畜禽业稿件信息
免疫治疗对骨肉瘤化疗促进作用的研究进展
杨文元（解放军联勤保障部队940医院肿瘤科 甘肃 兰州730050）
[摘要]：骨肉瘤是最常见的原发性骨肿瘤，其特点是易发生的肺转移和多种遗传变异，阻碍了化疗及靶向治疗的发展，预后差。迫切需要新的治疗策略。然而，临床前研究进行测试与免疫疗法和检查点抑制剂及化疗药物相结合的新方法，提示细胞免疫协同的化学治疗具有潜在机会。本文就免疫治疗对骨肉瘤化疗促进作用的研究进展作一简要综述。
Abstract: Osteosarcoma is the most common primary bone tumor, which is characterized by pulmonary metastasis and genetic variation, which hinders the development of chemotherapy and targeted therapy, and the prognosis is poor. New treatment strategies are urgently needed. However, preclinical studies combined with immunotherapy, checkpoint inhibitors and chemotherapeutic drugs suggest potential opportunities for chemotherapeutic cooperation with cellular immunity. This article reviews the progress of immunotherapy in promoting chemotherapy in osteosarcoma.
Keywords: osteosarcoma; immunotherapy; chemotherapy; combined strategy
骨肉瘤（OS）是儿童和青少年最常见的恶性肿瘤，通常表现为成骨细胞恶性生长 [1]。迄今为止，随着医疗水平的提高，总的存活率已经达到70%~80%[2，3]。然而，早期容易发生肺转移[3，4]，截肢术后骨骼重建难度，限制了手术的治疗[5]。化疗也是OS的常用治疗方法。研究人员通过大量的临床研究，利用增加细胞毒性药物的剂量的治疗方法来提高治疗效果，但结果在很大程度上证明是令人失望的。多重副作用和令人满意的药物短缺仍然困扰着临床医生和患者[6]。虽然新辅助化疗提高了患者的生活质量，但其毒性、肺转移和原位复发仍威胁着OS患者的生存[7，8]。因此，仍然需要有效的OS治疗。为了改变这种现状，这促使人们把注意力集中在恶性肿瘤的基本生物免疫学上，已经有了很大的提高。David S. Hong[9]等回顾性分析了I期临床在接受免疫治疗试验的50名患者中(骨10例；软组织40例)，我们发现了14种不同类型的肉瘤。皇家马斯登医院(RMH)预后评分<2(86%)。48例(96%)患者表现状态(PS)为0～1，既往治疗中位数为3例(0～12)。免疫治疗包括检查点抑制剂(82%：PD1=7，PD-L1=11，CTLA 4=22，其他=1)，其中42%是联合用药，还有疫苗(14%)和细胞因子(4%)。中位总生存期(OS)为13.4个月(11.2个月：未达到)。中位无进展生存期(PFS)为2.4个月(95%CI=1.9～3.2个月)。3例GIST、3例脂质体肉瘤(2例DDLS、1例WDLS)、2例ASPS、2例LEYOYO、1例骨科均有较好的疗效。3个月时PFS为34%(23%，50%)，6个月为16%(8%，30%)，1年为6%(2%，20%)。2例(4%)出现假性进展继发稳定疾病。3/4级不良反应包括皮疹(10%)、发热(6%)、疲劳(6%)、恶心呕吐(6%)。在接受试验的晚期肉瘤患者中，免疫治疗有良好的耐受性。传统的观点认为化疗主要通过细胞毒作用直接杀伤肿瘤细胞导致癌细胞凋亡，而免疫治疗主要通过调动机体免疫系统达到抑制肿瘤生长和长期控制肿瘤的目的。由于化疗存在降低免疫力的抑制作用，因此化疗联合免疫治疗的模式曾经一度受到质疑。但是，随着临床前研究的深入，越来越多的数据支持化疗和免疫治疗存在协同作用。从而为免疫治疗促进骨肉瘤的化疗提供了理论依据支持，特别是那些基于免疫检查点抑制剂的免疫疗法，在多种肿瘤类型（如恶性黑素瘤、肺、头和颈以及膀胱癌）中显示出了良好的活性。在欧洲获批用于与辅助化疗联合使用[10,11], 欧洲药物管理局批准的米非司酮(Mepact)对骨肉瘤免疫治疗。本文综述了当代临床试验前的最新发现，随着骨肉瘤生物学和基因组复杂性的进一步研究，以及利用免疫治疗对骨肉瘤化疗促进作用的研究进展。
