Park Anthony K, Monroy Isabel, Ren Yuwei, Lu Cathy, Chaurasiya Shyambabu, Valencia Hannah, Lent-Koop Jackson, Cook Colin, Kang Seonah, Lopez Lupita, Murad John P, Yamaguchi Yukiko, Urak Ryan, Chang Wen-Chung, Shah Monil, Chong Leslie Mi Ok, Fong Yuman, Forman Stephen J, Wang Xiuli, Priceman Saul J
Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California, USA.
Department of Medicine, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
J Immunother Cancer. 2025 Aug 11;13(8):e011051. doi: 10.1136/jitc-2024-011051.
BACKGROUND: Bispecific T cell engager (BiTE), such as blinatumomab, has demonstrated significant clinical success in treating hematological malignancies like B cell acute lymphoblastic leukemia and non-Hodgkin's lymphoma. However, the application of BiTEs in solid tumors has proven challenging, primarily due to the lack of targetable tumor antigens and the immunologically "cold" nature of the tumor microenvironment, which limits immune system activation. METHODS: We developed a novel oncolytic virus (OV) platform by engineering a chimeric vaccinia virus to express either a truncated non-signaling CD19 antigen (CD19t) or truncated B cell maturation antigen (BCMAt) on the surface of infected tumor cells. Here, we advance a combinatorial platform using an OV to redirect CD19-targeted or BCMA-targeted T cell engagers (TCEs) to drive antitumor responses against multiple solid tumors. RESULTS: We found that OV-infected tumor cells in combination with TCEs significantly improved tumor cell killing against solid tumor models, with efficacy comparable to that of chimeric antigen receptor T cells. This combination approach enhanced antitumor responses using in vivo human tumor xenograft models and promoted more effective elimination of solid tumor cells than either therapy alone. Our studies highlight OVs combined with clinically approved TCEs as a readily translatable, tumor-agnostic, off-the-shelf strategy to effectively target solid tumors. CONCLUSIONS: Our findings demonstrate that the combination of OV and TCEs offers a promising strategy to drive antitumor immune responses against solid tumors. This approach represents a novel and universal platform currently in phase 1 clinical trial combining TCE therapy with oncolytic virotherapy, overcoming antigen heterogeneity and immunological barriers for the effective treatment of solid tumors.
背景:双特异性T细胞衔接器(BiTE),如贝林妥欧单抗,在治疗血液系统恶性肿瘤(如B细胞急性淋巴细胞白血病和非霍奇金淋巴瘤)方面已取得显著的临床成功。然而,BiTE在实体瘤中的应用已被证明具有挑战性,主要原因是缺乏可靶向的肿瘤抗原以及肿瘤微环境的免疫“冷”性质,这限制了免疫系统的激活。 方法:我们通过改造嵌合痘苗病毒,使其在感染的肿瘤细胞表面表达截短的无信号CD19抗原(CD19t)或截短的B细胞成熟抗原(BCMAt),开发了一种新型溶瘤病毒(OV)平台。在此,我们推进了一个组合平台,使用OV来重新引导靶向CD19或靶向BCMA的T细胞衔接器(TCE),以驱动针对多种实体瘤的抗肿瘤反应。 结果:我们发现,OV感染的肿瘤细胞与TCE联合使用可显著提高对实体瘤模型的肿瘤细胞杀伤效果,其疗效与嵌合抗原受体T细胞相当。这种联合方法在体内人肿瘤异种移植模型中增强了抗肿瘤反应,并且比单独使用任何一种疗法都能更有效地消除实体瘤细胞。我们的研究强调,OV与临床批准的TCE联合使用是一种易于转化、不依赖肿瘤类型、现成可用的策略,可有效靶向实体瘤。 结论:我们的研究结果表明,OV和TCE的联合使用为驱动针对实体瘤的抗肿瘤免疫反应提供了一种有前景的策略。这种方法代表了一种目前正处于1期临床试验阶段的新型通用平台,将TCE疗法与溶瘤病毒疗法相结合,克服了抗原异质性和免疫障碍,可有效治疗实体瘤。
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