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

项目总结 接受有效抗逆转录病毒治疗(ART)的艾滋病毒携带者(PLWH)继续表现出残留免疫 与艾滋病毒阴性的人相比，他们的激活和炎症程度更高。这种未解决的免疫激活和 免疫功能障碍与持续的髓系激活、持续的I型干扰素信号有关，以及 并发症的增加，如不良心脏事件或恶性肿瘤，特别是在老龄化的PLWH 人口。事实上，在抗逆转录病毒治疗中被抑制的PLWH仍然处于发展为非艾滋病的更高风险中 定义癌症(血癌和实体癌)，其中许多癌症与共同病毒感染有关，作为病因 探员。在当今时代，旨在重振或重新设计抗癌T细胞的免疫疗法 免疫反应有可能给癌症治疗带来革命性的变化。具体地说，嵌合抗原受体 (CAR)T细胞疗法在治疗某些B细胞恶性肿瘤方面取得了成功。然而，直到最近， PLWH被排除在CAR T细胞治疗和其他癌症临床试验的候选之外，主要是因为 缺乏先前的临床数据和GMP生产的障碍。对于实体癌，使用免疫检查点 抑制疗法(ICT)已被发现在PLWH中是安全的，但抗癌T细胞能否重新激活 在抗逆转录病毒药物残留激活的背景下，反应可以持续，但仍不清楚。例如，它有 已经被几个小组观察到，在ART抑制后抑制持久性I型干扰素可以 增强CD8 T细胞应答。正如在CAR T细胞试验中一样，将PLWH排除在大多数临床试验之外 测试新出现的ICT策略进一步增加了关于肿瘤内残留激活如何的数据的缺乏 微环境可能影响抗癌T细胞的活化程度。根据我们的初步数据，这 应用程序将检验这样一种假设，即在接受抗逆转录病毒治疗时残余免疫激活是由升高的 I型干扰素(IFN-I)刺激的基因在肿瘤微环境中的表达，这将对 影响CAR T细胞治疗或免疫检查抑制后抗癌T细胞反应的功能 积分。第一个具体目标是评估CART19免疫疗法对血源性疾病的疗效 自体B细胞恶性肿瘤与持续的I型干扰素信号在抗癌中的作用 HIV感染、ART抑制的人源化小鼠体内的反应。第二个具体目标是评估T细胞 抗PDL-1治疗对患者来源实体瘤的侵袭和活化及对其的影响 持续的I型干扰素信号在HIV感染ART抑制的人源化小鼠的抗癌反应中的作用 活着。最终，确定最佳抗癌T细胞激活障碍的动物模型的发展。 ART抑制后的细胞策略将提供重要的资源，以创造更有效的 艾滋病毒/艾滋病相关癌症患者的免疫疗法。此应用程序独一无二地准备解决 美国国立卫生研究院优先关注艾滋病毒可能如何影响相关并存疾病(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).