Anti-Sox2 immunotherapy to prevent multiple myeloma relapse

抗 Sox2 免疫疗法预防多发性骨髓瘤复发

• 批准号: 10044600
• 负责人: Alfred L. Garfall
• 金额: $ 42.39万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044600
• 关键词: Aftercare; Alleles; Antigens; Autologous Stem Cell Transplantation; B-Lymphocytes; Behavior; Blood; Blood Cells; Bone Marrow; CD19 gene; CD8B1 gene; Cell Therapy; Cells; Cellular biology; Cessation of life; Clinical; Clinical Data; Clinical Trials; Clone Cells; Data; Data Set; Dependence; Development; Disease; Engraftment; Epitope spreading; Exhibits; Gene-Modified; Goals; Growth; Hematologic Neoplasms; Human; Immune response; Immunity; Immunotherapy; In Vitro; Indolent; Malignant Neoplasms; Minority; Modeling; Modernization; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mus; Oncogenes; Paper; Pathogenesis; Patients; Peptides; Phase; Phase I Clinical Trials; Phenotype; Plasma Cell Neoplasm; Plasma Cells; Pre-Clinical Model; Preclinical Testing; Progression-Free Survivals; Property; Public Health; Refractory; Relapse; Residual Tumors; Residual state; Risk; Sampling; Specificity; Specimen; Suggestion; T cell response; T cell therapy; T-Lymphocyte; Testing; Transgenic Organisms; Translating; Translations; Vaccine Therapy; Validation; Xenograft procedure; base; cancer therapy; cellular engineering; cellular transduction; chimeric antigen receptor T cells; clinical candidate; clinical translation; clinically relevant; disorder control; effective therapy; engineered T cells; exceptional responders; immunogenic cell death; immunotherapy trials; improved; improved outcome; in vitro Assay; in vivo; innovation; insight; mortality; mouse model; novel; novel therapeutics; pomalidomide; pre-clinical; prevent; research clinical testing; response; stem cells; therapeutic candidate; therapy development; tumor immunology

PROJECT SUMMARY/ABSTRACT Multiple myeloma (MM) is a hematologic malignancy of bone marrow plasma cells that is almost universally fatal. New therapies have improved survival and enabled initial disease control in almost all patients. Despite this progress, relapse with eventually fatal disease remains nearly inevitable. New treatments that specifically target the mechanisms of relapse have potential to amplify the incremental survival gains achieved with modern MM therapy. This proposal furthers a long-term goal to develop an immunotherapy that prevents MM relapse by targeting the stem-cell antigen Sox2. Prior studies and preliminary data show that post-treatment residual MM cells depend on Sox2 for survival in vivo and that anti-Sox2 immune responses may prevent development of MM from its indolent precursor condition MGUS. In a pilot clinical trial where anti-CD19 CAR T cells were used to target rare clonogenic MM cells, durable anti-Sox2 B and T cell responses were observed specifically in an extraordinary responder who is clinically MM-free five years post-treatment despite <100 days of in vivo CAR activity (Garfall et al NEJM 2015; Garfall et al JCI Insight 2018). This result is likely explained by CAR-induced immunogenic cell death, leading to durable and clinically active anti-Sox2 immunity. The hypothesis underlying this proposal is that anti-Sox2 T cells can prevent MM relapse by constraining or eliminating clonogenic Sox2- expressing MM cells that persist after cytoreductive therapy. To test this hypothesis, Sox2-specific T cells will be isolated from MGUS patients and long-term responders to CAR T cells (anti-BCMA and/or anti-CD19), using clinical data and specimens from our practice and ongoing MM clinical trials. Anti-Sox2 T cells will be character- ized for peptide and HLA specificity, and paired anti-Sox2 TCRαβ heterodimers will be cloned, sequenced, and functionally validated for Sox2 reactivity in vitro. Promising TCRs will be nominated for in vivo validation based on their in vitro antigen reactivity and HLA restriction. MM patient-derived xenografts (PDX) will be generated in MISTRG6 mice, which support multilineage human bone marrow engraftment and are uniquely suited to the microenvironment dependencies of MM PDXs. Adoptively transferred T cells transduced with anti-Sox2 TCRs will be tested in PDXs for their ability to prevent secondary PDX engraftment as a model of clonogenic growth required for MM relapse. Anti-Sox2 TCRs with validated ability to prevent MM relapse in preclinical models would be candidates for clinical translation as TCR-engineered cellular therapies; likewise, validated antigenic Sox2 peptides could be translated to vaccine therapies. These candidate therapeutics would have broad potential applications in MM and other cancers where Sox2 has emerged as an important oncogene. This collaborative proposal assembles access to unique clinical samples, specialized capabilities in human T cell biology and can- cer immunology, and expertise to rapidly translate findings to a phase 1 clinical trial.

项目摘要/摘要 多发性骨髓瘤（MM）是几乎普遍致命的骨髓浆细胞的血液系统恶性肿瘤。 新疗法的生存率提高了，几乎所有患者都可以控制初始疾病。尽管如此 进展，有时与致命疾病的继电器几乎是不可避免的。专门针对的新疗法 退休机制有可能扩大使用现代MM实现的增量生存利益 治疗。该提议进一步发展了开发免疫疗法的长期目标，该免疫疗法可防止MM接力 靶向干细胞抗原Sox2。先前的研究和初步数据表明，治疗后残留MM 细胞依赖Sox2在体内生存，抗SOX2免疫反应可能会阻止MM的发展 从其懒惰的前体状态mgus。在一项试验临床试验中，抗CD19 CAR T细胞用于 靶向罕见的克隆性MM细胞，耐用的抗SOX2 B和T细胞反应在 非凡的响应者在治疗后五年无临床MM <100天的体内汽车 活动（Garfall等人2015； Garfall等人JCI Insight 2018）。该结果可能通过汽车引起的解释 免疫原性的细胞死亡，导致耐用和临床活跃的抗SOX2免疫史。基础的假设 该建议是，抗SOX2 T细胞可以通过约束或消除克隆性SOX2-来防止MM继电器。 表达在细胞还原治疗后持续存在的MM细胞。为了检验该假设，SOX2特异性T细胞将是 使用MGUS患者和对CAR T细胞的长期响应者（抗BCMA和/或抗CD19）分离出来 我们的实践和正在进行的MM临床试验中的临床数据和标本。抗SOX2 T细胞将是特征 将肽和HLA特异性iz iz和配对的抗SOX2TCRαβ异二聚体进行克隆，测序，并且 在体外对SOX2反应性的功能验证。有希望的TCR将获得基于体内验证的提名 在其体外抗原反应性和HLA限制上。 MM患者衍生的Xenographictic（PDX）将在 Mistrg6小鼠，支持多琳的人体骨髓植入，非常适合 MM PDX的微环境依赖性。采用抗SOX2 TCR转移的T细胞转移 将在PDXS中测试其防止继发性PDX植入的能力 毫米缓解所需。具有验证能力预防临床前模型中MM缓解能力的抗SOX2 TCR将 作为TCR工程细胞疗法的临床翻译候选者；同样，经过验证的抗原Sox2 肽可以转化为疫苗疗法。这些候选疗法将具有广泛的潜力 在MM和其他癌症中，Sox2已成为重要的癌基因中的应用。这个合作 提案组装访问独特的临床样本，人类T细胞生物学方面的专门功能和可以 CER免疫学和专业知识将发现快速转化为1期临床试验。