Next Generation Autologous TIL Cancer Therapy: Development of GMP manufacturing process

下一代自体 TIL 癌症疗法：GMP 制造工艺的开发

基本信息

批准号：
10472171
负责人：
RENE GONZALEZ
金额：
$ 100万
依托单位：
TRAMPOLINE PHARMA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10472171
关键词：
Adaptor Signaling Protein Address Adoptive Cell Transfers Advanced Malignant Neoplasm Affinity Antigen Targeting Antitumor Response Applications Grants Attention Australia Autologous Tumor-Infiltrating Lymphocyte Avidity Biological Assay Biological Sciences Biomanufacturing Canada Cell Line Cell Survival Cell Therapy Cell surface Cells Cellular immunotherapy Chemotherapy-Oncologic Procedure Clinical Clinical Trials Collaborations Colorado Contracts Cytokine Receptors Cytotoxic T-Lymphocytes Deposition Development Dose Eligibility Determination Engineered Gene Engineering Engraftment Europe Future Genetic Engineering Goals Head and neck structure Homing Human Immune Immunotherapy Infusion procedures Intellectual Property Interleukin-2 Japan Laboratories Lead Legal patent Licensing MHC antigen Malignant Neoplasms Medical Methods Modeling Mus MyD88 protein Patients Phase Phase I Clinical Trials Process Property Publishing Recording of previous events Recurrence Refractory Regimen Research Retroviral Vector Safety Signal Transduction Small Business Innovation Research Grant Solid Solid Neoplasm Stress Survival Rate T cell response T-Cell Receptor T-Lymphocyte Technology Therapeutic Therapy trial Toxic effect Tumor Antigens Tumor Immunity Tumor-Derived Tumor-Infiltrating Lymphocytes Tumor-infiltrating immune cells Universities Viral Vector Virus assay development base cancer clinical trial cancer therapy cancer type chemotherapy chimeric antigen receptor conditioning cytotoxic drug development engineered T cells exhaust exhaustion experience experimental study extracellular first-in-human gene delivery system immunogenic interest manufacturing facility manufacturing process melanoma member mouse model neoantigens neoplastic cell next generation novel operation patient subsets pre-clinical programs receptor response safety assessment sarcoma therapy development tumor tumor infiltrating lymphocyte therapy viral gene delivery

项目摘要

The overall goal of this Phase II SBIR grant proposal is to research and develop the GMP manufacturing process for next-generation tumor infiltrating lymphocyte (TIL) cancer therapeutic for solid tumors. In clinical trials, TIL-based immunotherapies have demonstrated tumor regression and increased survival rates against different cancer types. Despite these encouraging clinical results, durable antitumor responses are typically observed in a subset of patients with advanced cancers like melanoma. This stresses the need to develop more effective TIL-based strategies and to expand efficacy against different cancer types. TIL therapies are hindered in part by low TIL accumulation into tumors, low persistence, weak T cell receptor (TCR) affinity and/or avidity as well as the low expression of tumor antigens on the cell’s surface. Additionally, the presence of suppressive signals on T cells such as Lag3, Tim3, CD39, pose a major obstacle to generating effective and long-lived antitumor T cell responses. In our published and preliminary studies, activating MyD88 signaling in human or mouse T cells, increases antitumor activity and prolongs T cell survival. By fusing the high affinity CD8α (extracellular) to MyD88 (intracellular; CD8α:MyD88) we have developed a novel and universal platform that activates MyD88 signaling strictly upon the engagement of the TCR with the MHC-antigen on tumor cells. CD8α:MyD88 expression in TILs cells substantially increases responses to weak and suboptimal levels of tumor antigens including neoantigens, and in preliminary studies has demonstrated the extraordinary property of reducing the T cells entry into an ‘exhausted state’. Importantly, the use of the CD8α co-receptor represents a ‘universal’ approach to enhancing T cell responses, and can be used in patients regardless of the patient’s HLA type. Through this SBIR Phase II application, we propose the following aims. Aim 1 will research, develop, and manufacture GMP grade g-retroviral vectors. Here, we will generate high virus titer-producing CD8a:MyD88-EGFRt PG-13 cell lines, accompanying analytical assays, and manufacture the GMP CD8a:MyD88-EGFRt g-retroviral vectors. For this aim, we are partnering with a commercial contract development manufacturing organization (CDMO), Vigene Biosciences to generate GMP viral vectors. In Aim 2, we propose to develop and manufacture GMP CD8a:MYD88 engineered TILs (coR8:AMPTM TILs). In collaboration with the Gates Manufacturing Facility (GBF) at the University of Colorado Anschutz Medical Campus (UCAMC) we will conduct process & analytical assay, QC release assay, develop and manufacture of GMP grade coR8:AMPTM TILs. The successful completion of these aims will lead to the pre-IND and IND filings with the FDA for a Phase I clinical trial in patients with immune refractory solid tumors. This activity will be conducted in collaboration with the UCAMC’s Cell Therapy Operations Program (CTOP), Gates Biomanufacturing Facility, and our team members who have extensive experience in cell therapy drug development.

