CN114848681A - 一种免疫治疗组合物及其用途 - Google Patents
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Abstract
一种免疫治疗组合物及其用途,包括:亲脂性胞壁酰二肽(MDP)类似物‑微脂粒包裹的胞壁酰三肽磷脂酰乙醇胺,该免疫治疗组合物含有分支杆菌胞壁成分,为一种天然免疫刺激剂,其脂质体制剂易被组织(尤其是肺)中巨噬细胞摄取,而肺为骨肉瘤的常见转移部位。其具多种生物学反应调节活性,可刺激宿主防御机制,抑制肿瘤转移;可增强癌症病人体内外周淋巴细胞和肿瘤浸润淋巴细胞的运动迁移能,且可致黑色素瘤患者受损的肿瘤浸润淋巴细胞运动迁移能力恢复。
Description
技术领域
本发明涉及医学领域,尤其涉及一种免疫治疗组合物及其用途。
背景技术
癌症是世界范围内的第一大死亡起因,而且开发针对癌症的有效疗法仍然是研究和临床开发的最活跃领域之一。尽管已提出许多新办法来治疗和预防癌症,但许多癌症仍然具有较高的死亡率且可能难以治疗或对常规疗法相对不响应。
人的大多数癌症和血液学恶性的特征至少部分在于称为粘蛋白-1(MUC1)的蛋白质的异常过表达,该蛋白的正常功能是帮助保护上皮细胞免于毒素、微生物和其他类型的外部环境应激(Kufe等,MUC1是从两个亚基的非共价相互作用形成的异二聚体蛋白,所述两个亚基由单个转录本编码,然后翻译后加工成亚基,称为MUC1-N和MUC1-C。MUC1正常见于分泌性内皮细胞的顶端边界,且当细胞应答应激而失去极性时(正常细胞的一种可逆过程),MUC1能与通常位于基底外侧边界的分子相互作用。另外,应答应激环境,MUC1-N亚基(一种含有用O-连接的多糖大量糖基化的可变数目串联重复(VNTR)的大蛋白)可脱落。
发明内容
针对现有技术中的上述不足,本发明提供了一种免疫治疗组合物及其用途,其具多种生物学反应调节活性,可刺激宿主防御机制,抑制肿瘤转移;可增强癌症病人体内外周淋巴细胞和肿瘤浸润淋巴细胞的运动迁移能,且可致黑色素瘤患者受损的肿瘤浸润淋巴细胞运动迁移能力恢复。
为了达到上述发明目的,本发明采用的具体方案为:
一种免疫治疗组合物及其用途,包括:亲脂性胞壁酰二肽(MDP)类似物-微脂粒包裹的胞壁酰三肽磷脂酰乙醇胺,该免疫治疗组合物含有分支杆菌胞壁成分,为一种天然免疫刺激剂,其脂质体制剂易被组织(尤其是肺)中巨噬细胞摄取,而肺为骨肉瘤的常见转移部位。
优选地,该免疫治疗组合物可致人单核细胞趋化和活化因子(MCAF)mRNA的表达呈快速而短暂的增加,但对淋巴细胞中MCAFmRNA水平无影响,表明MCAF可能参与了该免疫治疗组合物发挥肿瘤杀伤和免疫刺激活性的过程;该免疫治疗组合物可诱导单核细胞中细胞因子(IL-1α、-1β、-6和-8以及TNF-α)基因表达的增加,但对淋巴细胞无此作用,表明该免疫治疗组合物导致这些细胞因子的产生和分泌,可能是其发挥抗肿瘤作用的机制之一。
优选地,在45名无症状HIV阳性受试者中进行的一项小型试验显示,经3次给予Env2-3疫苗加mifamurtide乳剂的治疗,受试者因HIV包膜抗原所致淋巴细胞增殖反应和抗体反应均明显增强;在骨肉瘤患者中进行的一项试验显示,在手术切除肺转移灶后,持续给予该免疫治疗组合物脂质体治疗,可明显推迟肿瘤的复发。
优选地,在复发性骨肉瘤患者中进行的一项Ⅱ期临床试验显示,该免疫治疗组合物与异环磷酰胺联用治疗的耐受性良好,且不会导致因该免疫治疗组合物而引起的单核细胞活化减弱;在另一项Ⅱ期临床试验中,患复发性骨肉瘤且有肺转移而术后无病生存的28名受试病人使用2mg·m-2该免疫治疗组合物治疗,先每周2次,持续12周,再每周1次,持续12周,结果其肿瘤复发时间显著推迟,但最初的12周治疗无显著疗效。
优选地,又一项临床试验中,复发型骨肉瘤患者在术后24周里,每周2次接受2mg·m-2该免疫治疗组合物的1小时输注治疗,结果,其无恶化生存率较历史数据对照组明显提高。
