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T-cell receptor repertoire analysis of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody [TCR-seq]

ABSTRACT: T-cell receptor repertoire analysis of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody [TCR-seq]

PROVIDER: PRJNA491658 | ENA |

REPOSITORIES: ENA

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T-cell receptor repertoire analysis of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody [TCR-seq]

Project description:Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed cell death-1 monoclonal antibodies (mAbs) agents or these combinations has improved outcomes of various cancers.However, still not a few patients fail to achieve clinical benefit, this highlights the importance of additional treatment to overcome its resistance. Previously, we showed that administration of the anti-CD4 mAb alone had strong anti-tumor effects that were superior to those elicited by CD25+ Treg depletion or other immune checkpoint mAbs in B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models. IT1208 (IDAC Theranostics, Tokyo, Japan) is a humanized anti-CD4 immunoglobulin G1 (IgG1) monoclonal antibody with a defucosylated Fc region, which markedly enhances antibody dependent cellular cytotoxicity. In a first-in-human, phase I, open-label, dose-escalation study, we performed T cell repertoire analysis of T cell subsets in the tumors and peripheral blood mononuclear cells (PBMCs) to clarify T cell responses against IT1208 monotherapy in patients with advanced solid tumors.

2019-08-06 | GSE120101 | GEO

TCR repertoire and transcriptomic analyses of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-08-06 | GSE120102 | GEO

TCR repertoire and transcriptomic analyses of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody

Project description:TCR repertoire and transcriptomic analyses of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody

| PRJNA491656 | ENA

Transcriptomic analysis of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody [3'SAGE-seq]

Project description:Immune checkpoint inhibitors such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed cell death-1 monoclonal antibodies (mAbs) agents or these combinations has improved outcomes of various cancers.However, still not a few patients fail to achieve clinical benefit, this highlights the importance of additional treatment to overcome its resistance. Previously, we showed that administration of the anti-CD4 mAb alone had strong anti-tumor effects that were superior to those elicited by CD25+ Treg depletion or other immune checkpoint mAbs in B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models. IT1208 (IDAC Theranostics, Tokyo, Japan) is a humanized anti-CD4 immunoglobulin G1 (IgG1) monoclonal antibody with a defucosylated Fc region, which markedly enhances antibody dependent cellular cytotoxicity. In a first-in-human, phase I, open-label, dose-escalation study, we performed transcriptomic analysis of tumors to clarify molecular responses against IT1208 monotherapy in patients with advanced solid tumors.

2019-08-06 | GSE120028 | GEO

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

Project description:BackgroundTransient 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.MethodsPatients 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.ResultsEleven 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.ConclusionsIT1208 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.

| S-EPMC6657210 | biostudies-literature

Transcriptomic analysis of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody [3'SAGE-seq]

Project description:Transcriptomic analysis of advanced solid tumors in first-in-human phase 1 study of IT1208, a defucosylated humanized anti-CD4 depleting antibody [3'SAGE-seq]

| PRJNA491654 | ENA

Systemically administered extremely low HMGN1 with anti-CD4 depleting antibody exerts synergistic anti-tumor effects

Project description:Recently there has been growing interest in the immunomodulatory effects of endogenous danger signals known as alarmins. In this study, we explore a new combination therapy of anti-CD4 depleting antibody with an alarmin, high mobility group nucleosome binding protein 1 (HMGN1). Extremely low dose of HMGN1 with anti-CD4 depleting antibody exerted robust anti-tumor effects in Colon26 subtaneous murine model. To understand transcriptomic differences of CD8+ T cells in the tumor-bearing mice after treated with anti-CD4 depleting antibody or combination therapy of HMGN1 with anti-CD4 depleting antibody, we performed CD8 T cell transcriptome analysis using 3'SAGE-seq and Ion Proton sequencer.

2019-02-07 | GSE113307 | GEO

First-in-human phase I clinical trial of RG7356, an anti-CD44 humanized antibody, in patients with advanced, CD44-expressing solid tumors.

Project description:Transmembrane glycoprotein CD44 is overexpressed in various malignancies. Interactions between CD44 and hyaluronic acid are associated with poor prognosis, making CD44 an attractive therapeutic target. We report results from a first-in-human phase I trial of RG7356, a recombinant anti-CD44 immunoglobulin G1 humanized monoclonal antibody, in patients with advanced CD44-expressing solid malignancies.Sixty-five heavily pretreated patients not amenable to standard therapy were enrolled and received RG7356 intravenously biweekly (q2w) or weekly (qw) in escalating doses from 100 mg to 2,250 mg. RG7356 was well tolerated. Most frequent adverse events were fever, headache and fatigue. Dose-limiting toxicities included headache (1,500 mg q2w and 1,350 mg qw) and febrile neutropenia (2,250 mg q2w). The maximum tolerated dose with q2w dosing was 1,500 mg, but was not defined for qw dosing due to early study termination. Clinical efficacy was modest; 13/61 patients (21%) experienced disease stabilization lasting a median of 12 (range, 6-35) weeks. No apparent dose- or dose schedule-dependent changes in biological activity were reported from blood or tissue analyses. Tumor-targeting by positron emission tomography (PET) using 89Zr-labeled RG7356 was observed for doses ≥200 mg (q2w) warranting further investigation of this agent in combination regimens.

| S-EPMC5346770 | biostudies-literature

Maytansinoid DM4-Conjugated Humanized Monoclonal Antibody huC242 in Treating Patients With Solid Tumors

Project description:RATIONALE: Monoclonal antibodies, such as maytansinoid DM4-conjugated humanized monoclonal antibody huC242, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. PURPOSE: This phase I trial is studying the side effects and best dose of maytansinoid DM4-conjugated humanized monoclonal antibody huC242 in treating patients with solid tumors that cannot be removed by surgery or have spread to other parts of the body.

| 2030868 | ecrin-mdr-crc

Depleting T regulatory cells by targeting intracellular Foxp3 with a TCR mimic antibody.

Project description:Depletion of T regulatory cells (Tregs) in the tumor microenvironment is a promising cancer immunotherapy strategy. Current approaches for depleting Tregs are limited by lack of specificity and concurrent depletion of anti-tumor effector T cells. The transcription factor forkhead box p3 (Foxp3) plays a central role in the development and function of Tregs and is an ideal target in Tregs, but Foxp3 is an intracellular, undruggable protein to date. We have generated a T cell receptor mimic antibody, "Foxp3-#32," recognizing a Foxp3-derived epitope in the context of HLA-A*02:01. The mAb Foxp3-#32 selectively recognizes CD4 + CD25 + CD127low and Foxp3 + Tregs also expressing HLA-A*02:01 and depletes these cells via antibody-mediated cellular cytotoxicity. Foxp3-#32 mAb depleted Tregs in xenografts of PBMCs from a healthy donor and ascites fluid from a cancer patient. A TCRm mAb targeting intracellular Foxp3 epitope represents an approach to deplete Tregs.

| S-EPMC6527296 | biostudies-literature

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