第二阶段 SBIR 拨款提案的总体目标是研究和开发 GMP 制造下一代肿瘤浸润淋巴细胞（TIL）癌症治疗实体瘤的过程。试验表明，基于 TIL 的免疫疗法已证明肿瘤消退并提高了生存率尽管有这些令人鼓舞的临床结果，但持久的抗肿瘤反应通常是不同的。在黑色素瘤等晚期癌症患者中观察到的这一现象强调了开发的必要性。更有效的基于 TIL 的策略并扩大针对不同癌症类型的疗效。部分原因是肿瘤中 TIL 积累低、持久性低、T 细胞受体 (TCR) 亲和力弱和/或亲合力以及细胞表面肿瘤抗原的低表达。 T 细胞上的抑制信号，如 Lag3、Tim3、CD39，对产生效率和在我们发表的初步研究中，激活 MyD88 信号传导。人类或小鼠 T 细胞，通过融合高亲和力提高抗肿瘤活性并延长 T 细胞存活时间。 CD8α（细胞外）到 MyD88（细胞内；CD8α:MyD88）我们开发了一个新颖且通用的平台它严格在 TCR 与肿瘤细胞上的 MHC 抗原结合时激活 MyD88 信号传导。 TIL 细胞中的 CD8α:MyD88 表达显着增加了对弱和次优水平的反应肿瘤抗原包括新抗原，并在初步研究中已证明了非凡的特性重要的是，CD8α 辅助受体的使用代表了减少 T 细胞进入“疲惫状态”。一种增强 T 细胞反应的“通用”方法，无论患者的病情如何，都可以用于患者 HLA 类型。通过此 SBIR II 期申请，我们提出以下目标：在这里，我们将开发和生产 GMP 级 g 逆转录病毒载体。 CD8a:MyD88-EGFRt PG-13 细胞系，伴随分析测定，并制造 GMP CD8a:MyD88-EGFRt g 逆转录病毒载体为此目的，我们正在与商业合同合作。开发制造组织 (CDMO)、Vigene Biosciences 旨在生成 GMP 病毒载体。 2，我们建议开发和生产 GMP CD8a:MYD88 工程化 TILs (coR8:AMPTM TILs)。与科罗拉多大学安舒茨医学院的盖茨制造工厂 (GBF) 合作校园 (UCAMC) 我们将进行工艺和分析测定、QC 放行测定、开发和制造 GMP 级 coR8:AMPTM TIL 的成功完成将导致 IND 前和 IND 申请。该活动将与 FDA 合作，在免疫难治性实体瘤患者中进行 I 期临床试验。与 UCAMC 的细胞治疗运营计划 (CTOP)、盖茨合作进行生物制造设施，以及我们在细胞治疗药物方面拥有丰富经验的团队成员发展。