Cw豆花叶病毒(CPMV)是一种核蛋白纳米颗粒,在瘤内给药时可用作高效的免疫调节剂,并用作原位疫苗。CPMV原位疫苗接种重塑了肿瘤微环境,并引发了高度有效的,系统性,和持久的抗肿瘤免疫应答对治疗和未治疗,远处转移部位(远隔效应)。在多种肿瘤小鼠模型中证明了有效的疗效,最重要的是,在犬癌症患者自发性肿瘤。数据表明抗CPMV抗体的存在不是中和的,并且实际上调理作用导致增强的功效。植物病毒是食物链的一部分,但迄今为止,没有关于人类接触CPMV的信息。因此,检测患者血清中是否存在抗CPMV的免疫球蛋白,事实上,>50%的去鉴定患者样品检测为CPMV抗体阳性。为了更广泛地了解植物病毒在人类中的暴露和免疫原性,我们还测试了血清中抗烟草花叶病毒的抗体(>90%的患者检测呈阳性),马铃薯病毒X(<20%的患者检测呈阳性),和cow豆褪绿斑驳病毒(未检测到抗体)。Further,分析患者血清中是否存在针对大肠杆菌噬菌体Qβ的抗体,目前正在进行原位疫苗接种临床试验的平台技术;我们发现60%的患者存在抗Qβ抗体.因此,数据表明人类暴露于CPMV和其他植物病毒和噬菌体。接下来,我们认为要解决农艺安全问题;即,我们检查了肿瘤内治疗和口服灌胃(模拟食物消耗)后CPMV的命运。因为使用了实时CPMV,一个重要的问题是,是否有任何证据表明小鼠或患者的感染性颗粒脱落。CPMV对哺乳动物是非传染性的;然而,它对包括黑眼豌豆和其他豆类在内的植物具有传染性。荷瘤小鼠和健康小鼠的生物分布数据表明,几乎没有从肿瘤中浸出,并通过网状内皮系统清除,然后进行胆汁排泄。虽然有证据表明粪便中的RNA脱落,当植物受到粪便提取物的攻击时,没有感染颗粒的证据,从而表明农艺安全。这些数据一起帮助CPMV作为癌症免疫疗法的候选药物的转化发展。
Cowpea mosaic virus (CPMV) is a nucleoprotein nanoparticle that functions as a highly potent immunomodulator when administered intratumorally and is used as an in situ vaccine. CPMV in situ vaccination remodels the tumor microenvironment and primes a highly potent, systemic, and durable antitumor immune response against the treated and untreated, distant metastatic sites (abscopal effect). Potent efficacy was demonstrated in multiple tumor mouse models and, most importantly, in canine cancer patients with spontaneous tumors. Data indicate that presence of anti-CPMV antibodies are not neutralizing and that in fact opsonization leads to enhanced efficacy. Plant viruses are part of the food chain, but to date, there is no information on human exposure to CPMV. Therefore, patient sera were tested for the presence of immunoglobulins against CPMV, and indeed, >50% of deidentified patient samples tested positive for CPMV antibodies. To get a broader sense of plant virus exposure and immunogenicity in humans, we also tested sera for antibodies against tobacco mosaic virus (>90% patients tested positive), potato virus X (<20% patients tested positive), and cowpea chlorotic mottle virus (no antibodies were detected). Further, patient sera were analyzed for the presence of antibodies against the coliphage Qβ, a platform technology currently undergoing clinical trials for in situ vaccination; we found that 60% of patients present with anti-Qβ antibodies. Thus, data indicate human exposure to CPMV and other plant viruses and phages. Next, we thought to address agronomical safety; i.e., we examined the fate of CPMV after intratumoral treatment and oral gavage (to mimic consumption by food). Because live CPMV is used, an important question is whether there is any evidence of shedding of infectious particles from mice or patients. CPMV is noninfectious toward mammals; however, it is infectious toward plants including black-eyed peas and other legumes. Biodistribution data in tumor-bearing and healthy mice indicate little leaching from tumors and clearance via the reticuloendothelial system followed by biliary excretion. While there was evidence of shedding of RNA in stool, there was no evidence of infectious particles when plants were challenged with stool extracts, thus indicating agronomical safety. Together these data aid the translational development of CPMV as a drug candidate for cancer immunotherapy.