD, T-DXd enhances tumor antigen uptake by macrophages and stimulates antigen-specific CD8+ T cells better than T-DM1. Importantly, DXd cytotoxicity also upregulates tumor CD47 expression, which engages with SIRPα to suppress ADCP. To assess the importance of this regulatory axis in T- DXd efficacy, we explored the use of CD47/SIRPα checkpoint blockade antibodies in combination with T-DXd. Our in vivo studies revealed that this combination synergistically enhanced anti-tumor efficacy in a HER2-transgenic BC mouse model, while inducing CD8+ T cell immune memory and preventing tumor recurrence after therapy cessation. In sum, these studies highlight the important role of T-DXd in stimulating innate and adaptive immune responses against HER2-positive BC and demonstrate the enhancement of this anti-tumor mechanism through combination with CD47/SIRPα checkpoint blockade.Citation Format: Li-Chung Tsao, John S. Wang, Xingru Ma, Sirajbir Sodhi, Herbert Kim Lyerly, Zachary C. Hartman. Enhancing Antitumor Immune Responses: Trastuzumab Deruxtecan (T- DXd) Induces Immunogenic Cell Death and Phagocytosis, Synergizing with CD47/SIRPα Checkpoint Blockade [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B009.
