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M7824, a novel bifunctional anti-PD-L1/TGF? Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine.

ABSTRACT: Tumors evade host immune surveillance through multiple mechanisms, including the generation of a tumor microenvironment that suppresses immune effector function. Secretion of TGF? and upregulation of immune checkpoint programmed cell death ligand-1 (PD-L1) are two main contributors to immune evasion and tumor progression. Here, we examined the efficacy of a first-in-class bifunctional checkpoint inhibitor, the fusion protein M7824, comprising the extracellular domain of human TGF?RII (TGF? Trap) linked to the C-terminus of human anti-PD-L1 heavy chain (?PD-L1). We demonstrate that M7824 reduces plasma TGF?1, binds to PD-L1 in the tumor, and decreases TGF?-induced signaling in the tumor microenvironment in mice. In murine breast and colon carcinoma models, M7824 decreased tumor burden and increased overall survival as compared to targeting TGF? alone. M7824 treatment promoted CD8+ T cell and NK cell activation, and both of these immune populations were required for optimal M7824-mediated tumor control. M7824 was superior to TGF?- or ?PD-L1-targeted therapies when in combination with a therapeutic cancer vaccine. These findings demonstrate the value of using M7824 to simultaneously target TGF? and PD-L1/PD-1 immunosuppressive pathways to promote anti-tumor responses and efficacy. The studies also support the potential clinical use of M7824 as a monotherapy or in combination with other immunotherapies, such as therapeutic cancer vaccines, including for patients who have progressed on ?PD-L1/?PD-1 checkpoint blockade therapies.

SUBMITTER: Knudson KM

PROVIDER: S-EPMC5927523 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine.

Knudson Karin M KM Hicks Kristin C KC Luo Xiaoling X Chen Jin-Qiu JQ Schlom Jeffrey J Gameiro Sofia R SR

Oncoimmunology 20180214 5

Tumors evade host immune surveillance through multiple mechanisms, including the generation of a tumor microenvironment that suppresses immune effector function. Secretion of TGFβ and upregulation of immune checkpoint programmed cell death ligand-1 (PD-L1) are two main contributors to immune evasion and tumor progression. Here, we examined the efficacy of a first-in-class bifunctional checkpoint inhibitor, the fusion protein M7824, comprising the extracellular domain of human TGFβRII (TGFβ Trap) ...[more]

PMID: 29721396

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Project description:Abstract BACKGROUND TGF- signaling promotes tumor immunosuppression; TGF- inhibition in the tumor microenvironment may enhance the response to antiPD-L1 treatment. M7824 is an innovative, first-in-class, bifunctional fusion protein composed of a human antiPD-L1 IgG1 monoclonal antibody fused with two extracellular domains of TGF RII to function as a TGF- trap. We report safety and efficacy of M7824 in patients with rGBM. METHODS In this efficacy expansion cohort of the ongoing, phase 1 trial NCT02517398, patients with rGBM who progressed after chemoradiation received M7824 1200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal. The primary objective was disease control rate (DCR) per RANO; secondary objectives included safety/tolerability. RESULTS Among 35 patients, median age was 57 years, 68.6% were male, and 91.4% were at first recurrence. At 15 months minimum follow-up, median treatment duration was 8.1 (range, 2.0–72.1) weeks; four patients remained on treatment at >1 year, and one additional patient decided to stop treatment per protocol at 12 months. Two patients had a partial response, and nine had stable disease (DCR, 31.4% [95% CI, 16.9–49.3]), of which two exhibited early progressive disease and subsequent durable stable disease ongoing for >12 months per investigators assessment. The most common treatment-related adverse events (TRAEs) were gingival bleeding (17.1%), asthenia (14.3%), pruritus, and rash (each 11.4%). Grade 3 TRAEs (6 patients, 17.1%) included diarrhea, eczema, increased liver/pancreatic enzymes, papular rash, papules, one grade 4 asymptomatic increased lipase, and one grade 5 intratumoral hemorrhage (investigator-assessed) coterminous with disease progression. CONCLUSIONS M7824 demonstrated a manageable safety profile and encouraging efficacy in rGBM, including two durable partial responses and a DCR of 31.4%. Further investigation of M7824 in GBM is warranted; future development aims to define molecular characteristics of responders.