优选地,还有一项小型临床试验显示,具有高复发风险的18名可切除黑色素瘤患者在术前1个月和术后5个月期间接受了该免疫治疗组合物治疗,结果虽然所有受试者的若干免疫学参数指标得以改善,但只有单核细胞的肿瘤杀伤活性和肿瘤增殖检测的临床表现最为突出。
本发明的有益效果为:
其具多种生物学反应调节活性,可刺激宿主防御机制,抑制肿瘤转移;可增强癌症病人体内外周淋巴细胞和肿瘤浸润淋巴细胞的运动迁移能,且可致黑色素瘤患者受损的肿瘤浸润淋巴细胞运动迁移能力恢复。
具体实施方式
以下通过具体实施例进一步描述本发明,但本发明不仅仅限于以下实施例。在本发明的范围内或者在不脱离本发明的内容、精神和范围内,对本发明进行的变更、组合或替换,对于本领域的技术人员来说是显而易见的,且包含在本发明的范围之内。
一种免疫治疗组合物及其用途,包括:亲脂性胞壁酰二肽(MDP)类似物-微脂粒包裹的胞壁酰三肽磷脂酰乙醇胺,该免疫治疗组合物含有分支杆菌胞壁成分,为一种天然免疫刺激剂,其脂质体制剂易被组织(尤其是肺)中巨噬细胞摄取,而肺为骨肉瘤的常见转移部位。
该免疫治疗组合物可致人单核细胞趋化和活化因子(MCAF)mRNA的表达呈快速而短暂的增加,但对淋巴细胞中MCAFmRNA水平无影响,表明MCAF可能参与了该免疫治疗组合物发挥肿瘤杀伤和免疫刺激活性的过程;该免疫治疗组合物可诱导单核细胞中细胞因子(IL-1α、-1β、-6和-8以及TNF-α)基因表达的增加,但对淋巴细胞无此作用,表明该免疫治疗组合物导致这些细胞因子的产生和分泌,可能是其发挥抗肿瘤作用的机制之一。在45名无症状HIV阳性受试者中进行的一项小型试验显示,经3次给予Env2-3疫苗加mifamurtide乳剂的治疗,受试者因HIV包膜抗原所致淋巴细胞增殖反应和抗体反应均明显增强;在骨肉瘤患者中进行的一项试验显示,在手术切除肺转移灶后,持续给予该免疫治疗组合物脂质体治疗,可明显推迟肿瘤的复发。在复发性骨肉瘤患者中进行的一项Ⅱ期临床试验显示,该免疫治疗组合物与异环磷酰胺联用治疗的耐受性良好,且不会导致因该免疫治疗组合物而引起的单核细胞活化减弱;在另一项Ⅱ期临床试验中,患复发性骨肉瘤且有肺转移而术后无病生存的28名受试病人使用2mg·m-2该免疫治疗组合物治疗,先每周2次,持续12周,再每周1次,持续12周,结果其肿瘤复发时间显著推迟,但最初的12周治疗无显著疗效。又一项临床试验中,复发型骨肉瘤患者在术后24周里,每周2次接受2mg·m-2该免疫治疗组合物的1小时输注治疗,结果,其无恶化生存率较历史数据对照组明显提高。还有一项小型临床试验显示,具有高复发风险的18名可切除黑色素瘤患者在术前1个月和术后5个月期间接受了该免疫治疗组合物治疗,结果虽然所有受试者的若干免疫学参数指标得以改善,但只有单核细胞的肿瘤杀伤活性和肿瘤增殖检测的临床表现最为突出。
实施例:一系列小鼠模型试验显示,全身性给予mifamurtide脂质体,可有效激活环孢素诱导免疫抑制小鼠的肺泡巨噬细胞,从而杀死肿瘤细胞,但并不阻断环孢素介导的对T淋巴细胞依赖性抗原SRBC的抗体产生的抑制作用;将该免疫治疗组合物溶于磷酸盐缓冲液中形成胶束后,以单剂量或多剂量经,给予小鼠,可诱导激活肺和腹膜巨噬细胞而杀灭肿瘤细胞,然而,经静脉或腹膜注射给予该免疫治疗组合物脂质体,则只能分别激活肺或腹膜巨噬细胞;对C57BL/6小鼠每周2次经,给予该免疫治疗组合物,可抑制同源B16黑色素瘤细胞的肺和淋巴结转移,但该免疫治疗组合物对已转移的黑色素瘤无作用;小鼠经单次亚致死剂量的辐射后,再接受该免疫治疗组合物脂质体治疗,可刺激血细胞生成,促进造血功能的恢复;对具免疫功能的肺炎杆菌性败血病小鼠单次给予预防性剂量的该免疫治疗组合物或其脂质体,可显著提高小鼠存活率,而多次给予预防性剂量的该免疫治疗组合物脂质体则