Monophosphoryl Lipid A (MPL) as an Adjuvant for Anti-Cancer Vaccines: Clinical Results
Monophosphoryl Lipid A (MPL) as an Adjuvant for Anti-Cancer Vaccines: Clinical Results
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DOI：
10.1007/978-1-4419-1603-7_10
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发表时间：
2009-01-01
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影响因子：
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通讯作者：
Cluff, Christopher W.
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作者：
Cluff, Christopher W.
随着技术的进步，可以识别可引起适应性免疫反应的肿瘤相关抗原(TAA)，开发治疗癌症的疫苗的努力继续获得势头。其中一些疫苗针对的是来自特定组织的肿瘤表达的分化抗原(例如，Melan-A/Mart-1、酪氨酸酶、GP 100)。一些靶抗原在不同类型的肿瘤中特异表达，但在正常组织中不表达(如MAGE-3)，而另一些可能的靶抗原是在正常组织中低水平表达的抗原，在不同类型的肿瘤中过表达(如HER2、MUC 1)。癌基因(HER2/neu、RAS、E7HPV16)、抑癌基因(P53)或肿瘤特异性翻译后修饰蛋白(低糖基化的MUC-1)也可用作癌症疫苗候选。在任何一种情况下，这些抗原本身的免疫原性都很差，含有它们的疫苗通常需要包括强大的免疫佐剂，以便在人类身上产生强大的抗肿瘤免疫反应。目前许多用于癌症疫苗的佐剂正在评估中，通过Toll样受体(TLRs)激活相关的抗原提呈细胞，如树突状细胞和巨噬细胞，促进抗原的有效摄取、处理和呈递到引流淋巴结内的T细胞。脂A是革兰氏阴性细菌细胞壁成分脂多糖(LPS)的生物活性部分，已知具有强大的免疫刺激特性，20多年来一直被评估为促进对包括TAAs在内的最低免疫原性抗原的免疫反应的佐剂。最近发现的TLRs和TLR4是类脂A的信号受体，这使得人们能够更好地了解这种免疫刺激剂如何在诱导先天和获得性免疫反应方面发挥作用。尽管包括脂多糖和合成类似物在内的几种类脂A已经被开发和测试为治疗癌症的单一疗法，(1-8)在已发表的人类临床试验中，只有3-O-去酰基-4‘-单磷脂A(MPL)被评估为癌症疫苗佐剂。MPL由明尼苏达州沙门氏菌的脂类组成，通过连续的酸和碱水解，去除了(R)-3-羟基四甲酰基和1-磷酸的一部分。(9)脂多糖和MPL诱导相似的细胞因子谱，但MPL的毒性至少低100倍。(9，10)在下一代疫苗的研究中，MPL已在30多万名人类受试者中使用。(11)在本章中，发表的临床试验评估了含有MPL的各种癌症疫苗的安全性和/或有效性，无论是单独使用还是与其他免疫刺激剂结合使用，例如草分枝杆菌的细胞壁骨架(CWS)(在佐剂DetoxTM中；Biomira，Inc.)，将概述皂苷QS-21(在佐剂AS01B和AS02B中；GSK生物制品)或与QS-21和CpG寡核苷酸(在佐剂AS 15中；GSK生物制品)。MPL与其他免疫刺激剂联合使用已被证明在许多情况下是有利的，可能需要激发实现有效免疫反应所需的全部活性，并克服肿瘤逃避免疫系统攻击的能力。在本章中，第一节将介绍针对特定癌症的疫苗的相关信息，而第二节将介绍通过诱导对共享的TAA的免疫反应而针对多种肿瘤类型的疫苗的相关信息。
As technological advances allow for the identification of tumor-associated antigens (TAAs) against which adaptive immune responses can be raised, efforts to develop vaccines for the treatment of cancer continue to gain momentum. Some of these vaccines target differentiation antigens that are expressed by tumors derived from one particular tissue (e.g., Melan-A/MART-1, tyrosinase, gp 100). Some target antigens are specifically expressed in tumors of different types but not in normal tissues (e.g., MAGE-3), while other possible targets are antigens that are expressed at low level in normal tissues and are over-expressed in tumors of different types (e.g., HER2, Muc 1). Oncogenes (HER2/neu, Ras, E7 HPV 16), tumor suppressor genes (p53) or tumor-specific post-translational modified proteins (underglycosylated Muc 1) can also be used as cancer vaccine candidates. In either case, these antigens tend to be poorly inmmunogenic by themselves and vaccines containing them generally require the inclusion of potent immunological adjuvants in order to generate robust anti-tumor immune responses in humans. Many adjuvants currently under evaluation for use in cancer vaccines activate relevant antigen presenting cells, such as dendritic cells and macrophages, via toll-like receptors (TLRs) and promote effective uptake, processing and presentation of antigen to T-cells in draining lymph nodes.Lipid A, the biologically active portion of the gram-negative bacterial cell wall constituent lipopolysaccharide (LPS), is known to possess strong immunostimulatory properties and has been evaluated for more than two decades as an adjuvant for promoting immune responses to minimally immunogenic antigens, including TAAs. The relatively recent discovery of TLRs and the identification of TLR4 as the signaling receptor for lipid A have allowed for a better understanding of how this immunostimulant functions with regard to induction of innate and adaptive immune responses.Although several lipid A species, including LPS and synthetic analogs, have been developed and tested as monotherapeutics for the treatment of cancer,(1-8) only 3-O-desacyl-4'-monophosphoryl lipid A (MPL) has been evaluated as a cancer vaccine adjuvant in published human clinical trials. MPL comprises the lipid A portion of Salmonella minnesota LPS from which the (R)-3-hydroxytetrade canoyl group and the 1-phosphate have been removed by successive acid and base hydrolysis.(9) LPS and MPL induce similar cytokine profiles, but MPL is at least 100-fold less toxic.(9,10) MPL has been administered to more than 300,000 human subjects in studies of next-generation vaccines.(11)In this chapter, published clinical trials conducted to evaluate the safety and/or efficacy of various cancer vaccines containing MPL, either alone or combined with other immunostimulants, such as cell wall skeleton (CWS) of Mycobacterium phlei (in the adjuvant Detox (TM); Biomira, Inc.), the saponin QS-21 (in the adjuvants AS01B and AS02B; GSK Biologicals) or with QS-21 and CpG oligonucleotides (in the adjuvant AS 15; GSK Biologicals) will be summarized. Combining MPL with other immunostimulants has been demonstrated to be advantageous in many cases and may be required to elicit the full complement of activities necessary to achieve an effective immune response and overcome the ability of tumors to evade attack by the immune system. In this chapter, information relating to vaccines targeting specific cancers will be presented in the first section, while information relating to vaccines targeting multiple tumor types by the induction of immune responses to shared TAAs is presented in the second section.