Project description:BACKGROUND:Avelumab has recently been approved by the Food and Drug Administration for the therapy of Merkel cell carcinoma and urothelial carcinoma. M7824 is a novel first-in-class bifunctional fusion protein comprising a monoclonal antibody against programmed death-ligand 1 (PD-L1, avelumab), fused to the extracellular domain of human transforming growth factor beta (TGF?) receptor 2, which functions as a TGF? "trap." Advanced urothelial tumors have been shown to express TGF?, which possesses immunosuppressive properties that promote cancer progression and metastasis. The rationale for a combined molecule is to block the PD-1/PD-L1 interaction between tumor cells and immune cell infiltrate and simultaneously reduce or eliminate TGF? from the tumor microenvironment. In this study, we explored the effect of M7824 on invasive urothelial carcinoma cell lines. METHODS:Human urothelial (transitional cell) carcinoma cell lines HTB-4, HTB-1, and HTB-5 were treated with M7824, M7824mut (M7824 that is mutated in the anti-PD-L1 portion of the molecule and thus does not bind PD-L1), anti-PD-L1 (avelumab), or IgG1 isotype control monoclonal antibody, and were assessed for gene expression, cell-surface phenotype, and sensitivity to lysis by TRAIL, antigen-specific cytotoxic T lymphocytes and natural killer cells. RESULTS:M7824 retains the ability to mediate antibody-dependent cellular cytotoxicity of tumor cells, although in some cases to a lesser extent than anti-PD-L1. However, compared to anti-PD-L1, M7824 increases (A) gene expression of molecules involved in T-cell trafficking in the tumor (e.g., CXCL11), (B) TRAIL-mediated tumor cell lysis, and (C) antigen-specific CD8+ T-cell-mediated lysis of tumor cells. CONCLUSIONS:These studies demonstrate the immunomodulatory properties of M7824 on both tumor cell phenotype and immune-mediated lysis. Compared to anti-PD-L1 or M7824mut, M7824 induces immunogenic modulation of urothelial carcinoma cell lines, rendering them more susceptible to immune-mediated recognition and lysis. These findings show the relevance of the dual blockade of PD-L1 and TGF? in urothelial carcinoma cell lines and thus support the rationale for future clinical studies of M7824 in patients with urothelial cancer.

Project description:Background Biliary tract cancers (BTCs) are a group of cancers with poor prognosis and few treatment options. For 2L chemotherapy, no standard-of-care therapy exists, and overall response rates ORRs) are <10%. M7824 is an innovative first-in-class bifunctional fusion protein composed of 2 extracellular domains of transforming growth factor (TGF)-βRII (a TGF-β “trap”) fused to a human IgG1 mAb against PD-L1. We report the safety and efficacy of M7824 in Asian patients with pretreated BTC. Methods Patients with BTC [including intrahepatic (IHCC) and extrahepatic (EHCC) cholangiocarcinomas, gallbladder carcinoma (GC), and ampullary carcinoma (AC)] who progressed after ≥1 line of chemotherapy received M7824 1,200 mg q2w until disease progression, unacceptable toxicity, or trial withdrawal in this expansion cohort of the ongoing phase 1, open-label trial NCT02699515. The primary objective is safety/tolerability; secondary objectives include best overall response per RECIST v1.1. Results At 39 weeks median follow-up, 30 patients received M7824 for a median of 8.9 (range, 2.0–57.6) weeks; 5 patients were on active treatment. Treatment-related adverse events (TRAEs) occurred in 60% of patients; most common were maculopapular rash and pyrexia (13.3% each), as well as lipase increase and rash (10.0% each). Ten patients (33.3%) experienced grade ≥3 TRAEs, including 3 of grade 5 [1 septic shock (bacteremia, unknown etiology; 249 and 14 days after first and last dose, respectively), 2 interstitial lung disease (ILD) AEs (1 on treatment post 3 doses, 1 occurring 6 months after initial ILD diagnosis and last dose)]. Objective responses were observed in 7 patients (ORR, 23.3%; IHCC, 4/10 patients; EHCC, 1/7 patients; GC, 2/12 patients; AC, 0/1 patients), with 1 durable CR (5.6+ months) and 4/6 PRs ongoing at data cutoff (0.7+, 2.8, 3.9+, 5.5+, 5.6, 6.9+ months). One additional patient with GC had an ongoing PR for 7.6+ months after initial pseudoprogression. Conclusions M7824 monotherapy has an acceptable safety profile and promising efficacy in Asian patients with pretreated BTC, with durable responses in 8/30 patients (27%; includes 1 patient with pseudoprogression) across BTC subtypes, including responses in patients with IHCC, EHCC, and GC (ORRs, 40%, 14%, and 17%, respectively). Previously presented at ESMO Asia 2018, FPN 153O, Yoo et al. Reused with permission.

Dataset Information

M7824, a novel bifunctional anti-PD-L1/TGF? Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine.

Publications

M7824, a novel bifunctional anti-PD-L1/TGFβ Trap fusion protein, promotes anti-tumor efficacy as monotherapy and in combination with vaccine.

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