效果更好;对白细胞缺乏症小鼠重复给予预防性剂量的该免疫治疗组合物脂质体,也可提高小鼠存活率,但并不能增加小鼠白细胞数量;对肾腺癌小鼠经给予该免疫治疗组合物脂质体,可极为有效地抑制肿瘤的特发性肺转移;预先给小鼠使用该免疫治疗组合物,再对其辐射,可使小鼠造血功能得以恢复,并使其免于死亡,而在辐射前,联合使用该免疫治疗组合物和吲哚美辛,则能加强这种保护作用;对BALB/c小鼠每日1次经给予该免疫治疗组合物卵磷脂脂质体,可持久性激活肺泡巨噬细胞,并预防肾细胞癌的实验性肺转移;接受过该免疫治疗组合物治疗的小鼠经辐射后,其骨髓和血液中核酸含量的恢复较未接受过治疗的小鼠明显更快。
大鼠结肠癌肝转移模型试验显示,该免疫治疗组合物脂质体可显著抑制肝中肿瘤的生长,其作用机制可能是促进具细胞毒性作用的巨噬细胞数量增加和间接通过肝巨噬细胞诱导细胞因子产生。犬模型试验显示,患特发性骨肉瘤和血管肉瘤的犬经手术后,再接受该免疫治疗组合物与化疗联用治疗;可有效安全地治疗转移灶;患口腔原发恶性黑色素瘤的犬经手术切除后,再接受该免疫治疗组合物治疗,可延缓肿瘤转移,显著提高存活率。
以上所述仅为本发明专利的较佳实施例而已,并不用以限制本发明专利,凡在本发明专利的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明专利的保护范围之内。
Claims (6)
1.一种免疫治疗组合物及其用途,其特征在于,包括:亲脂性胞壁酰二肽(MDP)类似物-微脂粒包裹的胞壁酰三肽磷脂酰乙醇胺,该免疫治疗组合物含有分支杆菌胞壁成分,为一种天然免疫刺激剂,其脂质体制剂易被组织(尤其是肺)中巨噬细胞摄取,而肺为骨肉瘤的常见转移部位。
2.根据权利要求1所述的一种免疫治疗组合物及其用途,其特征在于,该免疫治疗组合物可致人单核细胞趋化和活化因子(MCAF)mRNA的表达呈快速而短暂的增加,但对淋巴细胞中MCAFmRNA水平无影响,表明MCAF可能参与了本品发挥肿瘤杀伤和免疫刺激活性的过程;本品可诱导单核细胞中细胞因子(IL-1α、-1β、-6和-8以及TNF-α)基因表达的增加,但对淋巴细胞无此作用,表明本品导致这些细胞因子的产生和分泌,可能是其发挥抗肿瘤作用的机制之一。
3.根据权利要求1所述的一种免疫治疗组合物及其用途,其特征在于,在45名无症状HIV阳性受试者中进行的一项小型试验显示,经3次给予Env2-3疫苗加mifamurtide乳剂的治疗,受试者因HIV包膜抗原所致淋巴细胞增殖反应和抗体反应均明显增强;在骨肉瘤患者中进行的一项试验显示,在手术切除肺转移灶后,持续给予本品脂质体治疗,可明显推迟肿瘤的复发。
4.根据权利要求1所述的一种免疫治疗组合物及其用途,其特征在于,在复发性骨肉瘤患者中进行的一项Ⅱ期临床试验显示,该免疫治疗组合物与异环磷酰胺联用治疗的耐受性良好,且不会导致因本品而引起的单核细胞活化减弱;在另一项Ⅱ期临床试验中,患复发性骨肉瘤且有肺转移而术后无病生存的28名受试病人使用2mg·m-2本品治疗,先每周2次,持续12周,再每周1次,持续12周,结果其肿瘤复发时间显著推迟,但最初的12周治疗无显著疗效。
5.根据权利要求1所述的一种免疫治疗组合物及其用途,其特征在于,又一项临床试验中,复发型骨肉瘤患者在术后24周里,每周2次接受2mg·m-2该免疫治疗组合物的1小时输注治疗,结果,其无恶化生存率较历史数据对照组明显提高。
6.根据权利要求1所述的一种免疫治疗组合物及其用途,其特征在于,还有一项小型临床试验显示,具有高复发风险的18名可切除黑色素瘤患者在术前1个月和术后5个月期间接受了该免疫治疗组合物治疗,结果虽然所有受试者的若干免疫学参数指标得以改善,但只有单核细胞的肿瘤杀伤活性和肿瘤增殖检测的临床表现最为突出。
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