Antigen Specific T Cells

项目3 项目摘要 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的 化疗和/或放疗以进一步根除残留的白血病， 并溶解残留的肿瘤细胞，称为移植物抗白血病（GVL）效应。然而，高风险患者 或持续性疾病继续经历一个令人沮丧的预后，尽管BMT，范围从10-40%的生存率， 5年因此，开发用于骨髓恶性肿瘤的新疗法至关重要。T细胞免疫治疗后 使用病毒特异性细胞毒性T淋巴细胞的BMT在治疗病毒- BMT后相关疾病（包括EBV+淋巴瘤）。然而，只有有限的研究已经 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。的 表达CD 19的嵌合抗原受体（CAR）的T细胞的开发已经显示出显著的前景 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点来逃避免疫系统 抗原此外，这种方法只能靶向在细胞表面表达的肿瘤抗原，并且许多肿瘤抗原不能靶向在细胞表面表达的肿瘤抗原。 肿瘤相关抗原（TAA）是细胞内的。此外，到目前为止，CAR-T细胞疗法还没有被广泛应用。 CD 19-CAR T细胞在骨髓恶性肿瘤患者的临床上是成功的，因为CD 19-CAR T细胞已经用于骨髓恶性肿瘤患者。 所有.为了将T细胞治疗扩展到异基因BMT后的AML/MDS患者，我们开发了一种新的 重新激活和扩增对多种TAA具有特异性T细胞的策略：存活素、PRAME和WT 1， 总体上由>90%的髓样母细胞表达。我们认为同时针对多个TAA 将肿瘤免疫逃逸降至最低对BMT的兴趣也在增加，认为它是清除HIV-1的潜在手段， 从受感染的人的受感染的细胞，并实现HIV感染的功能性治愈。然而，中断 移植后ART与危及生命的HIV反弹有关。因此，我们建议重组 BMT后早期的免疫系统，过继转移离体扩增的TAA和HIV特异性T细胞， 携带CCR 5 Δ32突变的细胞将提供防止复发的保护，并且可以重建有效的免疫原性。 艾滋病病毒的细胞免疫反应，以防止这种不受控制的反弹。我们的主要假设是：（一） BMT后的GVL效应将通过靶向多个TAA的T细胞的过继转移来增强，以及（ii） 这种方法可以应用于HIV相关的恶性肿瘤， 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.在中，我们将从符合条件的BMT供体中产生并输注T细胞产品，这些产品靶向多个TAA（+/-） HIV阳性和HIV阴性AML/MDS患者。目的二是评价其抗肿瘤和抗病毒的临床疗效 和T细胞输注后的免疫应答。总之，这种方法可以使T细胞免疫疗法， 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.