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1115 T-DXd increases immune cell infiltration and enhances activity of immune checkpoint blockade in murine tumor models
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  1. Liam Jenkins1,
  2. Matt Wilson1,
  3. Jerome Mettetal2 and
  4. Theresa Proia2
  1. 1AstraZeneca UK Ltd, Cambridge, UK
  2. 2AstraZeneca Pharmaceuticals LP, Waltham, MA, USA

Abstract

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.

References

  1. 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.

  2. 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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