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Aptamer mediated silencing of the spliceosome machinery to increase the immunogenicity of metastatic breast cancer

适体介导的剪接体机制沉默以增加转移性乳腺癌的免疫原性

基本信息

批准号：
10286216
负责人：
Paolo Serafini
金额：
$ 17.94万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-04 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286216
关键词：
4T1 Affect Affinity Alternative Splicing Antigens Antitumor Response Award Binding Biodistribution Breast Cancer Cell Breast cancer metastasis Cells Chemicals Chimera organism Clinic Clinical Trials Containment Disease Disseminated Malignant Neoplasm Drug Kinetics Epitopes FDA approved Future Genes Genetic Genetic Transcription Human Immune Immune checkpoint inhibitor Immune system Immunocompetent Immunotherapeutic agent Immunotherapy In Vitro Intelligence Intervention Introns Ligands Malignant Neoplasms Measures Mediating Metastatic breast cancer Mus Mutation Neoplasm Metastasis Oligonucleotides Oncoproteins Paclitaxel Pathway interactions Patients RNA Reagent Resistance Ribonucleases Role Safety Side Small Interfering RNA Somatic Mutation Spliceosomes Structure Testing Therapeutic Therapeutic Effect Tissues Toxic effect Transfection Translations Tumor Immunity Up-Regulation Vaccination Vertebral column Viral Vector anti-PD-1 aptamer bioinformatics tool cancer cell cancer therapy checkpoint inhibition checkpoint therapy clinically relevant efficacy testing experimental study high reward high risk immune checkpoint blockade immunogenicity immunological intervention improved in vivo mRNA Precursor malignant breast neoplasm mouse model nanoparticle neoantigens neoplastic cell preclinical development programmed cell death ligand 1 receptor response screening siRNA delivery side effect success targeted delivery targeted treatment three dimensional structure transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor microenvironment tumor progression

项目摘要

Even with the FDA approval of Atezolizumab in combination with nab-Paclitaxel for PDL1 positive triple negative breast cancer, metastatic breast cancer is still a deadly disease. The modest impact of checkpoint inhibitor therapy in this disease can be partially explained by the relatively low tumor mutation burden, by the low expression of neoantigens and the overall low immunogenicity of metastatic breast cancer compare to other malignancies in which checkpoint inhibitors are highly effective. Recent RNA sequencing and MHC-peptidome analyses of tumors from patients undergoing checkpoint inhibition therapy revealed the important contribution of intron-derived epitopes in the neoantigen pools. In breast cancer these intron-derived neoantigens are poorly expressed because of the constitutive upregulation of the spliceosome machinery. Here we will test the hypothesis that aptamer mediated targeted silencing snRPE, a key component of the spliceosome machinery, can increase breast cancer immunogenicity and synergize with anti-PD1 in the eradication of metastatic breast cancer. Toward this targeted therapy, we have identified two RNA aptamers that can recognize and mouse and human metastatic breast cancer cells in vitro and in vivo. RNA aptamers are small oligonucleotides that because of their 3D structure can recognize their ligand with high affinity. Aptamers are chemically synthetized with a backbone that confer RNAse resistance and lack of immunogenicity and can be modified for improved pharmacokinetic and for therapeutic delivery. We have conjugated our aptamer with siRNA against snRPE and showed their in vitro efficacy. In this study, we will employ two aggressive model of mouse breast cancer: the 4T1 and the E0771 in two different genetic backgrounds. First, we will characterize the role of the immune system in the antitumor response using NSG and immune competent mice, depletion experiments, and by characterizing the tumor microenvironment and the anti-tumor immunity. Then, we will measure the therapeutic effect of aptamer chimera as monotherapy or in conjunction with checkpoint inhibition therapy and vaccination against intron derived neoepitopes for the treatment of metastatic breast cancer. We expect that this treatment will be well tolerated and will increase tumor immunogenicity and the efficacy of checkpoint inhibition therapy. Since our aptamers recognize both mouse and human metastatic cancers, the translation of positive finding in the clinic might should be facilitated and might have, in the future, an important impact on metastatic breast cancer allowing its eradication and/or containment with minimal side effect.

即使FDA批准Atezolizumab联合nab-Paclitaxel治疗PDL1阳性三联症