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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）

基本信息

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
项目类别：
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

项目摘要

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).

项目总结