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

在 ART 抑制的 HIV 感染中增强血液和实体瘤微环境中的 T 细胞免疫治疗效果（免疫/微环境）

• 批准号: 10620011
• 负责人: Dario C Altieri
• 金额: $ 12.42万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620011
• 关键词: AIDS related cancer; Address; Affect; Aging; Animal Model; Autologous; B lymphoid malignancy; Blood; CAR T cell therapy; CD34 gene; CD8-Positive T-Lymphocytes; Cardiac; Cellular immunotherapy; Clinical Data; Clinical Trials; Data; Engineering; Etiology; Event; Exclusion; Exhibits; Generations; Genes; Growth; HIV; HIV Infections; HIV Seronegativity; Hematopoietic Neoplasms; Hematopoietic stem cells; Hodgkin Disease; Human Herpesvirus 4; Immune; Immune System Diseases; Immune response; Immunotherapy; Impact evaluation; Individual; Inflammation; Interferon Type I; Interferons; Knowledge; Malignant Neoplasms; Mediating; Modeling; Myelogenous; Outcome; Patients; Persons; Population; Publishing; Research; Residual state; Resources; Risk; Signal Transduction; Solid; Solid Neoplasm; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Tissues; Tumor-infiltrating immune cells; Umbilical Cord Blood; United States National Institutes of Health; Viral; Virus Diseases; animal model development; anti-PD-L1; anti-cancer; antiretroviral therapy; base; cancer clinical trial; cancer immunotherapy; cancer therapy; checkpoint inhibition; chimeric antigen receptor T cells; comorbidity; compare effectiveness; efficacy evaluation; high risk; humanized mouse; immune activation; immunotherapy trials; in vivo; mouse model; novel; reconstitution; response; therapy outcome; tool; tumor microenvironment; tumor-immune system interactions

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).

项目概要 接受有效抗逆转录病毒治疗 (ART) 的艾滋病毒感染者 (PLWH) 继续表现出残余免疫 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激活、持续的 I 型干扰素信号传导以及 不良心脏事件或恶性肿瘤等合并症增加，尤其是老年感染者 人口。事实上，接受抗逆转录病毒疗法抑制的感染者患非艾滋病的风险仍然增加 定义癌症（血液癌和实体癌），其中许多与作为病因的共病毒感染有关 代理人。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。具体而言，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 被排除在 CAR T 细胞疗法和其他癌症临床试验候选者名单之外，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，使用免疫检查点 抑制疗法 (ICT) 已被发现对 PLWH 是安全的，但抗癌 T 细胞的重新激活是否有效？ 在 ART 残留激活的情况下反应能否持续仍未知。例如，它有 几个小组观察到，ART 抑制后持续抑制 I 型干扰素可以 增加 CD8 T 细胞反应。与 CAR T 细胞试验一样，大多数临床试验都将感染者排除在外 测试新兴的 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 微环境可能会影响抗癌T细胞的激活程度。根据我们的初步数据，这 应用程序将测试以下假设：接受 ART 时残余免疫激活是由升高介导的 I 型干扰素 (IFN-I) 刺激肿瘤微环境中基因的表达，这会对肿瘤微环境产生不利影响。 影响 CAR T 细胞治疗后的抗癌 T 细胞反应功能或抑制免疫检查- 点。第一个具体目标将评估 CART19 免疫疗法针对血液基病毒的疗效 自体 B 细胞恶性肿瘤和持续 I 型干扰素信号传导对抗癌的影响 感染艾滋病毒、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 针对患者源性实体瘤的抗 PDL-1 治疗后的浸润和激活及其影响 在 HIV 感染的 ART 抑制人源化小鼠的抗癌反应中持续 I 型干扰素信号传导 体内。最终，开发动物模型来识别最佳抗癌T-激活的障碍 ART抑制后的细胞策略将为创造更有效的细胞策略提供重要资源 针对艾滋病毒/艾滋病相关癌症患者的免疫疗法。该应用程序专门用于解决 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。