In situ genetic engineering of tumors for long-lasting and systemic immunotherapy
In situ genetic engineering of tumors for long-lasting and systemic immunotherapy
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DOI：
10.1073/pnas.1916039117
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发表时间：
2020-02-25
影响因子：
11.1
通讯作者：
Green, Jordan J.
中科院分区：
文献类型：
--
作者：
Tzeng, Stephany Y.;Patel, Kisha K.;Green, Jordan J.
癌症免疫治疗一直是广泛研究的主题，但高效和广泛适用的方法仍然难以捉摸。此外，产生内源性患者特异性细胞疗法的一般方法，而不需要肿瘤抗原的先验知识、离体细胞操作或细胞制造，可以显著降低成本并扩大可及性。在这里，我们描述了一种基于合成的生物可降解纳米颗粒的生物技术，该纳米颗粒可以原位对癌细胞及其微环境进行基因重编程，从而使癌细胞可以通过诱导共刺激分子（4-1BBL）和免疫刺激细胞因子（IL-12）的共表达来充当肿瘤相关抗原呈递细胞（tAPC）。在B16-F10黑色素瘤和MC 38结直肠癌小鼠模型中，重编程纳米颗粒与检查点阻断相结合，随着时间的推移显着降低了肿瘤生长，在某些情况下，清除了肿瘤，导致长期存活者，然后在远处再次激发时对新肿瘤的形成具有抵抗力。体外和体内分析证实，局部递送的tAPC重编程纳米颗粒导致显著的细胞介导的细胞毒性免疫应答，具有全身效应。系统性肿瘤特异性和细胞介导的免疫治疗反应是在不需要肿瘤表达抗原的先验知识的情况下实现的，并反映了这种纳米药物的转化潜力。
Cancer immunotherapy has been the subject of extensive research, but highly effective and broadly applicable methods remain elusive. Moreover, a general approach to engender endogenous patient-specific cellular therapy, without the need for a priori knowledge of tumor antigen, ex vivo cellular manipulation, or cellular manufacture, could dramatically reduce costs and broaden accessibility. Here, we describe a biotechnology based on synthetic, biodegradable nanoparticles that can genetically reprogram cancer cells and their microenvironment in situ so that the cancer cells can act as tumor-associated antigen-presenting cells (tAPCs) by inducing coexpression of a costimulatory molecule (4-1BBL) and immunostimulatory cytokine (IL-12). In B16-F10 melanoma and MC38 colorectal carcinoma mouse models, reprogramming nanoparticles in combination with checkpoint blockade significantly reduced tumor growth over time and, in some cases, cleared the tumor, leading to long-term survivors that were then resistant to the formation of new tumors upon rechallenge at a distant site. In vitro and in vivo analyses confirmed that locally delivered tAPC-reprogramming nanoparticles led to a significant cell-mediated cytotoxic immune response with systemic effects. The systemic tumor-specific and cell-mediated immunotherapy response was achieved without requiring a priori knowledge of tumor-expressed antigens and reflects the translational potential of this nanomedicine.