Abstract 2944: Trastuzumab-deruxtecan (T-Dxd) induces superior macrophage/DC activation, antigen-presentation and anti-tumor adaptive immune responses, which can be augmented by CD47/SIRPA blockade
Authors: Tsao Li-Chung , Hartman Zachary Conrad 
Published: April 2023

Abstract
Background: T-DXd is a new antibody-drug conjugate targeting HER2 that has demonstrated superior clinical efficacy over previous HER2-targeting agent Trastuzumab emtansine (T-DM1) in patients with advanced-stage HER2+ breast cancer (BC). T-Dxd consists of the anti-HER2 antibody Trastuzumab conjugated to Dxd (a topoisomerase-I inhibitor). While the HER2-mediated internalization of Dxd leads to direct and bystander tumor cell killing, it is unclear whether T-Dxd retains Fc-mediated induction of immunity and how these responses may interact with Dxd-mediated tumor cell killing. Therefore, in this study we investigated tumor-specific innate and adaptive immune responses elicited upon T-Dxd treatment versus other HER2-targeting agents.
Method: We first compared immune responses of T-Dxd versus T-DM1 or Trastuzumab on macrophage activation after co-culture with HER2+ BC cells. We next utilized JEDI T cells to model tumor-antigen presentation by those macrophages. We also investigated the therapeutic effect of T-Dxd in an endogenous HER2 transgenic mouse model, and measured HER2-specific adaptive immune responses, in combination with immune checkpoint blockades.
Results: We found that T-Dxd retains the capability to engage with FCGRs and promote ADCP of HER2+ BC cells by macrophages, with comparable efficacy to Trastuzumab. Interestingly, T-Dxd mediated ADCP combined with Dxd-mediated immunogenic cell death promoted superior macrophage activation over Trastuzumab and T-DM1, resulting in increased expression of antigen presentation genes, chemokines, and interferon-stimulated genes. In co-culture experiments with JEDI T cells, macrophages that have phagocytosed eGFP-expressing tumor cells after T-Dxd treatment showed superior activation of antigen-specific effector T cells. In vivo, T-Dxd demonstrated exceptional tumor growth inhibition over Trastuzumab, accompanied by increased HER2-specific adaptive T cell responses. Lastly, T-Dxd therapy showed synergistic antitumor activity when combined with immune checkpoint blockade of the CD47/SIRPA axis.
Conclusion: T-Dxd retains antibody-mediated antitumor mechanisms of Trastuzumab such as FCGR activation and ADCP of HER2+ tumor cells. Importantly, this is synergized with T-Dxd induced immunogenic tumor cell death, which results in enhanced macrophage activation upon tumor cell phagocytosis. This result in enhanced tumor antigen presentation and activation of adaptive immunity in vitro and in preclinical mouse models, which may illustrate T-Dxd’s superior and long-lasting clinical efficacy in HER2+ BC patients. Combination therapy of T-Dxd with CD47/SIRPA checkpoint blockade resulted in synergistic therapeutic benefits in our mouse model studies, and further clinical research with this combination is warranted.
Citation Format: Li-Chung Tsao, Zachary Conrad Hartman. Trastuzumab-deruxtecan (T-Dxd) induces superior macrophage/DC activation, antigen-presentation and anti-tumor adaptive immune responses, which can be augmented by CD47/SIRPA blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2944.