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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：
10461876
负责人：
Paolo Serafini
金额：
$ 21.1万
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/10461876
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-Paclitazone治疗PDL 1阳性三联乳腺癌阴性，转移性乳腺癌仍然是一种致命的疾病。检查点的适度影响这种疾病的抑制剂治疗可以部分解释为相对较低的肿瘤突变负荷，新抗原的表达和转移性乳腺癌的总体低免疫原性相比，检查点抑制剂非常有效的恶性肿瘤。最近的RNA测序和MHC-肽组对接受检查点抑制治疗的患者的肿瘤分析显示，新抗原库中的内含子衍生表位。在乳腺癌中，这些内含子衍生的新抗原在乳腺癌细胞中的表达很差。由于剪接体机制的组成性上调而表达。在这里，我们将测试适体介导的靶向沉默snRPE的假设，snRPE是一个关键组成部分，剪接体机制，可以增加乳腺癌免疫原性，并与抗PD 1协同作用，根除转移性乳腺癌。针对这种靶向治疗，我们已经确定了两种RNA适体可以在体外和体内识别小鼠和人类转移性乳腺癌细胞。RNA适体是小的寡核苷酸，因为它们的3D结构可以以高亲和力识别它们的配体。适体是化学合成的，具有赋予RNA酶抗性和缺乏免疫原性的主链，可以被修饰以改善药代动力学和用于治疗递送。我们将适体与针对snRPE的siRNA并显示其体外功效。在本研究中，我们将采用两种侵袭性小鼠乳腺癌模型：4 T1和E0771，两种不同的基因背景首先，我们将描述免疫系统在抗肿瘤治疗中的作用。使用NSG和免疫活性小鼠，消耗实验，并通过表征肿瘤微环境和抗肿瘤免疫。然后，我们将测量适体嵌合体的治疗效果作为单一疗法或与检查点抑制疗法和针对内含子衍生的疫苗接种联合用于治疗转移性乳腺癌的新表位。我们预期这种治疗将具有良好的耐受性，并将增加肿瘤免疫原性，检查点抑制疗法的疗效。由于我们的适体识别小鼠和人类转移性肿瘤，癌症，在临床上的积极发现的翻译可能应该得到促进，并可能在未来，对转移性乳腺癌的重要影响，使其得以根除和/或遏制，效果