Background The combination of antibody-drug conjugates (ADCs) and immunotherapeutic agents has gained attention due to impressive activity demonstrated in bladder and triple-negative breast cancer. Trastuzumab deruxtecan (T-DXd) is an ADC composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor approved for HER2+ metastatic breast and gastric cancer. T-DXd has been shown to induce PD-L1 and MHC-I upregulation and demonstrated activity in combination with immune checkpoint inhibitors.1,2 We report the result of mechanistic studies of the immune response profile to T-DXd and immune checkpoint inhibitor combinations, utilizing an MMAE containing ADC as a comparator.
Methods Human PBMCs were treated with DXd, MMAE, T-DXd, and T-MMAE (trastuzumab-vc-MMAE) with and without CD3/CD28, and viability measured. Supernatant for co-culture assays was collected from human cancer cell lines treated in vitro with T-DXd or T-MMAE. In vivo, BALB/c mice bearing human HER2 expressing EMT6 tumors were treated with T-DXd or T-MMAE +/- anti-PD-L1 mAb and evaluated for pharmacodynamic changes and efficacy.
Results In vitro, treatment of human PBMCs with free DXd caused anti-proliferative effects (IC50 = 0.06uM); however, conjugation of DXd to trastuzumab (T-DXd IC50 = 60ug/mL) mitigated the anti-proliferative effects and was comparable to T-MMAE (IC50 = 12ug/mL). Incubation of human macrophages with supernatant collected from T-DXd treated, but not T-MMAE treated cancer cells resulted in greater than 1.5-fold increase in HLA-DR and CD86 expression, without notable increases in CD163 expression. In vivo, both compounds exhibited anti-tumor activity in a human HER2-EMT6 tumor model, with treatment resulting in tumor growth inhibition (TGI) of 25.7% (P = 0.001) for T-DXd, and 11.6% (P = 0.123) for T-MMAE. In combination with anti-PD-L1 treatment, T-DXd (TGI = 55.4%, P <0.001) but not T-MMAE (TGI = 10.8%, P = 0.280) significantly delayed tumor growth compared to anti-PD-L1 monotherapy (TGI = 16.5%, P = 0.063). Flow cytometric analysis of T-DXd-treated tumors revealed a significant increase in total CD45+ cells (1.9-fold, P = 0.028) and CD8+ T cells (2.8-fold, P = 0.018) that was not observed in T-MMAE-treated tumors. T-DXd treatment also promoted a significant increase in tumoral abundance of macrophages (2.2-fold, P = 0.001), Th cells (2.2-fold, P =0.028) and Tregs (2.6-fold, P = 0.018).
Conclusions These data demonstrate that T-DXd treatment enhances the immunogenicity of human cancer cell lines, promotes tumoral immune cell infiltration, and can be effectively combined with immune checkpoint blockade to enhance anti-tumor immune responses.
Iwata TN, Ishii C, Ishida S, Ogitani Y, Wada T, Agatsuma T. A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. Mol Cancer Ther. 2018;17(7):1494–1503. doi: 10.1158/1535-7163.MCT-17-0749. Epub 2018 Apr 27. PMID: 29703841.
Iwata TN, Sugihara K, Wada T, Agatsuma T. [Fam-] trastuzumab deruxtecan (DS-8201a)-induced antitumor immunity is facilitated by the anti-CTLA-4 antibody in a mouse model. PLoS One. 2019;14(10):e0222280. doi: 10.1371/journal.pone.0222280. PMID: 31574081; PMCID: PMC6772042.
Ethics Approval All animal studies were performed in accordance with AstraZeneca IACUC policies.
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