T-cell exhaustion induced by continuous bispecific antibody exposure is ameliorated by treatment-free intervals
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA805096 | ENA |
REPOSITORIES: ENA
Similar Datasets
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
Project description:T-cell-recruiting bispecific molecule 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 molecule 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 a 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%; 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.
| S-EPMC10652962 | biostudies-literature
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
Project description:A novel affinity-tuned dual-checkpoint bispecific antibody with potent PD-L1 and moderate CD47 affinity was designed to improve the selectivity to TME and thus enhance antitumor immunity and efficacy. The gene expression analysis using Nanostring platform was performed to examine the immune cell modulation in TME following the CD47/PD-L1 bispecific treatment.
2021-10-13 | GSE177053 | GEO
Project description:A novel affinity-tuned dual-checkpoint bispecific antibody with potent PD-L1 and moderate CD47 affinity was designed to improve the selectivity to TME and thus enhance antitumor immunity and efficacy. The scRNAseq analysis was performed to examine the immune cell modulation in TME following the CD47/PD-L1 bispecific treatment.
2022-04-20 | GSE180296 | GEO
Project description:Single-cell mRNA sequencing of anti-PD-1 GITR-L bispecific antibody treated CT26 mouse tumor model infiltrating leukocytes
2021-12-20 | GSE190105 | GEO
Project description:Purpose: Accumulating analyses of pro-oncogenic molecular mechanisms triggered a rapid development of targeted cancer therapies. Although many of these treatments produce impressive initial responses, eventual resistance onset is practically unavoidable. One of the main approaches for preventing this refractory condition relies on the implementation of combination therapies. This includes dual-specificity reagents that affect both of their targets with a high level of selectivity. Unfortunately, selection of target combinations for these treatments is often confounded by limitations in our understanding of tumor biology. Here, we describe and validate a multipronged unbiased strategy for predicting optimal co-targets for bispecific therapeutics. Experimental design: Our strategy integrates ex-vivo genome-wide loss of function screening, BioID interactome profiling and gene expression analysis of patient data to identify the best fit co-targets. Final validation of selected target combinations is done in tumorsphere cultures and xenograft models. Results: Integration of our experimental approaches unambiguously pointed towards EGFR and EPHA2 tyrosine kinase receptors as molecules of choice for co-targeting in multiple tumor types. Following this lead, we generated a human bispecific anti-EGFR/EPHA2 antibody that, as predicted, very effectively suppresses tumor growth, compared to its prototype anti-EGFR therapeutic antibody, cetuximab. Conclusion: Our work not only presents a new bispecific antibody with a high potential for being developed into clinically-relevant biologics, but more importantly, successfully validates a novel unbiased strategy for selecting biologically optimal target combinations. This is of a significant translational relevance, as such multifaceted unbiased approaches are likely to augment the development of effective combination therapies for cancer treatment.
2023-02-23 | GSE171920 | GEO
Project description:Bispecific antibodies are a successful and expanding therapeutic class, bridging two cell-types or engaging two different molecules on the same cell. Standard approaches to generate bispecifics are complicated by the need for disulfide reduction/oxidation or specialized formats. Here we present SpyMask, a modular approach to bispecifics using SpyTag/SpyCatcher spontaneous amidation. Two SpyTag-fused antigen-binding modules can be precisely conjugated onto DoubleCatcher, a tandem SpyCatcher where the second SpyCatcher is protease-activatable. We engineer a panel of structurally-distinct DoubleCatchers, from which binders project in different directions. We establish a generalized methodology for one-pot assembly and purification of bispecifics in 96-well plate format. A panel of binders recognizing different HER2 epitopes were coupled to DoubleCatcher, revealing unexpected combinations with anti-proliferative or pro-proliferative activity on HER2-addicted cancer cells. Bispecific activity depended sensitively on both binder orientation and the geometry of DoubleCatcher scaffolds. These findings support the need for straightforward assembly in different formats. SpyMask provides a scalable tool to discover synergy in bispecific activity, through modulating receptor organization and geometry. We use mass spectrometry to validate the protein building blocks of our bispecific assemblies, as well as to confirm precise heterodimerization of antigen-binding proteins.
2024-03-18 | PXD049393 | Pride
Project description:RATIONALE: Diagnostic procedures, such as radionuclide imaging using bispecific antibody, may help find colorectal cancer cells and learn the extent of disease.
PURPOSE: This phase I trial is studying how well a bispecific antibody works in finding tumor cells in patients with colorectal cancer.
| 2071852 | ecrin-mdr-crc
Project description:Co-stimulatory receptors such as GITR play key roles in regulating the effector functions of T cells. Agonistic anti-GITR antibodies have been investigated as a cancer immunotherapy with demonstrated efficacy in pre-clinical models. In human clinical trials, however, GITR agonist antibodies have shown limited therapeutic effect which may be due to a suboptimal receptor clustering-mediated signaling. To overcome this potential limitation, a rational protein engineering approach is needed to optimize GITR agonist-based immunotherapies. Here we show a novel bispecific molecule consisting of an anti-PD-1 antibody fused with a multimeric GITR ligand (anti-PD-1-GITR-L) that induces a PD-1-dependent and FcγR-independent GITR clustering, resulting in an enhanced activation, proliferation, and memory differentiation of primed antigen-specific GITR+PD-1+ T cells. The anti-PD-1-GITR-L bispecific is a PD-1 directed GITR-L construct that has a different mechanism of action (MoA) than the co-administration of anti-PD-1 plus GITR-L and demonstrated a dose-dependent immunologically driven tumor growth inhibition in syngeneic, genetically engineered and xenograft humanized mouse tumor models. Combination of anti-PD-1-GITR-L with TGFβ inhibition or chemotherapy (gemcitabine), respectively, resulted in tumor remission in immunogenically cold and checkpoint blockade resistant mouse models. Dose-dependent correlations between target saturation and Ki67 and TIGIT up-regulation on memory T cells have been observed following a single dose of anti-PD-1-GITR-L bispecific in mice and non-human primates. Anti-PD-1-GITR-L thus represents a novel bispecific approach for directing GITR agonism for cancer immunotherapy.
2021-12-20 | GSE189359 | GEO