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Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

ABSTRACT: Sarcomas are a rare type of a heterogeneous group of tumours arising from mesenchymal cells that form connective tissues. Surgery is the most common treatment for these tumours, but additional neoadjuvant or adjuvant chemotherapy or radiation therapies may be necessary. Unfortunately, a significant proportion of patients treated with conventional therapies will develop metastatic disease that is resistant to therapies. Currently, there is an urgent need to develop more effective and durable therapies for the treatment of sarcomas. In recent years immunotherapies have revolutionised the treatment of a variety of cancers by restoring patient anti-tumour immune responses or through the adoptive infusion of immune effectors able to kill and eliminate malignant cells. The clinicopathologic and genetic heterogeneity of sarcomas, together with the generally low burden of somatic mutations potentially generating neoantigens, are currently limited to broad application of immunotherapy for patients with sarcomas. Nevertheless, a better understanding of the microenvironmental factors hampering the efficacy of immunotherapy and the identification of new and suitable therapeutic targets may help to overcome current limitations. Moreover, the recent advances in the development of immunotherapies based on the direct exploitation or targeting of T cells and/or NK cells may offer new opportunities to improve the treatment of sarcomas, particularly those showing recurrence or resistance to standard of care treatments.

SUBMITTER: Chew HY

PROVIDER: S-EPMC7697818 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

Chew Hui Yi HY Chan Victor V Simpson Fiona F Dolcetti Riccardo R

Cancers 20201116 11

Sarcomas are a rare type of a heterogeneous group of tumours arising from mesenchymal cells that form connective tissues. Surgery is the most common treatment for these tumours, but additional neoadjuvant or adjuvant chemotherapy or radiation therapies may be necessary. Unfortunately, a significant proportion of patients treated with conventional therapies will develop metastatic disease that is resistant to therapies. Currently, there is an urgent need to develop more effective and durable ther ...[more]

PMID: 33207697

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Project description:BackgroundTrees belonging to the order of Fagales show a distinct geographical distribution. While alder and birch are endemic in the temperate zones of the Northern Hemisphere, hazel, hornbeam and oak prefer a warmer climate. However, specific immunotherapy of Fagales pollen-allergic patients is mainly performed using birch pollen extracts, thus limiting the success of this intervention in birch-free areas.ObjectivesT cells are considered key players in the modification of an allergic immune response during specific immunotherapy (SIT), therefore we thought to combine linear T cell epitope-containing stretches of the five most important Fagales allergens from birch, hazel, alder, oak and hornbeam resulting in a Fagales pollen hybrid (FPH) molecule applicable for SIT.MethodsA Fagales pollen hybrid was generated by PCR-based recombination of low IgE-binding allergen epitopes. Moreover, a structural-variant FPH4 was calculated by in silico mutagenesis, rendering the protein unable to adopt the Bet v 1-like fold. Both molecules were produced in Escherichia coli, characterized physico-chemically as well as immunologically, and tested in mouse models of allergic sensitization as well as allergy prophylaxis.ResultsUsing spectroscopic analyses, both proteins were monomeric, and the secondary structure elements of FPH resemble the ones typical for Bet v 1-like proteins, whereas FPH4 showed increased amounts of unordered structure. Both molecules displayed reduced binding capacities of Bet v 1-specific IgE antibodies. However, in a mouse model, the proteins were able to induce high IgG titres cross-reactive with all parental allergens. Moreover, prophylactic treatment with the hybrid proteins prevented pollen extract-induced allergic lung inflammation in vivo.ConclusionThe hybrid molecules showed a more efficient uptake and processing by dendritic cells resulting in a modified T cell response. The proteins had a lower IgE-binding capacity compared with the parental allergens, thus the high safety profile and increased efficacy emphasize clinical application for the treatment of Fagales multi-sensitization.

Dataset Information

Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

Publications

Will Next-Generation Immunotherapy Overcome the Intrinsic Diversity and Low Immunogenicity of Sarcomas to Improve Clinical Benefit?

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