Exploration of different immunotherapy modalities in osteosarcoma

骨肉瘤不同免疫治疗方式的探索

• 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
• 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

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原发骨恶性肿瘤，在儿童中占第三位 在美国，最常见的是成年人。过去20年的存活率没有变化。操作系统也是 狗最常见的恶性骨肿瘤(80%)。OS的治疗选择有限。免疫疗法 是一种很有前途的新方法，还没有在操作系统中得到充分的探索。嵌合抗原受体(CAR)T细胞 旨在表达针对特定肿瘤细胞表面抗原的重组受体，并促进T细胞- 导致癌细胞死亡。然而，CAR T细胞疗法最大的挑战之一是 免疫抑制肿瘤微环境(TME)。另一种免疫治疗策略是使用免疫 检查点抑制物，如抗PD-1的单抗。抗PD-1单抗已显示 在治疗多种肿瘤方面显著有效，但由于全身注射单抗而引起不良反应。 为了避免全身传播，溶瘤病毒可以设计成直接产生免疫检查点抑制物。 在TME中增强免疫系统，使T细胞能够杀死肿瘤细胞。条件性复制型腺病毒 (CRAds)仅在肿瘤细胞中复制、裂解，并在TME和远端部位激发抗肿瘤免疫 引起旁观者效应的疾病。然而，抗癌抗原的效应性T细胞数量有限 限制了此方法的有效性。因此，我们提出了一种联合疗法来协同这些策略。 来对抗肿瘤细胞。我们将结合CAR T细胞治疗、溶瘤病毒和PD-1/PD-L1抑制剂来靶向 骨肉瘤肿瘤细胞。我们已经开发出一种武装的溶瘤腺病毒，在小鼠体内产生抗PD-1抗体。 我也是。我们将再制造两种武装溶瘤病毒，它们将产生分泌型单域抗体(SdAb)。 至PD1和PDL1。我们将评估CRAd和CAR T细胞(抗B7-H3)诱导的肿瘤细胞裂解。这个 有条件复制的溶瘤病毒将在TME中产生抗PD1和抗PDL1 sdAb，从而减少对 全身给药的效果，增强抗肿瘤免疫。针对B7-H3的CAR T细胞将启动 在活化的TME中杀死肿瘤细胞。最终，在本提案的范围之外，将对这种方法进行测试 在犬自发性OS患者中，在移植到儿童OS患者之前。