Antigen Specific T Cells

抗原特异性 T 细胞

• 批准号: 10671624
• 负责人: Catherine M. Bollard
• 金额: $ 20.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-21 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10671624
• 关键词: AIDS related cancer; AML/MDS; Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adoptive Transfer; Allogeneic Bone Marrow Transplantation; Allogenic; Antigen Targeting; Antigens; B-Cell Acute Lymphoblastic Leukemia; B-Cell Antigen Receptor; Berlin; Binding; Biological Assay; Blood; Blood donor; Bone Marrow Transplantation; CAR T cell therapy; CD19 Antigens; CD19 gene; Cell Transplantation; Cell surface; Cells; Cellular immunotherapy; Chemotherapy and/or radiation; Clinical; Clinical Trials; Cytotoxic T-Lymphocytes; Development; Disease; Disease remission; Donor person; Dysmyelopoietic Syndromes; Eligibility Determination; Epitope spreading; Epstein-Barr Virus-Related Lymphoma; Flow Cytometry; Frequencies; HIV; HIV Antigens; HIV Genome; HIV Infections; HIV Seronegativity; HIV therapy; HIV-1; Hematologic Neoplasms; Hematopoietic stem cells; High Dose Chemotherapy; Immune; Immune mediated destruction; Immune response; Immune system; Immunity; Immunoassay; Immunotherapy; In complete remission; Incidence; Individual; Infection; Infusion procedures; Interruption; Length; Life; Malignant Neoplasms; Measures; Mutation; Myelogenous; Myeloproliferative disease; Natural Resistance; Patient-Focused Outcomes; Patients; Persons; Phase I Clinical Trials; Phase I/II Clinical Trial; Population; Prognosis; Proteins; Regimen; Registries; Relapse; Residual Neoplasm; Residual state; Resistance to infection; Risk; Safety; Specificity; Surface Antigens; T cell receptor repertoire sequencing; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Training; Treatment-related toxicity; Tumor Antigens; Tumor Escape; Tumor Expansion; Variant; Viral; Virus; WT1 gene; antigen-specific T cells; antiretroviral therapy; antiviral immunity; cancer/testis antigen; cell killing; chimeric antigen receptor; chimeric antigen receptor T cells; conditioning; digital; effective therapy; enzyme linked immunospot assay; experience; graft vs leukemia effect; high risk; human disease; immune reconstitution; improved outcome; in vivo; interest; leukemia; neoplastic cell; novel; novel strategies; novel therapeutics; personalized medicine; post-transplant; prevent; receptor; reconstitution; relapse prevention; response; safety and feasibility; safety assessment; success; survivin; targeted treatment; tumor

Project 3 Project Summary Bone Marrow Transplant (BMT) has improved outcomes for patients with high risk or relapsed acute myeloid leukemia (AML) and Myelodysplastic Syndrome (MDS). This is due to both the ability to give high doses of chemotherapy and/or radiation to further eradicate residual leukemia and because the donor cells may detect and lyse residual tumor cells, termed the graft-versus-leukemia (GVL) effect. However, patients with high risk or persistent disease continue to experience a dismal prognosis despite BMT, ranging from 10-40% survival at 5 years. Thus, developing novel therapeutics for myeloid malignancies is critical. T-cell immunotherapy post BMT using virus-specific cytotoxic T lymphocytes, has been highly successful for the treatment of virus- associated diseases (including EBV+ lymphomas) after BMT. However, only limited studies have been conducted utilizing T-cell therapies targeting non-viral tumor-associated antigens for patients after BMT. The development of T-cells expressing a chimeric antigen receptor (CAR) for CD19 has shown significant promise for patients with B-cell acute lymphoblastic leukemia (ALL). However, greater than 40% of the responses are not durable because the tumor evades the immune system by downregulating or modulating expressed target antigens. Furthermore, this approach can only target tumor antigens expressed on the cell surface and many tumor-associated antigens (TAAs) are intracellular. Furthermore, to date, CAR-T-cell therapy has not been as successful clinically for patients with myeloid malignancies as CD19-CAR T cells have been for patients with ALL. To extend T cell therapy to patients with AML/MDS post allogeneic BMT, we have developed a novel strategy to reactivate and expand T cells with specificity for multiple TAAs: Survivin, PRAME and WT1, which collectively are expressed by >90% of myeloid blasts. We reason that targeting multiple TAAs simultaneously will minimize tumor immune escape. Interest in BMT is also building as a potential means to clear HIV-1- infected cells from infected persons and achieve a functional cure of HIV infection. However, interruption of ART post-transplant is associated with life-threatening HIV rebound. Therefore, we propose that reconstitution of the immune system early post-BMT with the adoptive transfer of ex vivo expanded TAA and HIV-specific T cells carrying the CCR5Δ32 mutation would confer protection from relapse AND could reconstitute an effective HIV cellular immune response to prevent such uncontrolled rebound. Our central hypotheses are: (i) that the GVL effect post BMT will be enhanced by adoptive transfer of T-cells targeting multiple TAAs and (ii) that this approach can be applied to HIV-associated malignancies and will be effective for targeting multiple HIV and tumor associated antigens. We will test these hypotheses in clinical trials proposed for Aim 1. In we will generate and infuse T-cell products from eligible BMT donors that target multiple TAAs (+/- HIV) to HIV+ and HIVneg patients with AML/MDS. In Aim 2 we will evaluate the anti tumor and antiviral clinical and immune responses after T cell infusion. In summary, this approach may enable T-cell immunotherapy to become more broadly applied to all patients with malignancies after BMT.

项目3 项目概要 骨髓移植 (BMT) 改善了高危或复发性急性髓系白血病患者的预后 白血病（AML）和骨髓增生异常综合征（MDS）。这是由于能够给予高剂量 化疗和/或放疗以进一步根除残留的白血病，并且因为供体细胞可能检测到 并裂解残留的肿瘤细胞，称为移植物抗白血病（GVL）效应。然而，高危患者 尽管进行 BMT，但持续性疾病仍继续经历令人沮丧的预后，生存率在 10-40% 之间 5年。因此，开发针对骨髓恶性肿瘤的新疗法至关重要。 T细胞免疫治疗后 BMT 使用病毒特异性细胞毒性 T 淋巴细胞，在治疗病毒感染方面取得了巨大成功。 BMT 后的相关疾病（包括 EBV+ 淋巴瘤）。然而，仅进行了有限的研究 利用针对 BMT 后患者的非病毒肿瘤相关抗原的 T 细胞疗法进行治疗。这 表达 CD19 嵌合抗原受体 (CAR) 的 T 细胞的开发已显示出巨大的前景 适用于 B 细胞急性淋巴细胞白血病 (ALL) 患者。然而，超过 40% 的答复是 不持久，因为肿瘤通过下调或调节表达的靶标来逃避免疫系统 抗原。此外，这种方法只能针对细胞表面表达的肿瘤抗原，并且许多 肿瘤相关抗原（TAA）位于细胞内。此外，迄今为止，CAR-T细胞疗法还没有达到预期的效果。 CD19-CAR T 细胞已在治疗骨髓恶性肿瘤患者中取得了临床成功 全部。为了将 T 细胞疗法扩展到同种异体 BMT 后的 AML/MDS 患者，我们开发了一种新型 重新激活和扩增 T 细胞的策略，对多种 TAA 具有特异性：Survivin、PRAME 和 WT1，其中 > 90% 的髓系母细胞共同表达。我们认为同时针对多个 TAA 将最大限度地减少肿瘤的免疫逃逸。人们对 BMT 作为清除 HIV-1 的潜在手段的兴趣也在增强 来自感染者的感染细胞并实现艾滋病毒感染的功能性治愈。然而，中断 移植后抗逆转录病毒疗法与危及生命的艾滋病毒反弹有关。因此，我们建议重组 BMT 后早期的免疫系统通过过继转移体外扩增的 TAA 和 HIV 特异性 T 携带 CCR5Δ32 突变的细胞将提供防止复发的保护，并且可以重建有效的 HIV细胞免疫反应可以防止这种不受控制的反弹。我们的中心假设是：（i） BMT 后的 GVL 效应将通过靶向多个 TAA 的 T 细胞过继转移得到增强，并且 (ii) 这种方法可以应用于与艾滋病毒相关的恶性肿瘤，并且可以有效地靶向治疗 多种 HIV 和肿瘤相关抗原。我们将在临床试验中测试这些假设 目标 1. 我们将从合格的 BMT 捐赠者那里生成并注入 T 细胞产品，这些产品针对多个 TAA（+/- HIV）到患有 AML/MDS 的 HIV+ 和 HIVneg 患者。目标2我们将评估抗肿瘤和抗病毒临床 以及 T 细胞输注后的免疫反应。总之，这种方法可能使 T 细胞免疫疗法能够 更广泛地应用于 BMT 后的所有恶性肿瘤患者。