Generating rapid antitumor immunity with lymphocyte-reprogramming nanocarriers

到目前为止，医学缺乏一种可以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，但它们可能需要数月的时间才能做到这一点--通过 此时肿瘤可能变得致命。靶向肿瘤抗原的自体T细胞的输注在 体外方法是昂贵的和劳动密集型的，并且必须针对每个患者进行个性化的专门治疗。 细胞生产设施。我们提出了一种替代方案：这里概述的研究旨在开发一种非常规的 货架试剂，可以快速编程肿瘤识别能力进入T细胞，而无需提取它们， 实验室操作。具体来说，我们假设循环T细胞可以通过基因编程， 携带聚合物纳米颗粒（NPs）以表达嵌合抗原受体（汽车） 抗原，使他们能够介导快速和有力的排斥肿瘤。我们还假设，共同- 提供CRISPR基因组编辑系统来沉默免疫检查点将提高疗效， NP编程的T细胞的持久性。我们的免疫学家、生物工程师和 遗传学家已经开发出一种新的NP结构，可以成功地将白血病特异性 CAR受体基因进入循环淋巴细胞。重新编程的细胞继续产生这些 受体数周，使他们作为一个“活药”，积累在目标，数量增加， 连续破坏肿瘤细胞，并最终分化为长寿的记忆T细胞。我们的最终目标是 提供了一种实用、低成本、广泛适用的治疗方法，可以“按需”产生抗肿瘤免疫力， for oncologists肿瘤学家in a variety品种of settings设置.作为实现这一目标的重要步骤，我们提出了以下具体建议： 目的：（1）测量NP编程的CAR表达如何有效地引起晚期NSCLC的消退。 （2）确定当NP组合程序化时抗原丢失和肿瘤逃逸事件是否减少 （3）确定是否沉默T细胞功能的负调节因子 提高其抗肿瘤活性。我们希望我们的研究结果能为设计各种基因提供依据 可以产生针对任何类型癌症的免疫力的修饰系统。特别是，他们将减少 抗原逃逸变体的可能性，因为患者可以用定制的NP递送的CAR基因治疗， 他们肿瘤的抗原指纹这些颗粒可以很容易地适应程序淋巴细胞表达 高亲和力T细胞受体对各种病毒抗原的特异性，所以我们的研究结果也可能提供一种策略， 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.