Augmenting T-cell immunotherapy outcomes in blood and solid tumor microenvironment in ART-suppressed HIV infection (immune/microenvironment)

项目摘要 接受有效抗逆转录病毒治疗的艾滋病毒感染者继续表现出残余免疫力， 与HIV阴性个体相比，激活和炎症。这种未解决的免疫激活和 免疫功能障碍与持续的骨髓活化、持续的I型干扰素信号传导和 并发症增加，如不良心脏事件或恶性肿瘤，尤其是在老年PLWH中 人口事实上，在抗逆转录病毒治疗中受到抑制的艾滋病毒携带者， 定义癌症（血液和实体癌），其中许多与共同病毒感染有关， 剂在当今时代，免疫疗法旨在重振或重新设计抗癌T细胞， 免疫反应有可能彻底改变癌症治疗。具体地，嵌合抗原受体 (CAR)T细胞疗法已成功治疗某些B细胞恶性肿瘤。然而直到最近 PLWH已被排除作为CAR T细胞疗法和其他癌症临床试验的候选者，主要是由于 缺乏先前的临床数据和GMP生产的障碍。对于实体癌，免疫检查点的使用 已经发现抑制疗法（ICT）在PLWH中是安全，但是抗癌T细胞的再活化是否 在ART上的残余激活的背景下，反应可以持续仍然未知。例如， 几个研究小组观察到，ART抑制后持续抑制I型干扰素， 增加CD8 T细胞反应。正如在CAR T细胞试验中，从大多数临床试验中排除PLWH， 测试新兴的ICT策略进一步增加了缺乏关于肿瘤内残留激活如何的数据， 微环境可能影响抗癌T细胞活化的程度。根据我们的初步数据， 本申请将检验这样的假设，即在ART期间残留的免疫激活是由升高的免疫应答介导的。 I型干扰素（IFN-I）刺激基因在肿瘤微环境中的表达，这将不利地 影响CAR T细胞治疗后的抗癌T细胞应答功能或抑制免疫检查- 点第一个具体目标将评估CART 19免疫疗法对基于血液的肿瘤的疗效。 自体B细胞恶性肿瘤和持续的I型干扰素信号传导对抗癌的影响 HIV感染的ART抑制的人源化小鼠体内的免疫应答。第二个具体目标是评估T细胞 抗PDL-1治疗后对患者来源的实体瘤的浸润和活化以及 HIV感染ART抑制的人源化小鼠中持续的I型干扰素信号传导在抗癌应答中的作用 vivo.最终，开发一种动物模型，以确定最佳抗癌T细胞活化的障碍， ART抑制后的细胞策略将提供一个重要的资源， 艾滋病病毒/艾滋病相关癌症患者的免疫疗法。此应用程序是唯一准备解决 NIH OAR优先考虑HIV如何影响相关合并症（例如恶性肿瘤）的治疗结果。

PROJECT SUMMARY Persons living with HIV (PLWH) on effective antiretroviral therapy (ART) continue to exhibit residual immune activation and inflammation as compared to HIV-negative individuals. This unresolved immune activation and immune dysfunction is associated with sustained myeloid activation, sustained type I interferon signaling, and an increase in co-morbidities such as adverse cardiac events or malignancies, especially in the aging PLWH population. Indeed, PLWH that are suppressed on ART remain at an increased risk for developing Non-AIDS defining cancers (blood and solid cancers), many of which are associated with a co-viral infection as the etiologic agent. In the current era, immunotherapies aimed at reinvigorating or re-engineering the anti-cancer T-cell immune response have the potential to revolutionize cancer treatment. Specifically, chimeric antigen receptor (CAR) T cell therapies have been successful in treating certain B cell malignancies. However, until very recently, PLWH have been excluded as candidates for CAR T cell therapy and other cancer clinical trials, largely due to lack of prior clinical data and hurdles to GMP manufacturing. For solid cancers, the use of immune checkpoint inhibition therapy (ICT) has been found to be safe in PLWH but whether reactivation of anti-cancer T-cell responses can be sustained in the context of residual activation on ART remains unknown. For example, it has been observed by several groups that inhibition of persistent type-I interferon after ART-suppression can increase CD8 T-cell responses. As in CAR T cell trials, the exclusion of PLWH from the majority of clinical trials testing emerging ICT strategies further adds to the lack of data on how residual activation within the tumor microenvironment may affect the degree of anti-cancer T-cell activation. Based on our preliminary data, this application will test the hypothesis that residual immune activation while on ART is mediated by elevated expression of type I interferon (IFN-I) stimulated genes in the tumor microenvironment, and that this will adversely affect the function of anti-cancer T-cell responses following CAR T-cell therapy or inhibition of immune check- points. The first specific aim will evaluate the efficacy of CART19 immunotherapy against blood-based autologous B cell malignancies and the impact of sustained type-I interferon signaling on the anti-cancer response in HIV-infected, ART-suppressed humanized mice in vivo. The second specific aim will evaluate T-cell infiltration and activation following anti-PDL-1 therapy against patient-derived solid tumors and the impact of sustained type-I interferon signaling in anti-cancer response in HIV-infected ART-suppressed humanized mice in vivo. Ultimately, the development of an animal model to identify barriers to activation of optimal anti-cancer T- cell strategies following ART-suppression will provide an important resource to create more effective immunotherapies for patients with HIV/AIDS-related cancers. This application is uniquely poised to address the NIH OAR priority on how HIV may impact therapy outcomes for associated co-morbidities (e.g. malignancies).