Exploration of different immunotherapy modalities in osteosarcoma

骨肉瘤不同免疫治疗方式的探索

基本信息

批准号：
10730833
负责人：
Payal Agarwal
金额：
$ 44.06万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-05 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10730833
关键词：
Adaptive Immune System Adenovirus Vector Adult Adverse effects Affect Antigen Presentation Binding Biological Assay Bystander Effect CAR T cell therapy CAV2 gene CD276 gene Canis familiaris Cell Death Cell Line Cells Child Childhood Osteosarcoma Combined Modality Therapy Cytolysis Development Disease Disease-Free Survival Distant Down-Regulation Environment Generations Goals Immune checkpoint inhibitor Immune response Immune system Immunity Immunologic Stimulation Immunotherapy Individual Infiltration Inflammatory Response Laboratories Malignant Bone Neoplasm Malignant Neoplasms Measurement Mediating Membrane Proteins Modality Modeling Molecular Monoclonal Antibodies Oncolytic viruses Operative Surgical Procedures PD-1 inhibitors PD-1/PD-L1 PDL1 inhibitors Patients Pattern Production Proteins Recombinants Site Surface Antigens Survival Rate T-Lymphocyte Testing Transgenes Translations Tumor Antigens Tumor Immunity United States Virotherapy anti-PD-1 anti-PD-L1 anti-PD1 antibodies arm bone cancer cell cancer genetics cancer immunotherapeutics cancer immunotherapy cancer therapy cell killing chemokine chemotherapy chimeric antigen receptor T cells combat conditionally replicative adenovirus cytokine cytotoxic design effector T cell immune checkpoint interdisciplinary treatment approach long bone multimodality nanobodies neoantigens neoplastic cell novel novel strategies oncolytic adenovirus oncolytic virotherapy osteosarcoma programmed cell death ligand 1 programmed cell death protein 1 receptor response skills synergism targeted treatment three dimensional cell culture transmission process tumor tumor eradication tumor initiation tumor microenvironment tumor-immune system interactions vector

项目摘要

Project Summary/Abstract Osteosarcoma (OS) is the most common primary bone malignancy affecting long bones in children and the third most frequent in adults in the United States. The survival rates over the last 20 years are unchanged. OS is also the most common malignant bone tumor (80%) in dogs. Treatment options for OS are limited. Immunotherapy is a promising new approach that has yet to be fully explored in OS. Chimeric antigen receptor (CAR) T cells are designed to express recombinant receptors to target specific tumor cell surface antigens and promote T cell- mediated cancer cell death. However, one of the biggest challenges in CAR T cell therapy is the immunosuppressive tumor micro-environment (TME). Another immunotherapy strategy is the use of immune checkpoint inhibitors, such as monoclonal antibodies (mAb) against PD-1. Anti-PD-1 mAbs have shown significant efficiency in treating multiple tumors but cause adverse effects due to systemic delivery of the mAb. To avoid systemic delivery, oncolytic viruses can be designed to produce immune checkpoint inhibitors directly in TME to boost the immune system and enable T cells to kill tumor cells. Conditionally replicative adenoviruses (CRAds) replicate only in tumor cells, lyse them, and stimulate anti-tumor immunity in TME and at distant sites of disease, causing a bystander effect. However, the limited number of effector T cells against cancer antigens limits the efficacy of this approach. Therefore, we propose a combination therapy to synergize these strategies to combat tumor cells. We will combine CAR T cell therapy, oncolytic virus, and PD-1/PD-L1 inhibitor to target osteosarcoma tumor cells. We have developed an armed oncolytic adenovirus to produce anti-PD-1 Ab in the TME. We will create two more armed oncolytic viruses that will produce secreted single domain antibodies (sdAb) to PD1 and PDL1. We will evaluate CRAd and CAR T cell (against B7-H3) induced tumor cells lysis. The conditionally replicated oncolytic viruses will produce anti-PD1 and anti-PDL1 sdAb in TME, reducing the adverse effects of systemic administration, and enhancing anti-tumor immunity. CAR T cells against B7-H3 will initiate tumor cell killing in an activated TME. Ultimately, beyond the scope of this proposal, this approach will be tested in spontaneous OS in canine patients, before translation to pediatric OS patients.

项目摘要/摘要骨肉瘤（OS）是影响儿童长骨的最常见的主要骨恶性肿瘤，第三在美国成年人中最常见。过去20年中的存活率没有改变。操作系统也是狗中最常见的恶性骨肿瘤（80％）。 OS的治疗选择有限。免疫疗法是一种有希望的新方法，尚未在OS中进行全面探索。嵌合抗原受体（CAR）T细胞是旨在表达重组受体以靶向特定的肿瘤细胞表面抗原并促进T细胞介导的癌细胞死亡。但是，汽车T细胞疗法中最大的挑战之一是免疫抑制肿瘤微环境（TME）。另一个免疫疗法策略是使用免疫检查点抑制剂，例如针对PD-1的单克隆抗体（MAB）。抗PD-1 mAb已显示在治疗多个肿瘤方面的显着效率，但由于全身递送MAB而造成不利影响。为避免全身传递，可以设计溶瘤病毒以直接产生免疫检查点抑制剂在TME中以增强免疫系统并使T细胞杀死肿瘤细胞。有条件地复制腺病毒（Crads）仅在肿瘤细胞中复制，裂解它们，并刺激TME和远处的抗肿瘤免疫力疾病，导致旁观者效应。但是，针对癌症抗原的效应T细胞数量有限限制了这种方法的功效。因此，我们提出了一种结合疗法来协同这些策略打击肿瘤细胞。我们将CAR T细胞疗法，溶瘤病毒和PD-1/PD-L1抑制剂结合起来骨肉瘤肿瘤细胞。我们已经开发了一种武装的溶瘤腺病毒，以在 TME。我们将创建另外两个武装的溶瘤病毒，以产生分泌的单域抗体（SDAB）到PD1和PDL1。我们将评估CRAD和CAR T细胞（针对B7-H3）诱导的肿瘤细胞裂解。这有条件复制的溶瘤病毒将在TME中产生抗PD1和抗PDL1 SDAB，从而减少了不利的系统给药的影响，并增强抗肿瘤免疫力。针对B7-H3的CAR T细胞将启动激活的TME中的肿瘤细胞杀死。最终，除了该提案的范围之外，该方法将进行测试在犬类患者的自发OS中，在转化为儿科OS患者之前。