Overcoming effector T cell exhaustion in ovarian cancer ascites with a novel adenovirus encoding for a MUC1 bispecific antibody engager and IL-2 cytokine.
Saru Basnet, Mirte Van der Heijden, Dafne C A Quixabeira, Elise Jirovec, Susanna A M Grönberg-Vähä-Koskela, James H A Clubb, Anna Kanerva, Santeri Pakola, Lyna Haybout, Victor Arias, Otto Hemminki, Tatiana Kudling, Sadia Zafar, Victor Cervera-Carrascon, Joao M Santos, Akseli Hemminki
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引用次数: 0
Abstract
T cell-focused cancer immunotherapy including checkpoint inhibitors and cell therapies has been rapidly evolving over the past decade. Nevertheless, there remains a major unmet medical need in oncology generally and immuno-oncology specifically. We have constructed an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), which is armed with a human aMUC1aCD3 T cell engager and IL-2. TILT-322 treatment stimulated T cell cytotoxicity through the increased presence of granzyme B, perforin, and interferon-gamma. Additional immune profiling indicated TILT-322 increased gamma delta T cell activation and impacted other cell types such as natural killer cells and natural killer-like T cells that are traditionally involved in cancer immunotherapy. TILT-322 treatment also decreased the proportion of exhausted CD8+ T cells as demarked by immune checkpoint expression in ovarian ascites samples. Overall, our data showed that TILT-322 treatment led to an enhanced T cell activation and reversed T cell exhaustion translating into high antitumor efficacy when given locally or intravenously. The analysis of blood and tumors isolated from an in vivo patient-derived ovarian cancer xenograft model suggested TILT-322 mediated tumor control through improved T cell functions. Therefore, TILT-322 is a promising novel anti-tumor agent for clinical translation.
用编码 MUC1 双特异性抗体吸引子和 IL-2 细胞因子的新型腺病毒克服卵巢癌腹水中效应 T 细胞的衰竭。
以 T 细胞为重点的癌症免疫疗法(包括检查点抑制剂和细胞疗法)在过去十年中发展迅速。尽管如此,肿瘤学领域,特别是免疫肿瘤学领域仍有大量医疗需求未得到满足。我们构建了一种溶瘤腺病毒--Ad5/3-E2F-d24-aMUC1aCD3-IL-2(TILT-322),它含有人类 aMUC1aCD3 T 细胞吞噬因子和 IL-2。TILT-322通过增加颗粒酶-B、穿孔素和γ干扰素的存在刺激了T细胞的细胞毒性。其他免疫分析表明,TILT-322 增加了γ delta T 细胞的活化,并影响了其他细胞类型,如传统上参与癌症免疫疗法的自然杀伤细胞和类自然杀伤 T 细胞。根据卵巢腹水样本中免疫检查点的表达,TILT-322 治疗还能降低 CD8+ T 细胞衰竭的比例。总之,我们的数据显示,TILT-322 治疗可增强 T 细胞活化,逆转 T 细胞衰竭,从而在局部或静脉注射时产生较高的抗肿瘤疗效。对患者体内卵巢癌异种移植模型分离出的血液和肿瘤进行的分析表明,TILT-322 通过改善 T 细胞功能来控制肿瘤。因此,TILT-322 是一种有望应用于临床的新型抗肿瘤药物。
期刊介绍:
Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.