Dataset Information

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

ABSTRACT: A major paradigm in cancer immunotherapy is the use of checkpoint inhibitors to break regulatory mechanisms that usually guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example that helped establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent distinct and therapeutically separable activities of anti-CTLA-4 antibodies. The former is attributable to inactivation of the CTLA-4 checkpoint, while the latter is due to selective depletion of regulatory T cells (Treg) in a tumor microenvironment. Here we argue that for safer and more effective CTLA-4-targeting immune therapy, one should preserve rather than inhibit the CTLA-4 checkpoint while enhancing the efficacy and selectivity of Treg depletion in a tumor microenvironment.

SUBMITTER: Liu Y

PROVIDER: S-EPMC7210725 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Liu Yang Y Zheng Pan P

Trends in pharmacological sciences 20191210 1

A major paradigm in cancer immunotherapy is the use of checkpoint inhibitors to break regulatory mechanisms that usually guard the host against autoimmune diseases. CTLA-4-targeting immunotherapy was the first example that helped establish this paradigm. However, the clinically tested anti-CTLA-4 antibodies exhibit suboptimal efficacy but high toxicity. Recent studies have demonstrated that immunotherapy-related adverse events (irAE) and the cancer immunotherapeutic effect (CITE) represent disti ...[more]

PMID: 31836191

Similar Datasets

Project description:Background:Biological synthesis of nanomaterials possesses unprecedented potential in the production of nanomaterials due to their ability to produce nanomaterials with improved biocompatibility in addition to eco-friendly synthetic procedures. Methods:This article reports the isolation of an air-borne fungus from the campus of Integral University, Lucknow, with an exceptional ability to withstand very high concentrations of silver salt. The fungus was found to produce pentagonal silver nanoparticles (AgPgNps) when silver ions were reduced from silver nitrate. Molecular analysis and biochemical characterization techniques based on 18-seconds rRNA identified the fungus to belong to the Aspergillus sp. with the NCBI accession no KF913249. Material characterization techniques including ultraviolet (UV)-visible spectroscopy, transmission electron microscopy, and zeta potential analysis were used to satisfactorily characterize the as-synthesized AgPgNps. Results:The AgPgNps synthesized by the fungus Aspergillus sp. exhibit an absorption that is maximum centered at about 416 nm, with a standard particle size of 23.22±2 nm. These AgPgNps exhibited broad-spectrum antimicrobial activities against an array of bacterial pathogens with remarkable minimum inhibitory concentration (MIC50) values: Staphylococcus aureus (ATCC 25923) - 9.230 µg/mL, Bacillus sp. (ATCC 14593) - 12.781 µg/mL, Escherichia coli (ATCC 25922) - 5.063 µg/mL, and Klebsiella pneumoniae (ATCC 13883) - 5.426 µg/mL. In vitro cytotoxicity analysis of biosynthesized AgPgNps showed a dose-response activity against human cervical cancer cell line (HeLa) and adenocarcinoma cells (A549) with MIC50 values of 0.038 µg/mL and 0.044 µg/mL, respectively. Conclusion:These findings are very crucial to evaluate the biosynthetic process for the synthesis of nanoparticles (NPs) with unique properties. These NPs may find potential applications in sensing, medicine, and antimicrobial and anticancer therapies.

Project description:Concurrent sensitization to peanut (PN) and tree nuts (TN), the most dangerous food allergies, is common. Current oral immunotherapy (OIT) is not fully satisfactory.To determine whether the herbal formula B-FAHF-2 (BF2) ameliorates PN/TN OIT adverse reactions and enhances persistence of a tolerant state.Concurrently sensitized PN-, walnut- (WN) and cashew (CSH)-allergic mice received 1-day PN/WN/CSH rush OIT plus 3 weeks of maintenance dosing, with or without 3 weeks prior and 3 weeks BF2 co-treatment. Anaphylactic symptom scores, core body temperatures, plasma histamine levels, basophil numbers, antigen-specific IgE, cytokine levels, and IL-4, INF-? and Foxp3 gene promoter DNA methylation status, and their correlation with final challenge symptom scores were determined.BF2+OIT-treated mice experienced significantly fewer and less severe adverse reactions than OIT-only-treated mice (P<.01) during the 1-day rush OIT build-up dose phase. Both OIT-only and BF2+OIT mice showed significant desensitization (P<.01 and .001, respectively) at 1 week post-therapy challenge, being greater in BF2+OIT mice. All sham-treated and 91% of OIT-treated mice experienced anaphylaxis whereas only 21% of BF2+OIT-treated mice exhibited reactions during 5-6 weeks of dose escalation single PN and TN challenges. Greater and more persistent protection in BF2+OIT mice was associated with significantly lower plasma histamine and IgE levels, increased IFN-?/IL-4 and IL-10/IL-4 ratios, DNA remethylation at the IL-4 promoter and demethylation at IFN-? and Foxp3 promoters. Final challenge symptom scores were inversely correlated with IL-4 DNA methylation levels (P<.0002) and positively correlated with IFN-? and Foxp3 gene promoter methylation levels (P<.0011) (P<.0165).Combined BF2/OIT therapy was safer and produced longer post-treatment protection and more tolerance-prone immunological and epigenetic modifications than OIT alone. BF2/OIT may provide an additional OIT option for patients with concurrent PN/TN and other food allergies.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets