Antigen Specific T Cells

项目3 项目摘要 骨髓移植(BMT)改善了高危或复发急性髓系患者的预后 白血病(AML)和骨髓增生异常综合征(MDS)。这是因为既有能力给予高剂量的 化疗和/或放射以进一步根除残留白血病，因为捐赠者细胞可能会检测到 溶解残留的肿瘤细胞，称为移植物抗白血病(GVL)效应。然而，高危患者 或持续性疾病继续经历惨淡的预后，尽管BMT，从10%到40%的存活率不等 五年了。因此，开发治疗髓系恶性肿瘤的新疗法是至关重要的。T细胞免疫治疗后 骨髓移植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极大的成功。 骨髓移植后相关疾病(包括EBV+淋巴瘤)。然而，只有有限的研究被 利用针对非病毒肿瘤相关抗原的T细胞疗法对骨髓移植后的患者进行治疗。这个 表达CD19嵌合抗原受体(CAR)的T细胞的发展显示出重大的前景 适用于B细胞急性淋巴细胞白血病(ALL)患者。然而，超过40%的回复是 不耐久，因为肿瘤通过下调或调节表达的靶点来逃避免疫系统 抗原。此外，这种方法只能针对细胞表面表达的肿瘤抗原和许多 肿瘤相关抗原(TAA)位于细胞内。此外，到目前为止，CAR-T细胞疗法还没有像 作为CD19-CAR T细胞，CD19-CAR T细胞在临床上成功应用于髓系恶性肿瘤患者 全。为了将T细胞治疗扩展到异基因骨髓移植后AML/MDS患者，我们开发了一种新的 重新激活和扩增具有多个TAA特异性的T细胞的策略：Survivin、PRAME和WT1，其中 90%的髓系母细胞共同表达。我们的理由是同时瞄准多个TAA 将最大限度地减少肿瘤免疫逃逸。人们对骨髓移植的兴趣也越来越大，因为它是清除HIV-1的潜在手段- 从感染者身上分离出受感染的细胞，实现艾滋病毒感染的功能性治愈。然而，中断 ART移植后与危及生命的艾滋病毒反弹有关。因此，我们建议重组 体外扩增TAA和HIV特异性T细胞过继转移对骨髓移植后早期免疫系统的影响 携带CCR5Δ32突变的细胞将提供预防复发的保护，并可能重建有效的 艾滋病毒细胞免疫反应防止这种失控反弹。我们的中心假设是：(I) 靶向多个TAA的T细胞过继转移将增强骨髓移植后的GVL效应 这种方法可以应用于艾滋病毒相关的恶性肿瘤，并将有效地靶向 多种HIV和肿瘤相关抗原。我们将在拟议的临床试验中测试这些假设 目标1.我们将从符合条件的骨髓移植捐赠者那里产生并输注针对多个TAA(+/-)的T细胞产品 HIV+和患有AML/MDS的HIVneg患者。在目标2中，我们将评估抗肿瘤和抗病毒的临床应用。 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 更广泛地应用于所有BMT后的恶性肿瘤患者。

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.