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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310428 | GEO | 2026/06/01

REPOSITORIES: GEO

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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.

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

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Project description:Bispecific T-cell engager (BiTE)-based cancer therapies that activate the cytotoxic T cells of a patient’s own immune system have gained momentum with the recent FDA approval of Blinatumomab for treating B cell malignancies. However, this approach has had limited success in targeting solid tumors. We have reported the development of BiTE-sialidase fusion proteins that enhance tumor cell susceptibility to BiTE-mediated cytolysis by T cells via targeted desialylation at the BiTE-induced T cell-tumor cell interface. Targeted desialylation results in better immunological synapse formation, T-cell activation and effector function. As a result, BiTE-sialidase fusion proteins show remarkably increased efficacy in inducing T-cell-dependent tumor cell cytolysis in response to target antigens compared to the parent BiTE molecules alone. This enhanced function is seen both in vitro and in in vivo xenograft and syngeneic solid tumor mouse models. Our findings highlight BiTE-sialidase fusion proteins as promising candidates for the development of next-generation bispecific T-cell engaging molecules for cancer immunotherapy. This transcriptomic dataset documents the effect of BiTE-sialidase vs uncojugated BiTE on T cells including the upregulation of effector associated genes.

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2023-03-09 | GSE217245 | GEO

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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.

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T-cell exhaustion induced by continuous bispecific antibody exposure is ameliorated by treatment-free intervals

Project description:T-cell-recruiting bispecific antibody therapy has yielded promising results in patients with hematologic malignancies, however, resistance and subsequent relapse remains a major challenge. T-cell exhaustion induced by persistent antigen stimulation or tonic receptor signaling has been reported to compromise outcomes of T-cell based immunotherapies. The impact of continuous exposure to bispecifics on T-cell function, however, remains poorly understood. In relapsed/refractory B-cell precursor acute lymphoblastic leukemia patients, 28-day continuous infusion with the CD19xCD3 bispecific antibody blinatumomab led to declining T-cell function. In an in vitro model system, mimicking 28-day continuous infusion with the half-life-extended CD19xCD3 bispecific AMG 562, we identified hallmark features of exhaustion arising over time. Continuous AMG 562 exposure induced progressive loss of T-cell function (day 7 vs day 28 mean specific lysis: 88.4% vs 8.6%; n = 6; p = .0003). Treatment-free intervals (TFIs), achieved by AMG 562 withdrawal, were identified as powerful strategy for counteracting exhaustion. TFIs induced strong functional reinvigoration of T cells (continuous vs TFI specific lysis on day 14: 34.9% vs 93.4%; ± SEM; n = 6; p < .0001) and transcriptional reprogramming. Furthermore, use of a TFI led to improved T-cell expansion and tumor control in vivo. Our data demonstrate the relevance of T-cell exhaustion in bispecific antibody therapy and highlight that T cells can be functionally and transcriptionally rejuvenated with TFIs. In view of the growing number of bispecific molecules being evaluated in clinical trials, our findings emphasize the need to consider and evaluate TFIs in application schedules to improve clinical outcomes.

2022-07-26 | GSE196463 | GEO

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