Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab

Abstract

Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC.

A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint

“…27 , 33 Moreover, NK cell-mediated ADCC by avelumab was shown to enhance its therapeutic functionality. 33 , 34 Similarly, the human IgG1 domain present in PD-L1xEGFR may enhance its therapeutic activity as it promotes NK cell-mediated ADCC towards EGFR-expressing cancer cells.…”

PD-L1 Expression in Premalignant and Malignant Trophoblasts From Gestational Trophoblastic Diseases Is Ubiquitous and Independent of Clinical Outcomes

“…Indeed, recent studies reported ADCC with the fully human IgG1 antiYPD-L1 monoclonal antibody avelumab in solid tumors. 24,25 The ubiquitous expression of PD-L1 in GTD trophoblasts, along with the close contact to immune infiltrates containing granzyme B + NK cells, potentially prone to ADCC, would warrant investigation of avelumab, or similar drugs, in GTN patients. As a consequence, a phase 2 trial testing the efficacy of antiYPD-L1 in chemoresistant GTD has been activated.…”

Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial

“…In contrast to other PD-L1/PD-1 drugs assessed in clinical trials to date, avelumab binding to the surface of tumour cells via PD-L1 has the potential to induce natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC) of tumour cells, as shown by preclinical models, which may contribute to the clinical activity of avelumab. 19,20 A large, multicohort, phase 1 dose-escalation and dose-expansion trial is being conducted to assess the safety and activity of avelumab in patients with a range of advanced solid tumours. In the phase 1a dose-escalation part of the study, avelumab showed preliminary evidence of antitumour activity, including durable responses and stable disease.…”