Generating rapid antitumor immunity with lymphocyte-reprogramming nanocarriers

到目前为止，医学缺乏一种能够快速产生抗肿瘤免疫的干预措施。例如，疫苗 可以训练免疫系统选择性地摧毁癌细胞，然而，他们可能需要几个月的时间来做到这一点--通过 那时候肿瘤可能会变得致命。靶向肿瘤抗原的自体T细胞输注 体外方法是昂贵和劳动密集型的，并且必须为每个患者在专门的 电池生产设施。我们提出了一种替代方案：这里概述的研究试图开发一种现成的 一种搁置试剂，可以快速将肿瘤识别能力编程到T细胞中，而不需要提取它们用于 实验室操纵。具体地说，我们假设循环中的T细胞可以由基因- 携带聚合物纳米颗粒(NPs)来表达识别选定的嵌合抗原受体(CAR) 抗原，使其能够介导对肿瘤的快速和有力的排斥反应。我们还假设联合- 提供CRISPR基因组编辑系统来沉默免疫检查点将提高疗效和 NP-程序性T细胞的持久性。我们的多学科团队包括免疫学家、生物工程师和 遗传学家已经开发出一种新的NP配置，可以成功地引入白血病特异性 将CAR基因注入循环淋巴细胞。重新编程的细胞继续产生这些 受体持续数周，使它们成为在靶点蓄积的“活药物”，数量增加， 一连串地破坏肿瘤细胞，并最终分化为长寿记忆T细胞。我们的最终目标是 提供一种实用、低成本、可广泛应用的治疗方法，可按需产生抗肿瘤免疫 适用于各种环境下的肿瘤学家。作为实现这一目标的基本步骤，我们提出以下具体建议 目的：(1)测量NP编程的CAR表达如何有效地导致晚期癌症的退化 癌症；(2)确定当NP联合编程时是否减少了抗原丢失和肿瘤逃逸事件 T细胞靶向一系列抗原；以及(3)确定沉默T细胞功能的负调控因子 提高它们的抗肿瘤活性。我们希望我们的结果将为设计各种基因提供依据。 可以对任何类型的癌症产生免疫力的修饰系统。特别是，他们将减少 抗原逃逸变异的可能性，因为患者可以使用NP传递的CAR基因进行治疗 他们肿瘤的抗原性指纹。这些颗粒可以很容易地适应编程淋巴细胞表达 针对各种病毒抗原的高亲和力T细胞受体，因此我们的结果也可能为 治疗传染病。

So far, medicine lacks an intervention that can rapidly generate anti-tumor immunity. For example, vaccines can train the immune system to selectively destroy cancer cells, however they may require months to do so--by which time tumors may become lethal. Infusions of autologous T cells targeted against tumor antigens using in vitro approaches are expensive and labor-intensive, and must be personalized for each patient in specialized cell-production facilities. We propose an alternative: the research outlined here seeks to develop an off-the- shelf reagent that can quickly program tumor-recognizing capabilities into T cells without extracting them for laboratory manipulation. Specifically, we hypothesize that circulating T cells can be programmed by gene- carrying polymeric nanoparticles (NPs) to express chimeric antigen receptors (CARs) that recognize selected antigens, enabling them to mediate rapid and vigorous rejection of tumors. We also hypothesize that co- delivering a CRISPR genome editing system to silence immune checkpoints will improve the efficacy and persistence of NP-programmed T cells. Our multidisciplinary team of immunologists, bioengineers, and geneticists has already developed a novel NP configuration that can successfully introduce leukemia-specific CAR receptor genes into circulating lymphocytes. The reprogrammed cells continue to produce these receptors for weeks, allowing them to act as a `living drug' that accumulates at the target, increases in number, serially destroys tumor cells, and ultimately differentiates into long-lived memory T cells. Our eventual goal is to provide a practical, low-cost, broadly-applicable treatment that can generate anti-tumor immunity “on demand” for oncologists in a variety of settings. As essential steps toward achieving this goal, we propose these Specific Aims: (1) To measure how effectively NP-programmed CAR expression causes the regression of advanced cancer; (2) To determine if antigen loss and tumor escape events are reduced when NP combinations program T cells to target a spectrum of antigens; and (3) To determine if silencing negative regulators of T cell function improves their anti-tumor activity. We expect our results will provide a basis to design various gene modification systems that can generate immunity against any type of cancer. Especially, they will reduce the likelihood of antigen escape variants because patients can be treated with NP-delivered CAR genes tailored to their tumor's antigenic fingerprint. These particles could be easily adapted to program lymphocytes to express high-affinity T cell receptors specific for various viral antigens, so our results may also provide a strategy for treating infectious diseases.