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

被引:78
|
作者
D'Amico, Lucia [1 ]
Menzel, Ulrike [2 ]
Prummer, Michael [3 ,4 ]
Muller, Philipp [1 ,8 ]
Buchi, Melanie [1 ]
Kashyap, Abhishek [1 ]
Haessler, Ulrike [2 ]
Yermanos, Alexander [2 ]
Gebleux, Remy [5 ]
Briendl, Manfred [5 ]
Hell, Tamara [5 ]
Wolter, Fabian I. [5 ,9 ]
Beerli, Roger R. [5 ]
Truxova, Iva [6 ]
Radek, Spisek [6 ]
Vlajnic, Tatjana [7 ]
Grawunder, Ulf [5 ]
Reddy, Sai [2 ]
Zippelius, Alfred [1 ]
机构
[1] Univ Basel, Dept Biomed, Canc Immunol, Basel, Switzerland
[2] Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Basel, Switzerland
[3] Swiss Fed Inst Technol, NEXUS Personalized Hlth Technol, Zurich, Switzerland
[4] Swiss Inst Bioinformat, Zurich, Switzerland
[5] NBE Therapeut Ltd, Hochbergerstr 60C, CH-4057 Basel, Switzerland
[6] Sotio Sa, Jankovcova 1518-2, Prague 17000 7, Czech Republic
[7] Univ Basel Hosp, Inst Pathol, Basel, Switzerland
[8] Boehringer Ingelheim Pharma GmbH & Co KG, Dept Canc Immunol & Immune Modulat, Birkendorfer Str 65, D-88400 Biberach, Germany
[9] Celonic AG, Eulerstr 55, CH-4051 Basel, Switzerland
关键词
Antibody-drug conjugates; HER2-positive breast cancer; Anthracycline; Checkpoint inhibitor combination therapy; IMMUNOGENIC CELL-DEATH; TRASTUZUMAB EMTANSINE; RESISTANCE; CHEMOTHERAPY; THERAPY;
D O I
10.1186/s40425-018-0464-1
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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 TCR beta 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 alpha-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.
引用
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页数:15
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