Preserving the CTLA-4 Checkpoint for Safer and More Effective Cancer Immunotherapy

Liu, Yang; Zheng, Pan

doi:10.1016/j.tips.2019.11.003

Cited by 90 publications

(57 citation statements)

References 68 publications

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“…Current reagents typically display an unmodified hIgG1 isotype and although safe have not delivered strong anti-tumour effects [7]. These hIgG1 reagents would be expected to deliver the Treg deleting function indicated here but to date this activity has not been shown clearly in patients, with the topic currently debated for other Treg targets such as CTLA-4 [55][56][57]. Furthermore, their deletion may not be sufficient to elicit tumour regression in most human cancers, unlike the mouse models shown here.…”

Section: Discussionmentioning

confidence: 99%

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

Griffiths

Hussain

Smith

et al. 2020

Preprint

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AbstractPrevious data suggests that anti-OX40 mAb can elicit anti-tumour effects in mice through deletion of Tregs. However, OX40 also has powerful costimulatory effects on T cells which could evoke therapeutic responses. The contributions of these different effector mechanisms has not previously been systematically evaluated, particularly for mAb directed to human OX40. Therefore, we generated a novel human OX40 knock-in (KI) mouse to evaluate a panel of anti-hOX40 mAb and show that their activities relate directly to two key properties: 1) isotype – with mIgG1 mAb evoking receptor agonism and CD8+ T cell expansion and mIgG2a mAb evoking deletion of Treg and; 2) epitope - with membrane-proximal mAb delivering more powerful agonism. Intriguingly, both isotypes acted therapeutically in tumour models by engaging these different mechanisms. These findings highlight the significant impact of isotype and epitope on the modulation of anti-hOX40 mAb therapy, and indicate that CD8+ T cell expansion or Treg depletion might be preferable according to the composition of different tumours.SummaryHuman trials with anti-OX40 antibodies have been disappointing indicating that optimal reagents have not yet been developed. Here, using a new panel of antibodies, we show that isotype and epitope combine to determine agonistic and therapeutic activity.

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Section: Discussionmentioning

confidence: 99%

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

Griffiths

Hussain

Smith

et al. 2020

Preprint

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“…The development of tumour cells depends on the tumour microenvironment, which includes tumour cells, various other cells and extracellular components (7). The immunosuppressive cells in the tumour microenvironment, such as Tregs and MDSCs, not only affect each other, but their changes in number and types will affect tumour development (34,35). METTL3 is one of the Writers, and its role is to catalyse the m 6 A methylation of mRNA (and other nuclear RNAs); after the methylation of m 6…”

Section: Discussionmentioning

confidence: 99%

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

Zhang

Chen

et al. 2020

Preprint

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Background: Methyltransferase-like 3 (METTL3) is a member of the m6A methyltransferase family and acts as an oncogene in cancers. Recent studies suggest that host innate immunity is regulated by the enzymes controlling m6A epitranscriptomic changes. Here, we aim to explore the associations between the levels of METTL3 and CD33+ myeloid-derived suppressor cells (MDSCs) in tumour tissues and the survival of patients with cervical cancer (CC).Methods: Paraffin tumour specimens from 197 CC patients were collected. The expression of METTL3 and CD33 was measured by immunohistochemical (IHC) staining. The clinical associations of the IHC variants were analysed by Pearson's and Spearman's chi-square tests. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan–Meier method and log-rank test. Hazard ratios (HRs) and independent significance were obtained via Cox proportional hazards models for multivariate analyses.Results: We found that tumour tissues displayed increased levels of METTL3 and CD33+ MDSCs compared with tumour adjacent tissues from the same CC patients. Importantly, METTL3 expression was positively related to the density of CD33+ cells in tumour tissues (P = 0.011). The level of METTL3 in tumour microenvironments was significantly related to advanced tumour stages. The levels of METTL3 and CD33+ MDSCs in tumour tissues were notably associated with reduced DFS or OS. The Cox model analysis revealed that the level of METTL3 in tumour cells was an independent factor for patient survival, specifically for DFS (HR = 3.157, P = 0.022) and OS (HR = 3.271, P = 0.012), while CD33+ MDSC number was an independent predictor for DFS (HR: 3.958, P = 0.031). Interestingly, in patients with advanced-disease stages (II-IV), METTL3 in tumour cells was an independent factor for DFS (HR = 6.725, P= 0.010) and OS (HR = 5.140, P= 0.021), while CD33+ MDSC density was an independent factor for OS (HR = 8.802, P = 0.037).Conclusion: Our findings suggest that CD33+ MDSC expansion is linked to high levels of METTL3 and that METTL3 and CD33+ MDSCs are independent prognostic factors in CC.

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“…Notably, the CTLA-4 inactivation led to irAEs ( 26 ). The selective depletion of tumor-infiltrating Tregs enhanced by preserving CTLA-4 recycling led to the cancer therapeutic effect of anti-CTLA-4 antibodies ( 27 ). That is to say, the depletion of tumor-infiltrating Tregs was closely related to CTLA-4-related toxicities and CTLA-4 molecule inactivation.…”

Section: Predictive Biomarkers For Ctla-4 Inhibitors-related Toxicitimentioning

confidence: 99%

Predictive Biomarkers of Immune Checkpoint Inhibitors-Related Toxicities

Zhu

et al. 2020

Front. Immunol.

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The emergence and continuous development of immune checkpoint inhibitors (ICIs) therapy brings a revolution in cancer therapy history, but the major hurdle associated with their usage is the concomitant ICIs-related toxicities that present a challenge for oncologists. The toxicities may involve non-specific symptoms of multiple systems as for the unique mechanism of formation, which are not easily distinguishable from traditional toxicities. A few of these adverse events are self-limiting and readily manageable, but others may limit treatment, cause interruption and need to be treated with methylprednisolone or tumor necrosis factor-α (TNF-α) antibody infliximab, and even directly threaten life. Early accurate recognition and adequate management are critical to the patient's prognosis and overall survival (OS). Several biomarkers such as the expression of programmed cell death ligand 1 (PD-L1), tumor mutation burden (TMB), and microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) have been proved to be the predictors for anti-tumor efficacy of ICIs, but there is a gap in clinical needs for effective biomarkers that predict toxicities and help filter out the patients who may benefit most from these costly therapies while avoiding major risks of toxicities. Here, we summarize several types of risk factors correlated with ICIs-related toxicities to provide a reference for oncologists to predict the occurrence of ICIs-related toxicities resulting in a timely process in clinical practice.

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Preserving the CTLA-4 Checkpoint for Safer and More Effective Cancer Immunotherapy

Cited by 90 publications

References 68 publications

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

Domain Binding and Isotype Dictate the Activity of Anti-human OX40 Antibodies

Connecting METTL3 and intratumoural CD33+ MDSCs in predicting clinical outcome in cervical cancer

Predictive Biomarkers of Immune Checkpoint Inhibitors-Related Toxicities

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