Systemic delivery of an oncolytic adenovirus targeting TGFβ to enhance anti-PD-1 and anti-CTLA-4 therapy for triple negative breast cancer

全身递送靶向 TGFβ 的溶瘤腺病毒，以增强三阴性乳腺癌的抗 PD-1 和抗 CTLA-4 治疗

• 批准号: 10117795
• 负责人: Weidong Xu
• 金额: $ 39.51万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10117795
• 关键词: 4T1; Abraxane; Adenoviruses; Amino Acids; Antibodies; Antibody titer measurement; Antitumor Response; Attenuated; Binding; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer Treatment; CTLA4 gene; Cell Death; Cells; Clinical; Clinical Trials; Combination immunotherapy; Combined Modality Therapy; Complementarity Determining Regions; Cytometry; Development; FDA approved; Fiber; Future; Genes; Genetic Transcription; Goals; Hepatic; Homing; Human; Immune; Immune checkpoint inhibitor; Immunoglobulin G; Immunologics; Immunology procedure; Immunosuppressive Agents; Inflammatory; Liver; Lymphatic; Malignant Neoplasms; Mammary Neoplasms; Mediating; Metastatic Neoplasm to the Bone; Modeling; Mus; Neoplasm Metastasis; Normal tissue morphology; Oncogenes; Oncolytic viruses; Osteolytic; Paclitaxel; Pathway interactions; Patients; Peptides; Phenotype; Population; Prevalence; RNA; Research; Resistance; Role; Safety; Signal Pathway; Signal Transduction; Spleen; TGFB1 gene; Technology; Testing; Therapy Clinical Trials; Therapy trial; Toxic effect; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Tumor Immunity; Viral; Virus; Woman; anti-CTLA-4 therapy; anti-CTLA4; anti-PD-1; anti-PD-1/PD-L1; anti-PD-L1; anti-PD-L1 antibodies; anti-PD1 antibodies; anti-tumor immune response; antitumor agent; base; bone; cytokine; gene panel; immune activation; immunogenicity; improved; in vivo; interest; macrophage; molecular subtypes; nano-string; neoplastic cell; neutralizing antibody; novel; novel therapeutics; oncolytic adenovirus; peripheral blood; programmed cell death ligand 1; programmed cell death protein 1; receptor; research clinical testing; response; subcutaneous; systemic toxicity; therapy resistant; transcriptome; transcriptome sequencing; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor microenvironment; tumor specificity; uptake

PROJECT SUMMARY The development of novel therapies for the treatment of breast cancer is a major unmet need. In recent years, immune checkpoint inhibitors including anti-PD-1, anti-PD-L1 and anti-CTLA-4 have shown promise as antitumor agents, and are approved for the treatment of several malignancies. Clinical trials in breast cancer patients have shown that about 20% of triple negative breast cancers (TNBC) respond favorably to anti-PD-1 antibodies and Atezolizumab, an anti-PD-L1 antibody in combination with nab-paclitaxel (Abraxane) is now FDA approved for advanced stage TNBC patients with positive PDL-1 expression. However, many TNBC patients are resistant to anti-PD-1/PDL-1 and anti-CTLA-4 treatments which could be due to weak immunogenicity of the tumors and poor inflammatory but highly immune suppressive tumor microenvironment. In recent years TGFβ has been shown to be a strong immune suppressor and can potentially produce a tumor microenvironment that is resistant to anti-PD-1 and anti-CTLA-4 therapy. To overcome resistance to anti-PD-1 and anti-CTLA-4 we have developed adenoviruses (Ad) expressing sTGFβRIIFc (soluble TGFβ receptor II fused with human IgG Fc). sTGFβRIIFc acts as a TGFβ decoy, and can inhibit TGFβ pathways. Initially, we created Ad5 based Ad.sT expressing sTGFβRIIFc. To reduce hepatic/systemic toxicity associated with systemic delivery of Ad.sT, we created mHAd.sT, a liver-detargeted virus, by replacing hypervariable regions (HVRs) (1-7) of Ad.sT with Ad48 HVRs. To enhance tumor specificity, we have now created mHAdLyp.sT by introducing LyP-1 peptide, a 9-amino acid long tumor homing-cell peptide, into the HI loop of the mHAd.sT fiber. In this proposal, we will test the hypotheses that systemic administration of mHAdLyp.sT in mice bearing 4T1 triple negative mammary tumors will result in reduced hepatic/systemic toxicity but produce high levels of sTGFβRIIFc and inhibit TGFβ pathways. This will alter the tumor microenvironment, induce tumor immunity, and overcome resistance to anti-PD-1 and anti-CTLA-4., and examine the expression profiles of TGFβ-1, TGFβ-1 regulated genes, and PD-1 and CTLA-4 signaling pathways. We will examine immuno-phenotypes in tumors, peripheral blood and spleen (Aim 1). Next, we will examine mHAdLyp.sT, anti-PD-1 and anti-CTLA-4 combination therapies in mouse tumor models. We will conduct RNA-Seq analysis of the whole transcriptomes, and examine the role of immune activation in mediating the anti-tumor responses (Aim 2). We will test the hypothesis that systemic administration of mHLypAd.sT, in combination with anti-PD-1 and anti- CTLA-4 in mice with pre-established metastases will be effective (Aim 3). To guide us for the combination therapy trials with mHAdLyp.sT, anti-PD-1 and anti-CTLA-4, we will examine human TNBC tumors by Nanostring technology for RNA profiling, and will further examine the TGFβ-1 and other relevant biomarkers and TILS in human TNBC tumors. We will also screen the human population for the Ad neutralizing antibodies titers (Aim 4). We believe that our research described here is critical to bring forward our oncolytic virus mHAdLyp.sT targeting TGFβ in combination with anti-PD-1 and anti-CTLA-4 for clinical evaluation in TNBC patients.

项目总结