First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors

Lillian L Siu, Ding Wang, John Hilton, Ravit Geva, Drew Rasco, Ruth Perets, Anson K Abraham, Douglas C Wilson, Julia F Markensohn, Jared Lunceford, Leah Suttner, Shabana Siddiqi, Rachel A Altura, Corinne Maurice-Dror, Lillian L Siu, Ding Wang, John Hilton, Ravit Geva, Drew Rasco, Ruth Perets, Anson K Abraham, Douglas C Wilson, Julia F Markensohn, Jared Lunceford, Leah Suttner, Shabana Siddiqi, Rachel A Altura, Corinne Maurice-Dror

Abstract

Purpose: In this first-in-human study (NCT03564691) in advanced solid tumors, we investigated a novel first-in-class human IgG4 monoclonal antibody targeting the immunoglobulin-like transcript 4 (ILT4) receptor, MK-4830, as monotherapy and in combination with pembrolizumab.

Patients and methods: Patients with histologically/cytologically confirmed advanced solid tumors, measurable disease by RECIST v1.1, and evaluable baseline tumor sample received escalating doses of intravenous MK-4830 every 3 weeks as monotherapy (parts A and B) and in combination with pembrolizumab (part C). Safety and tolerability were the primary objectives. Pharmacokinetics, objective response rate per RECIST v1.1, and molecular biomarkers were also evaluated.

Results: Of 84 patients, 50 received monotherapy and 34 received combination therapy. No dose-limiting toxicities were observed; maximum tolerated dose was not reached. MK-4830 showed dose-related target engagement. Eleven of 34 patients in the dose-escalation phase who received combination therapy achieved objective responses; 5 previously had progressive disease on anti-PD-1/PD-L1 therapies. Exploratory evaluation of the association between response and pretreatment gene expression related to interferon-gamma signaling in tumors suggested higher sensitivity to T-cell inflammation with combination therapy than historically expected with pembrolizumab monotherapy, with greater response at more moderate levels of inflammation.

Conclusions: This first-in-class MK-4830 antibody dosed as monotherapy and in combination with pembrolizumab was well tolerated with no unexpected toxicities, and demonstrated dose-related evidence of target engagement and antitumor activity. Inflammation intrinsic to the ILT4 mechanism may be facilitated by alleviating the myeloid-suppressive components of the tumor microenvironment, supporting the target of ILT4 as a potential novel immunotherapy in combination with an anti-PD-1/PD-L1 agent.

©2021 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.
Figure 1.
Proposed mechanism of action of MK-4830. ILT4, immunoglobulin-like transcript 4; PD-1, programmed death 1.
Figure 2.
Figure 2.
Target lesion change over time (RECIST v1.1) in patients who received (A) MK-4830 monotherapy or (B) MK-4830 in combination with pembrolizumab. Best percentage change from baseline in target lesion based on investigator assessment (RECIST v1.1) in patients who received (C) MK-4830 monotherapy or (D) MK-4830 in combination with pembrolizumab. RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.
Figure 3.
Figure 3.
Association between response and (A) PD-L1 status, (B) TMB status, and (C) TcellinfGEP score. AUROC, area under the receiver operating characteristic; CI, confidence interval; CPS, combined positive score; CR, complete response; NR, nonresponder; PD, progressive disease; PD-L1, programmed death ligand 1; PR, partial response; R, responder; SD, stable disease; TcellinfGEP, T-cell–inflamed gene expression profile; TMB, tumor mutational burden.
Figure 4.
Figure 4.
Correlation between myeloid-specific biomarkers and (A) PD-L1 status, (B) TMB status, (C) TcellinfGEP score, and (D) other myeloid-specific biomarkers. CPS, combined positive score; CR, complete response; HLA-G, human leukocyte antigen G; LILRB2, leukocyte immunoglobulin-like receptor B2; mMDSC, monocytic myeloid-derived suppressor cell; NR, nonresponder; PD, progressive disease; PD-L1, programmed death ligand 1; PR, partial response; R, responder; SD, stable disease; TcellinfGEP, T-cell–inflamed gene expression profile; TMB, tumor mutational burden.
Figure 5.
Figure 5.
Association between response and TcellinfGEP-adjusted (A) LILRB2, (B) mMDSC, and (C) HLA-G. AUROC, area under the receiver operating characteristic; CI, confidence interval; CR, complete response; HLA-G, human leukocyte antigen G; LILRB2, leukocyte immunoglobulin-like receptor B2; mMDSC, monocytic myeloid-derived suppressor cell; NR, nonresponder; PD, progressive disease; PR, partial response; R, responder; SD, stable disease; TcellinfGEP, T-cell–inflamed gene expression profile.

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