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取得了进展，但胰腺癌患者仍然没有有效的选择接受治疗后，只有不到 10% 的患者能存活超过五年。在晚期实体瘤患者的子集中取得了积极的反应，代表着一个有希望的然而，低水平的抗原表达和免疫抑制性肿瘤。微环境损害抗原识别并限制 T 细胞的持久性和功能，阻碍一致性为了克服这些挑战，我们制定了改善抗肿瘤的策略。基于 T 细胞的平台中的反应在 80-85% 的胰腺肿瘤中表达，使得它是治疗胰腺癌的一个有吸引力的 TCR 靶点，我们已经验证了 T 的细胞溶解活性。用人类 HLA-A2 限制性 MSLN 特异性 TCR 改造的细胞，针对表达 MSLN 的胰腺肿瘤我们小组之前在小鼠胰腺模型中使用小鼠 Msln 特异性 TCR 进行的体外研究。癌症进一步证明工程化 T 细胞减少了体内肿瘤负荷，但缺乏持久性。寻求开发一种新型免疫疗法，将我们的 MSLN 特异性 TCR 与独特有效的联合疗法相结合合成 CD8α:MyD88 融合蛋白在转基因小鼠中的肿瘤反应性 T 细胞的刺激特性。表达 CD8α:MyD88 融合蛋白表明特定抗原会增加细胞因子的产生，与对照相比，增殖和细胞毒性，引起持久的肿瘤消退。作为胰腺癌的临床相关免疫治疗平台，我们将利用一种新型非病毒遗传在原代人体内共表达 MSLN 特异性 TCR 与 CD8α:MyD88 融合蛋白的工程方法 T 细胞的载体配置将通过评估稳定的 TCR 和 CD8α:MyD88 融合表面来优化。表达，以及 T 细胞表型、功能和体外对胰腺癌细胞的细胞毒性。优化的载体配置将在临床前动物模型中进行和测试，以评估安全性如果成功，我们的努力将带来创新性的新成果。免疫治疗策略，以克服阻碍胰腺显着改善的挑战癌症患者的结果。