Targeting HIV and EBV Antigens in Patients with HIV Lymphoma

项目总结 在这一应用中，我们提出了一种新的自体造血干细胞移植后的细胞治疗方法。 (ASCT)针对多种HIV抗原(GAG、POL和NEF)的HIV相关淋巴瘤(HRL)，目标是 耗尽持续的艾滋病毒感染。此外，我们还将针对EBV淋巴瘤相关的T细胞进行输注 抗原(LMP1、LMP2、EBNA1、BARF1)，如果淋巴瘤EBV阳性。这两个中心的调查人员都在 联盟已经开发和优化了针对EBV抗原的策略，这些策略已经显示出有希望的 结果自体移植后给免疫功能正常的EBV+淋巴瘤患者输注。最近，我们 已经制定了针对HIV的免疫治疗策略，并在一项正在进行的研究中安全地注入了 向HIV+患者提供自体HIV特异性T细胞，目的是根除病毒库。AS 抗逆转录病毒治疗不能消除病毒库中的艾滋病毒，艾滋病毒+淋巴瘤患者仍在 免疫受损的人假设我们可以利用淋巴耗尽的环境 ASCT将自体HIV特异性T细胞注入到一个促进扩张和持久性的环境中。 此外，由于近一半的HRL是EBV阳性的，我们将在这个队列中注入EBV特异性T细胞，目标是 减少复发的风险。在目标1中，我们将进行两个ARM第二阶段的临床试验，在这个试验中，我们将给HIV HIV淋巴瘤患者的特异性T细胞在自体移植后早期给所有患者，也将给予自体 HRL为EBV+ve的患者的EBV特异性T细胞。在目标2中，我们将描绘坚持不懈和 过继转移的T细胞的抗病毒作用。这项研究的结果将为以下方法提供参考 根除艾滋病毒蓄积物，增强艾滋病毒相关淋巴瘤患者的免疫功能。这 由于艾滋病毒淋巴瘤的发病率，该策略需要进行多中心试验，我们的建议是可行的，因为 CTN此前曾对HIV淋巴瘤的自体移植进行过一项研究。此外，我们的中心有 具有开发、实施和完成复杂生物疗法的丰富经验 基因治疗产品，并成功赞助和实施了100多种细胞和基因治疗 50多名研究人员发起的INDS研究，包括II期多中心研究。

PROJECT SUMMARY In this application we propose a novel cellular therapy after autologous hemopoietic stem cell transplant (ASCT) for HIV related lymphoma (HRL) targeting multiple HIV antigens (gag, pol and nef) with the goal of depleting persistent HIV infection. In addition, we will also infuse T cells targeting EBV lymphoma associated antigens (LMP1, LMP2, EBNA1, BARF1) if the lymphoma is EBV positive. Investigators in both centers in this consortium have developed and optimized strategies to target EBV antigens which have shown promising results when infused post autograft to immunocompetent individuals with EBV+ lymphoma. More recently we have developed immunotherapy strategies to target HIV and in an ongoing study have safely infused autologous HIV specific T cells to HIV+ individuals with the goal of eradicating the virus reservoir. As antiretroviral therapy does not eliminate HIV in viral reservoirs and HIV+ individuals with lymphoma remain immunologically impaired we hypothesize that we can take advantage of the lympodepleted environment post ASCT to infuse autologous HIV specific T cells in a milieu that will promote expansion and persistence. Moreover, as nearly half of HRLis EBV positive we will infuse EBV specific T cells in this cohort with the goal of reducing the risk of relapse. In Aim 1 we will conduct a two arm Phase II clinical trial in which we will give HIV specific T cells to patients with HIV lymphoma early post autograft to all patients and will also give autologous EBV-specific T cells to patients with an HRL that is EBV+ve. In Aim 2, we will delineate the persistence and the anti-viral effects of the adoptively transferred T cells. The results of this study will inform approaches to eradicate the HIV reservoir and enhance immune function in patients with HIV related lymphomas. This strategy requires a multicenter trial due to the incidence of HIV lymphoma and our proposal is feasible since CTN has previously conducted a study of autograft in HIV lymphoma. Furthermore, our centers have extensive experience developing, implementing and completing complex biological therapies with cell and gene therapy products and have successfully sponsored and implemented over 100 cell and gene therapy studies under more than 50 investigator initiated INDs, including Phase II multicenter studies.