Engineering T cells to overcome inhibitory receptor signals that limit the efficacy of adoptive cell therapy against ovarian cancer

改造 T 细胞以克服抑制性受体信号,这些信号限制了过继性细胞疗法对卵巢癌的疗效

基本信息

  • 批准号:
    10526155
  • 负责人:
  • 金额:
    $ 19.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-06-05 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Over 20,000 women are diagnosed with ovarian cancer in the United States annually, and over half will die within five years. Outcomes have changed little in the last 20 years, highlighting the need for more effective therapies. One promising new strategy employs immune T cells engineered to target proteins uniquely overexpressed in tumors; such T cell immunotherapies have the potential to control tumor growth without toxicity to healthy tissues. My ongoing work targets the antigen mesothelin (Msln), which contributes to malignancy and invasive progression in ovarian cancer but has limited expression in healthy cells. I showed that T cells engineered to express a human or mouse Msln-specific high-affinity T cell receptor (TCRMsln) can kill human ovarian cancer cell lines or the murine ID8 cell line, respectively. In a disseminated ID8 tumor model, adoptively transferred TCRMsln T cells preferentially accumulated within established tumors, delayed ovarian tumor growth and significantly prolonged mouse survival. However, data also revealed that the ovarian tumor microenvironment (TME) limits engineered T cell persistence and anti-cancer efficacy. Tumor-specific T cells express inhibitory receptors upon encountering antigen, reducing antitumor cytokine production. I detected the ligands for the PD-1, Tim-3 and Lag-3 inhibitory receptors (immune checkpoints) expressed in human and ID8 ovarian tumors. Moreover, tumor-infiltrating TCRMsln T cells expressed PD-1, Tim- 3 and Lag-3, which correlated with reduced cytokine production. I hypothesized that immune checkpoint blockade could overcome inhibitory receptor ligation-driven suppression of engineered T cells. Therefore, I treated tumor-bearing mice with TCRMsln T cells plus anti-PD-1, anti-Tim-3 and/or anti-Lag-3 checkpoint- blocking antibodies, targeting up to three inhibitory receptors simultaneously. Triple checkpoint blockade dramatically increased anti-tumor cytokine production by intratumoral TCRMsln T cells, but treatment also produced greater off-tumor toxicities. I now propose to use preclinical mouse models (Aim 1) and a novel human slice culture system (Aim 2) to interrogate the transcriptomic and functional changes that occur in engineered T cells and the ovarian TME after checkpoint blockade. I plan to use T cell engineering to knock down endogenous inhibitory receptor expression in tumor-specific T cells and determine if anti-tumor function is improved without the immune- related toxicities observed with systemic combination checkpoint blockade. Many solid tumors overexpress Msln and share the same T cell inhibitory pathways. Therefore, the findings from these new studies will likely inform the development of clinically-relevant T cell engineering strategies that are more resistant to immune suppression within the solid TME of many malignancies.
项目总结 在美国,每年有2万多名女性被诊断出患有卵巢癌,其中一半以上将死亡 在五年内。在过去的20年里,结果几乎没有变化,突显出需要更有效的 治疗。一种有希望的新策略是利用免疫T细胞以独特的蛋白质为靶点 在肿瘤中过度表达;这种T细胞免疫疗法有可能控制肿瘤生长,而不是 对健康组织的毒性。我正在进行的工作是针对抗原间鞘蛋白(MSLN),它有助于 卵巢癌的恶性和侵袭性进展,但在健康细胞中的表达有限。我展示了 经工程设计表达人或小鼠Msln特异性高亲和力T细胞受体(TCRMsln)的T细胞可以 分别杀灭人卵巢癌细胞系和小鼠ID8细胞系。在播散性ID8肿瘤中 模型,过继转移的TCRMsln T细胞优先聚集在已建立的肿瘤内,延迟 卵巢肿瘤生长并显著延长小鼠存活时间。然而,数据也显示,卵巢 肿瘤微环境(TME)限制了工程化T细胞的持久性和抗癌效果。 肿瘤特异性T细胞遇到抗原后表达抑制性受体,减少抗肿瘤细胞因子 制作。我检测了PD-1、TIM-3和LAG-3抑制受体的配体(免疫检查点) 在人和ID8卵巢肿瘤中表达。此外,肿瘤浸润性TCRMsln T细胞表达PD-1、TIM-1。 3和LAG-3,它们与细胞因子的产生减少有关。我假设免疫检查站 BLOCKADE可以克服受体连接抑制引起的工程化T细胞抑制。因此,我 TCRMsln T细胞联合抗PD-1、抗TIM-3和/或抗LAG-3检查点治疗荷瘤小鼠 阻断抗体,同时靶向多达三个抑制性受体。三重检查站封锁 肿瘤内TCRMsln T细胞显著增加抗肿瘤细胞因子的产生,但治疗也 产生了更大的非肿瘤毒性。 我现在提议使用临床前小鼠模型(目标1)和一种新的人类切片培养系统(目标2)来 询问在工程T细胞和卵巢TME中发生的转录和功能变化 在检查站封锁之后。我计划使用T细胞工程来击倒内源性抑制性受体 在肿瘤特异性T细胞中表达,并确定在没有免疫应答的情况下抗肿瘤功能是否得到改善 全身联合检查点阻断观察相关毒副作用。许多实体瘤过度表达 MSLN和T细胞抑制途径相同。因此,这些新研究的结果很可能 告知临床相关T细胞工程策略的发展,这些策略对免疫具有更强的抵抗力 许多恶性肿瘤的固体TME内的抑制。

项目成果

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Kristin Gail Anderson其他文献

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