Dataset Information

First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors.

ABSTRACT:

Background

Transient CD4⁺ T cell depletion led to the proliferation of tumor-specific CD8⁺ T cells in the draining lymph node and increased infiltration of PD-1⁺CD8⁺ T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice. This is a first-in-human study of IT1208, a defucosylated humanized anti-CD4 monoclonal antibody, engineered to exert potent antibody-dependent cellular cytotoxicity.

Methods

Patients with advanced solid tumors were treated with intravenous IT1208 at doses of 0.1 or 1.0?mg/kg. The first patient in each cohort received a single administration, and the other patients received two administrations of IT1208 on days 1 and 8.

Results

Eleven patients were enrolled in the 0.1?mg/kg (n =?4) and 1.0?mg/kg cohorts (n =?7). Grade 1 or 2 infusion-related reactions was observed in all patients. Decreased CD4⁺ T cells in peripheral blood due to IT1208 were observed in all patients and especially in those receiving two administrations of 1.0?mg/kg. CD8⁺ T cells increased on day 29 compared with baseline in most patients, resulting in remarkably decreased CD4/8 ratios. One microsatellite-stable colon cancer patient achieved durable partial response showing increased infiltration of both CD4⁺ and CD8⁺ T cells into tumors after IT1208 administration. Moreover, transcriptomic profiling of the liver metastasis of the patient revealed upregulation of the expression of interferon-stimulated genes, T cell activation-related genes, and antigen presentation-related genes after IT1208 administration. Two additional patients with gastric or esophageal cancer achieved stable disease lasting at least 3?months.

Conclusions

IT1208 monotherapy successfully depleted CD4⁺ T cells with a manageable safety profile and encouraging preliminary efficacy signals, which warrants further investigations, especially in combination with immune checkpoint inhibitors.

SUBMITTER: Shitara K

PROVIDER: S-EPMC6657210 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors.

Shitara Kohei K Ueha Satoshi S Shichino Shigeyuki S Aoki Hiroyasu H Ogiwara Haru H Nakatsura Tetsuya T Suzuki Toshihiro T Shimomura Manami M Yoshikawa Toshiaki T Shoda Kayoko K Kitano Shigehisa S Yamashita Makiko M Nakayama Takayuki T Sato Akihiro A Kuroda Sakiko S Wakabayashi Masashi M Nomura Shogo S Yokochi Shoji S Ito Satoru S Matsushima Kouji K Doi Toshihiko T

Journal for immunotherapy of cancer 20190724 1

<h4>Background</h4>Transient CD4<sup>+</sup> T cell depletion led to the proliferation of tumor-specific CD8<sup>+</sup> T cells in the draining lymph node and increased infiltration of PD-1<sup>+</sup>CD8<sup>+</sup> T cells into the tumor, which resulted in strong anti-tumor effects in tumor-bearing mice. This is a first-in-human study of IT1208, a defucosylated humanized anti-CD4 monoclonal antibody, engineered to exert potent antibody-dependent cellular cytotoxicity.<h4>Methods</h4>Patients ...[more]

PMID: 31340866

Similar Datasets

Project description:BackgroundActivation of leukemia inhibitory factor (LIF) is linked to an immunosuppressive tumor microenvironment (TME), with a strong association between LIF expression and tumor-associated macrophages (TAMs). MSC-1 (AZD0171) is a humanized monoclonal antibody that binds with high affinity to LIF, promoting antitumor inflammation through TAM modulation and cancer stem cell inhibition, slowing tumor growth. In this phase I, first-in-human, open-label, dose-escalation study, MSC-1 monotherapy was assessed in patients with advanced, unresectable solid tumors.Materials and methodsUsing accelerated-titration dose escalation followed by a 3 + 3 design, MSC-1 doses of 75-1500 mg were administered intravenously every 3 weeks (Q3W) until progression or unmanageable toxicity. Additional patients were enrolled in selected cohorts to further evaluate safety, pharmacokinetics (PK), and pharmacodynamics after escalation to the next dose had been approved. The primary objective was characterizing safety and determining the recommended phase II dose (RP2D). Evaluating antitumor activity and progression-free survival (PFS) by RECIST v1.1, PK and immunogenicity were secondary objectives. Exploratory objectives included pharmacodynamic effects on circulating LIF and TME immune markers.ResultsForty-one patients received treatment. MSC-1 monotherapy was safe and well tolerated at all doses, with no dose-limiting toxicities. The maximum tolerated dose was not reached and the RP2D was determined to be 1500 mg Q3W. Almost half of the patients had treatment-related adverse events (TRAEs), with no apparent trends across doses; no patients withdrew due to TRAEs. There were no objective responses; 23.7% had stable disease for ≥2 consecutive tumor assessments. Median PFS was 5.9 weeks; 23.7% had PFS >16 weeks. On-treatment changes in circulating LIF and TME signal transducers and activators of transcription 3 signaling, M1:M2 macrophage populations, and CD8+ T-cell infiltration were consistent with the hypothesized mechanism of action.ConclusionsMSC-1 was very well tolerated across doses, with prolonged PFS in some patients. Biomarker and preclinical data suggest potential synergy with checkpoint inhibitors.

Dataset Information

First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors.

Background

Methods

Results

Conclusions

Publications

First-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody, in patients with advanced solid tumors.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets