IL-12-producing cytokine factories induce precursor exhausted T cells and elimination of primary and metastatic tumors.

IF 10.3 1区 医学 Q1 IMMUNOLOGY
Amanda Nash, Jonathon DeBonis, Danna Murungi, Bertha Castillo, Boram Kim, Fangheng Hu, Courtney Chambers, Annie Nguyen, Andrea Hernandez, Zeshi Wang, Peter D Rios, Sofia Ghani, Ira Joshi, Douglas Isa, Ningbo Zheng, Weiyi Peng, Oleg A Igoshin, Jose Oberholzer, H Courtney Hodges, Nathan Reticker-Flynn, Omid Veiseh
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引用次数: 0

Abstract

Background: Curative responses to immunotherapy require the generation of robust systemic immunity with limited toxicity. Recruitment of T cell populations such as precursor exhausted T cells (Tpex) from lymphoid tissues to tumors is a hallmark of effective treatment. However, the ability to efficiently induce this recruitment is lacking in current immunotherapy approaches. Furthermore, systemic administration of immunotherapies frequently results in dose-limiting toxicities, yielding an inadequate therapeutic window for eliciting durable responses.

Methods: In this investigation, we evaluated the safety and antitumor efficacy of locally administered interleukin 12 (IL-12) using a clinically translatable cytokine delivery platform (NCT05538624) to identify Tpex recruitment capabilities at tolerable cytokine doses.

Results: We show IL-12 cytokine factories can effectively treat a broad spectrum of cancer types. Single-cell RNA sequencing data suggests that the antitumor efficacy seen in our studies was due to retinal pigmented epithelial cells-mIL12 treatment inducing differentiation of Tpex cells within the tumor microenvironment. When administered in combination with checkpoint therapy, IL-12 cytokine factory treatment generated systemic abscopal immunity, preventing subcutaneous tumor outgrowth in 8/9 mice with colorectal cancer and lung metastasis in mice with melanoma. Furthermore, this platform was well tolerated in a non-human primate without signs of toxicity.

Conclusions: Our new immunotherapy approach provides a robust strategy for inducing Tpex recruitment and systemic immunity against a range of solid peritoneal malignancies, many incurable with current immunotherapy strategies. Notably, these features were achieved using IL-12, and by leveraging our technology, we avoided the toxicities that have prevented the translation of IL-12 to the clinic. Our findings provide a strong rationale for the clinical development of IL-12 cytokine factories.

产生il -12的细胞因子工厂诱导前体耗竭T细胞和原发性和转移性肿瘤的消除。
背景:免疫治疗的疗效反应需要产生强大的全身免疫和有限的毒性。T细胞群的募集,如前体耗竭T细胞(Tpex)从淋巴组织到肿瘤是有效治疗的标志。然而,目前的免疫治疗方法缺乏有效诱导这种招募的能力。此外,全身免疫治疗经常导致剂量限制性毒性,产生不充分的治疗窗口,以引起持久的反应。方法:在这项研究中,我们使用临床可翻译的细胞因子传递平台(NCT05538624)评估局部给予白介素12 (IL-12)的安全性和抗肿瘤疗效,以确定耐受剂量的细胞因子对Tpex的募集能力。结果:我们发现IL-12细胞因子工厂可以有效治疗多种类型的癌症。单细胞RNA测序数据表明,我们研究中看到的抗肿瘤效果是由于视网膜色素上皮细胞- mil12治疗诱导肿瘤微环境中Tpex细胞的分化。当与检查点治疗联合使用时,IL-12细胞因子工厂治疗产生全身体外免疫,防止8/9结直肠癌小鼠皮下肿瘤生长和黑色素瘤小鼠肺转移。此外,该平台在非人类灵长类动物中耐受性良好,没有毒性迹象。结论:我们的新免疫治疗方法为诱导Tpex募集和对一系列腹膜实体恶性肿瘤的全身免疫提供了一种强大的策略,目前的免疫治疗策略无法治愈许多恶性肿瘤。值得注意的是,这些特征是利用IL-12实现的,通过利用我们的技术,我们避免了阻止IL-12转化为临床的毒性。我们的发现为IL-12细胞因子工厂的临床开发提供了强有力的理论依据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Journal for Immunotherapy of Cancer
Journal for Immunotherapy of Cancer Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
17.70
自引率
4.60%
发文量
522
审稿时长
18 weeks
期刊介绍: The Journal for ImmunoTherapy of Cancer (JITC) is a peer-reviewed publication that promotes scientific exchange and deepens knowledge in the constantly evolving fields of tumor immunology and cancer immunotherapy. With an open access format, JITC encourages widespread access to its findings. The journal covers a wide range of topics, spanning from basic science to translational and clinical research. Key areas of interest include tumor-host interactions, the intricate tumor microenvironment, animal models, the identification of predictive and prognostic immune biomarkers, groundbreaking pharmaceutical and cellular therapies, innovative vaccines, combination immune-based treatments, and the study of immune-related toxicity.
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