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A TCR/anti-CD3 bispecific fusion protein targeting gp100 potently activated anti-tumor immune responses in metastatic melanoma

ABSTRACT: A TCR/anti-CD3 bispecific fusion protein targeting gp100 potently activated anti-tumor immune responses in metastatic melanoma

PROVIDER: PRJNA580267 | ENA |

REPOSITORIES: ENA

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A TCR/anti-CD3 bispecific fusion protein targeting gp100 potently activated anti-tumor immune responses in metastatic melanoma

Project description:Tumor-specific cytotoxic T cells are required for effective immunotherapy. Here we introduce a bispecific fusion protein (tebentafusp) designed to target gp100 (a melanoma-associated antigen) through a high affinity T cell receptor binding domain, and through an anti-CD3 effector domain re-directs any cytotoxic T cell, regardless of its intrinsic specificity, to kill gp100-expressing tumor cells. In patients with metastatic melanoma, tebentafusp showed anti-tumor activity and manageable and predictable side effects. Notably, tebentafusp induced an increase in serum CXCL10 (a T cell attractant), and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment (TME). Furthermore, the appearance of rash, likely due to cytotoxic T cells targeting of gp100-expressing skin melanocytes, or an increase in serum CXCL10 showed a positive association with patient survival. Taken together, these results suggest that re-directing T cells using a gp100-targeting T cell receptor/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma.

2019-10-30 | GSE139566 | GEO

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

Project description:CD3-bispecific antibodies represent an important therapeutic strategy in oncology. These molecules work by redirecting cytotoxic T cells to antigen-bearing tumor cells. Although CD3-bispecific antibodies have been developed for several clinical indications, cases of cancer-derived resistance are an emerging limitation to the more generalized application of these molecules. Here, we devised whole-genome CRISPR screens to identify cancer resistance mechanisms to CD3-bispecific antibodies across multiple targets and cancer types. By validating the screen hits, we found that deficiency in IFNγ signaling has a prominent role in cancer resistance. Interestingly, IFNγ functions by stimulating the expression of T cell killing-related molecules in a cell type-specific manner. Additionally, by assessing resistance to the clinical CD3-bispecific antibody flotetuzumab, we identified core fucosylation as a novel and critical pathway to regulate flotetuzumab binding to the CD123 antigen. Disruption of this pathway resulted in significant resistance to flotetuzumab treatment. Moreover, proper fucosylation of CD123 is required for its normal biological functions. In order to treat the resistance associated with fucosylation loss, flotetuzumab in combination with an alternative targeting CD3-bispecific antibody demonstrated superior efficacy. Together, our study reveals multiple mechanisms that can be targeted to enhance the clinical potential of current and future T cell engaging CD3-bispecific antibody therapies.

2020-11-12 | GSE159547 | GEO

Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma.

Project description: Not available

| S-EPMC9210997 | biostudies-literature

DNA hypomethylating agents potentiate the efficacy of CD3 bispecific T cell engagers [scATAC-seq]

Project description:Bispecific T cell engagers targeting tumor-associated antigens and CD3 are promising novel targeted therapeutic agents for both solid and hematologic cancers. However, prolonged TCR stimulation can lead to chromatin rewiring and T cell dysfunction. Here, we investigate the combination of bispecific T cell engagers with the DNA hypomethylating agent decitabine and observe suppressed tumor growth in preclinical models. Utilizing the PSMAxCD3 bispecific antibody for the treatment of prostate carcinoma and in vivo humanized models, we catalog, at the single-cell level, the dynamics of T cell epigenetic states during bispecific therapy, and in combination with decitabine. Importantly, this combination preserves a progenitor exhausted T cell population and delays acquisition of a dysfunctional state, at both chromatin and protein levels. At the DNA methylation level, TCR stimulation in the presence of decitabine maintains a naive-like pattern in gene loci associated with T cell stemness. This study provides a rich resource for understanding the evolution of T cell states during immunotherapy and mechanistic support for combining epigenetic modifiers with bispecific T cell engagers in the clinic.

2026-06-01 | GSE310545 | GEO

DNA hypomethylating agents potentiate the efficacy of CD3 bispecific T cell engagers [BiSulfite-seq]

2026-06-01 | GSE310428 | GEO

Targeting dendritic cells with a PD-L1 based bispecific antibody rejuvenates specific anti-tumor T cells

Project description:Bispecific T-cell engagers (BiTEs) that preferentially target tumor-associated antigens to engage CD3 signaling have been approved to treat acute B-cell lymphoblastic leukemia. However, their applications in solid tumors have been hampered by short half-life and severe toxicity at therapeutic doses. Whether antigen-specific T cells would be rejuvenated by directing to tumor cells remains unclear. To address this, we designed a bispecific antibody (BsAb) which simultaneously targets CD3 and immune checkpoint PD-L1. Compared with conventional tumor cell targeting BsAb, PD-L1xCD3 generates superior anti-tumor immune responses in vivo. By single-cell sequencing of tumor-infiltrated T cells in different BiTE treatment, we found that PD-L1xCD3 treatment generate unique T cell subsets in the tumor microenvironment which contribute to the increased antitumor efficacy and reduced side effect.

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Study of Activated Cytokine-induced Killer Armed With Bispecific Antibody for Advanced Colorectal Cancer

Project description:This is a phase II Randomized comparison clinical trial of activated CIK armed with anti-CD3-MUC1 bispecific antibody for advanced colorectal cancer. And the aim of this research is to study the clinical efficacy and safety of activated CIK armed with anti-CD3-MUC1 bispecific antibody for colorectal cancer.

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Gene expression profile of CD4+ T-cells restimulated by anti-CD3 and anti-ICOS compared to anti-CD3 alone

Project description:Engagement of the ICOS receptor represents a key event in a process that culminates in Bcl6 expression and acquisition of the TFH and TFR phenotype. To better understand the essentials of ICOS-mediated signaling pathway, we profiled the changes in gene expression elicited after co-ligation of ICOS and CD3 compared with CD3 ligation alone. Naïve CD4+ T-cells were purified from single cell suspensions of B6 spleen and stimulated with anti-CD3 and anti-CD28 for 2d followed by resting overnight before 20 min of incubation with anti-CD3 and/or anti-ICOS and cross-linking with goat anti-hamster Ab for 8h. RNA was prepared, amplified, labeled and hybridized to Mouse Gene 1.0 ST Array (Affymetrix), in quadruplicates for anti-CD3 ligation and duplicates for anti-CD3/ anti-ICOS co-ligation.

2014-09-23 | E-GEOD-61284 | biostudies-arrayexpress

A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

Project description:A CRISPR Screen Reveals Resistance Mechanisms to CD3-Bispecific Antibody Therapy

| PRJNA669680 | ENA

Anti-CD3 model of intestinal inflammation

Project description:Anti-CD3 model of intestinal inflammation

| PRJEB85305 | ENA