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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

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

ABSTRACT

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

PAGES

16

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s40425-018-0464-1

DOI

http://dx.doi.org/10.1186/s40425-018-0464-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1111576887

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30665463


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