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.
Highlights
Epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in about 20% of all breast cancer patients [1, 2]
While EMT6-human HER2 (hHER2) cells showed sensitivity towards T-PNU treatment, they were unresponsive to T-DM1
Despite the very promising therapeutic efficacy of antibody-drug conjugates (ADCs) armed with microtubule-destabilizing warheads, resistance, either intrinsic or acquired, remains a clinical challenge in the management of patients
Summary
Epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in about 20% of all breast cancer patients [1, 2]. D’Amico et al Journal for ImmunoTherapy of Cancer (2019) 7:16 develop various and complex resistance mechanisms [7]. This urges expansion of the therapeutic arsenal by development of drugs that are more potent and/or target novel pathways. In the ADC field, efforts are currently under way to develop site-specific conjugation technologies, novel compounds with increased cytotoxicity, and combination therapies with checkpoint inhibitors [8,9,10]. We tested a recently developed, novel HER2-targeting ADC composed of trastuzumab conjugated to a derivate of the highly potent anthracycline PNU-159682 through a non-cleavable peptide linker by sortase-mediated antibody conjugation (SMAC) technology [11, 12], hereafter called T-PNU. The SMAC technology allows for homogenous and stable ADC preparations with defined and favorable drug-to-antibody ratios and high in vitro and in vivo potency [11, 12]
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