A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer

• DOI: 10.1186/s40425-018-0464-1
• Publication Date: 2019-01-21T14:02:51Z
• Authors: Lucia D’Amico; Ulrike Menzel; Michael Prummer; Philipp Müller; Mélanie Buchi; Abhishek Kashyap; Ulrike Haessler; Alexander Yermanos; Rémy Gébleux; Manfred Briendl; Tamara Hell; Fabian I. Wolter; Roger R. Beerli; Iva Truxova; Špíšek Radek; Tatjana Vlajnic; Ulf Grawunder; Sai Reddy; Alfred Zippelius
• Keywords: Immunogenic cell death; Immune checkpoint

Increasing evidence suggests that antibody-drug conjugates (ADCs) can enhance anti-tumor immunity and improve clinical outcome. Here, we elucidate the therapeutic efficacy immune-mediated mechanisms of a novel HER2-targeting ADC bearing potent anthracycline derivate as payload (T-PNU) in human HER2-expressing syngeneic breast cancer model resistant to trastuzumab ado-trastuzumab emtansine. Mechanistically, component induced immunogenic cell death leading exposure secretion danger-associated molecular signals. RNA sequencing derived immunogenomic signatures TCRβ clonotype analysis tumor-infiltrating lymphocytes revealed prominent role adaptive immune system regulation T-PNU mediated anti-cancer activity. Depletion CD8 T cells severely reduced efficacy, thus confirming cytotoxic drivers response. Furthermore, therapy promoted immunological memory formation tumor-bearing animals protecting those from tumor rechallenge. Finally, combination checkpoint inhibition, such α-PD1, significantly enhanced eradication following treatment. In summary, PNU-armed, elicited long-lasting protection murine orthotopic other HER2-directed therapies. Our findings delineate potential this support its development for patients potentially HER2 expressing malignancies.