MyD88 fusion protein with antigen specific T Cell therapy for enhanced response in solid tumors

MyD88 融合蛋白与抗原特异性 T 细胞疗法可增强实体瘤的反应

基本信息

批准号：
10080228
负责人：
Samantha Dunmire
金额：
$ 39.74万
依托单位：
LUMINARY THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-08 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080228
关键词：
Affect Affinity Animal Model Antigen Receptors Antigens Antitumor Response Autologous Biotechnology CD4 Positive T Lymphocytes CD8 receptor CD8-Positive T-Lymphocytes CD8B1 gene Cancer Prognosis Cell Line Cell Therapy Cell model Cell physiology Cells Chimeric Proteins Clinical Trials Cytotoxic T-Lymphocytes Data Enhancers Exhibits Future Gene Transfer Genetic Engineering HLA-A2 Antigen Human Human Resources Immune Immune signaling Immunosuppression Immunotherapeutic agent Immunotherapy Impairment In Vitro Inflammatory Longevity Malignant neoplasm of pancreas Membrane Memory Methods Mus Pancreatic Ductal Adenocarcinoma Pathway interactions Patient-Focused Outcomes Peptides Phase Phenotype Physiologic pulse Production Property Protein Engineering Publishing Safety Signal Transduction Solid Neoplasm Specificity Stains Study models Surface Survival Rate T Chain T cell therapy T-Cell Proliferation T-Cell Receptor T-Lymphocyte Technology Technology Transfer Testing Therapeutic Toxic effect Transgenic Mice Transgenic Organisms Tumor Burden Validation Variant Work Xenograft procedure advanced pancreatic cancer antigen-specific T cells base cancer therapy cell killing chimeric antigen receptor clinically relevant cytokine cytotoxic cytotoxicity density design effective therapy efficacy testing engineered T cells exhaustion experience improved in vitro activity in vivo innovation mesothelin mouse model neoplastic cell novel outcome forecast overexpression pancreatic cancer cells pancreatic cancer model pancreatic cancer patients pancreatic neoplasm patient subsets peripheral tolerance pre-clinical prevent protein aminoacid sequence receptor response stem success technological innovation tumor tumor microenvironment tumor-immune system interactions vector virtual

项目摘要

Abstract Despite recent advances in cancer treatment, patients with pancreatic cancer still do not have effective options for treatment and fewer than 10% survive more than five years. T cell receptor (TCR) based therapies have achieved positive responses in a subset of patients with advanced solid tumors, representing a promising approach for pancreatic cancer. However, low level antigen expression and the immunosuppressive tumor microenvironment impair antigen recognition and limit T cell persistence and function, impeding consistent success against solid tumors. To surmount these challenges, we have devised a strategy to improve anti-tumoral responses in a T cel- based platform. Mesothelin (MSLN) is expressed by 80-85% of pancreatic tumors, making it an attractive TCR target for the treatment of pancreatic cancer. We have validated the cytolytic activity of T cells engineered with human HLA-A2 restricted MSLN specific TCRs against MSLN expressing pancreatic tumor cells in vitro. Previous work from our group with murine Msln specific TCRs in a mouse model of pancreatic cancer further demonstrated engineered T cells reduced tumor burden in vivo but lacked persistence. We thus seek to develop a novel immunotherapy that combines our MSLN specific TCRs with the uniquely potent co- stimulatory properties of a synthetic CD8α:MyD88 fusion protein. In transgenic mice, tumor reactive T cells expressing the CD8α:MyD88 fusion protein demonstrate antigen specific increases in cytokine production, proliferation, and cytotoxicity, eliciting durable tumor regression compared to controls. To evaluate this approach as a clinically relevant immunotherapy platform for pancreatic cancer we will utilize a novel non-viral genetic engineering approach to co-express MSLN specific TCRs with the CD8α:MyD88 fusion protein in primary human T cells. Vector configuration will be optimized by evaluating stable TCR and CD8α:MyD88 fusion surface expression, as well as T cell phenotype, function, and cytotoxicity against pancreatic cancer cells in vitro. Optimized vector configurations will be carried forward and tested in preclinical animal models to evaluate safety and efficacy in support of follow-on IND enabling studies. If successful, our efforts will lead to an innovative new immunotherapeutic strategy to overcome challenges that have prevented meaningful improvement in pancreatic cancer patient outcomes.

抽象的尽管癌症治疗最近进展，但胰腺癌患者仍然没有有效的选择用于治疗，不到10％的人存活超过五年。基于T细胞受体（TCR）疗法具有在患有晚期实体瘤患者的一部分中达到了阳性反应，代表了承诺胰腺癌的方法。但是，低水平的抗原表达和免疫抑制肿瘤微环境会损害抗原识别并限制T细胞的持久性和功能，阻碍一致对实体瘤的成功。为了克服这些挑战，我们制定了一种改善反肿瘤的策略基于T CEL的平台的响应。间皮素（MSLN）由80-85％的胰腺肿瘤表达，使它是治疗胰腺癌的有吸引力的TCR靶标。我们已经验证了T 用人HLA-A2设计的细胞将MSLN特异性TCR限制为表达胰腺肿瘤的MSLN 细胞体外。胰腺模型中的小鼠MSLN特异性TCR的先前工作癌症进一步证明了工程的T细胞可减少体内肿瘤燃烧，但缺乏持久性。我们这样寻求开发一种新型的免疫疗法，将我们的MSLN特异性TCR与独特的潜在共同共同结合在一起合成CD8α的刺激特性：MyD88融合蛋白。在转基因小鼠中，肿瘤反应性T细胞表达CD8α：MyD88融合蛋白表现出细胞因子产生的抗原特异性增加，与对照组相比，增殖和细胞毒性，引起耐用的肿瘤消退。评估这种方法作为胰腺癌临床相关的免疫疗法平台，我们将使用一种新型的非病毒通用性与CD8α的共表达MSLN特异性TCR的工程方法：原代人中的MyD88融合蛋白 T细胞。矢量配置将通过评估稳定的TCR和CD8α：MYD88融合表面进行优化在体外，对胰腺癌细胞的表达以及T细胞表型，功能和细胞毒性。优化的矢量配置将在临床前动物模型中进行并测试以评估安全性并轻松支持后续研究。如果成功，我们的努力将导致创新的新免疫治疗策略以克服挑战，这些挑战阻止了胰腺的有意义改善癌症患者的结果。