Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody

Renee N Donahue,Italia Grenga,Ravi A Madan,Massimo Fantini,Jeffrey Schlom,James L Gulley,Caroline Jochems,Christopher R Heery,Lauren M Lepone

doi:10.1186/s40425-017-0220-y

Renee N Donahue, Italia Grenga + Show 7 more

Open Access

https://doi.org/10.1186/s40425-017-0220-y

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Abstract

BackgroundMultiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. All except one have been designed or engineered to omit the possibility to mediate antibody-dependent cell-mediated cytotoxicity (ADCC) as a second potential mode of anti-tumor activity; the reason for this is the concern of lysis of PD-L1 positive immune cells. Avelumab is a fully human IgG1 MAb which has been shown in prior in vitro studies to mediate ADCC versus a range of human tumor cells, and clinical studies have demonstrated anti-tumor activity versus a range of human cancers. This study was designed to investigate the effect on immune cell subsets in the peripheral blood of cancer patients prior to and following multiple administrations of avelumab.MethodsOne hundred twenty-three distinct immune cell subsets in the peripheral blood of cancer patients (n = 28) in a phase I trial were analyzed by flow cytometry prior to and following one, three, and nine cycles of avelumab. Changes in soluble (s) CD27 and sCD40L in plasma were also evaluated. In vitro studies were also performed to determine if avelumab would mediate ADCC of PBMC.ResultsNo statistically significant changes in any of the 123 immune cell subsets analyzed were observed at any dose level, or number of doses, of avelumab. Increases in the ratio of sCD27:sCD40L were observed, suggesting potential immune activation. Controlled in vitro studies also showed lysis of tumor cells by avelumab versus no lysis of PBMC from five donors.ConclusionsThese studies demonstrate the lack of any significant effect on multiple immune cell subsets, even those expressing PD-L1, following multiple cycles of avelumab. These results complement prior studies showing anti-tumor effects of avelumab and comparable levels of adverse events with avelumab versus other anti-PD-1/PD-L1 MAbs. These studies provide the rationale to further exploit the potential ADCC mechanism of action of avelumab as well as other human IgG1 checkpoint inhibitors.Trial registrationClinicalTrials.gov identifier: NCT01772004 (first received: 1/14/13; start date: January 2013) and NCT00001846 (first received date: 11/3/99; start date: August 1999).

Highlights

Multiple anti-Programmed cell death protein-1 ligand (PD-L1)/Programmed cell death protein 1 (PD-1) checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit
We have previously shown that avelumab can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro using as targets a range of human tumor cell lines that express PD-L1, and that this lysis can be blocked using an anti-CD16 antibody to inhibit the interaction of CD16 on natural killer (NK) cells with the IgG1 Fc receptor on avelumab [3,4,5]
Experiments were undertaken to ensure that the PD-L1 clone used to detect surface PD-L1 in the various immune cell subsets was not blocked by the potential binding of avelumab to the immune cells

Summary

Introduction

Multiple anti-PD-L1/PD-1 checkpoint monoclonal antibodies (MAb) have shown clear evidence of clinical benefit. One caution in the use of this approach is that several human immune cell populations express PD-L1, and could potentially be susceptible to ADCC-mediated lysis It is for this reason that, with one exception, all of the anti-PD-L1 MAbs in clinical studies to date were constructed as either an IgG4 isotype that cannot mediate ADCC, or an IgG1 MAb engineered to be devoid of ADCC activity; the one exception is the development of the human IgG1 anti-PD-L1 MAb avelumab (MSB0010718C). We have previously shown that avelumab can mediate ADCC in vitro using as targets a range of human tumor cell lines that express PD-L1, and that this lysis can be blocked using an anti-CD16 antibody to inhibit the interaction of CD16 on NK cells with the IgG1 Fc receptor on avelumab [3,4,5]. At the time of writing, multiple Phase III trials of avelumab are ongoing in patients with a range of tumor types and stages

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