CD偶联物
目前OS治疗的标准策略是新辅助化疗，其次是手术和术后化疗.为了提高患者的生存率，人们对新的治疗方法进行了评估，主要是用抗体-药物结合物或免疫结合物进行免疫治疗。这些分子由与有毒分子(药物、放射性核素或毒素)连接的载体(通常是抗体)组成。虽然已经进行了一些免疫结合的临床试验，主要是在血液病中，但它们作为治疗药物的潜力在许多类型的癌症中相对较少被发掘。Sun Z [12]等开展临床前研究Pd-1/Pd-L1通路与血管生成双重识别纳米粒对恶性肿瘤化疗的促进作用的机制。可通过抑制肿瘤浸润淋巴细胞(TILS)诱导免疫抑制。PD-1/PD-L1通路涉及受体-配体相互作用，Pd-L1(程序性细胞死亡配体1)识别肽DPPA-1与cgkrk序列(即肿瘤血管亲和肽)偶联，形成一种新的分子CD肽[13]。新合成的CD分子为肿瘤细胞和血管生成双靶向药物递送和修饰紫杉醇(PTX)负载的PCL纳米颗粒。纳米颗粒对肿瘤脉管系统内皮细胞和肿瘤细胞都具有高亲和力，从而提高了对肿瘤细胞的杀伤作用，抑制了血管生成。研究证明肿瘤脉管系统Pd-1/Pd-L1通路与血管生成双重识别纳米粒对恶性肿瘤化疗的促进作用[14]。PTX是一种广泛应用的化疗药物，对多种实体肿瘤如骨肉瘤、乳腺癌和脑胶质瘤具有抗肿瘤作用 [15,16]。然而，细胞免疫抑制严重影响恶性肿瘤的化疗[17]。阻断跨膜蛋白程序性细胞死亡蛋白1与配体pd-Ll之间的相互作用已成为治疗癌症的一种很有前景的免疫治疗方法[18]。上述研究以pd-1/pd-L1拮抗剂-DPPA-1肽和肿瘤血管生成靶向肽cgkrk修饰载药纳米粒子，有望成为肿瘤免疫化疗的候选药物，开创了肿瘤免疫治疗与化疗的新组合。
随着免疫治疗癌症的临床工作的开展，人们利用T细胞免疫功能来治疗实体肿瘤，包括骨肉瘤。这最好的例子是使用免疫检查点阻断抗体，这种抗体抗原复合物改变了对黑色素瘤、肾细胞癌和非小细胞肺癌等肿瘤的治疗前景 [19-21] 。骨肉瘤对检查点抑制剂的治疗具有较强的抵抗力 [22] ，是因为它的相对免疫耗竭(“冷”)微环境，缺乏肿瘤浸润的淋巴细胞(TILs)和低强度细胞毒性T淋巴细胞(CTL)的表达来杀死肿瘤 [23-24] 。这些数据也与观察到的肿瘤细胞倾向于表达低负荷的非同义DNA突变相一致，作为肿瘤抗原的新抗原，能够诱导一个强大的T细胞应答 [25-26] 。这也符合这样的观点，即非同义突变负荷高的肿瘤是对免疫检查点抑制剂最敏感的 [27-28] 。除了其“冷”的免疫状态外，骨肉瘤肿瘤部位的强免疫抑制微环境阻止了有效的T细胞活化 [29] 。这包括一些免疫抑制机制的贡献，这些机制比检查点阻断抗体靶点所针对的检查点受体更具有压迫性。除了免疫检查点抑制剂用于启动免疫治疗外，化疗还能对免疫系统产生积极影响，导致骨肉瘤肿瘤部位TIL密度增加，这与疾病预后的提高相关。在本文中，我们报告了针对骨肉瘤表面抗原的免疫结合物，考虑到体内和体外的研究。到目前为止，已经在临床前环境中进行了几次尝试，报告了令人兴奋的结果，并证明了这一想法的有效性。了解免疫复合物与化疗结合治疗骨肉瘤的真正效果，可能会提供更多关于病人选择的信息。此外，新的机会可能出现在正在进行的临床试验的骨肉瘤患者的未结合抗体，可以代表未来的候选作为载体的免疫结合。
在众多的临床前肿瘤模型中，免疫治疗提高了肿瘤化疗和肿瘤靶向及抗血管生成抗体的疗效。在非小细胞肺癌异种移植中，免疫抑制剂增强了抗EGFR肿瘤靶向抗体西妥昔单抗联合化疗的抗肿瘤效果[30]。在一种表达细胞表面蛋白MUC 1的同基因T细胞淋巴瘤模型中，IMPRIME显著增强了抗MUC 1肿瘤靶向抗体的活性。该模型的机制研究揭示了补体蛋白C3、补体受体3(CR3)和Gr1阳性髓系免疫细胞在IMPRI[31-32]抗肿瘤活性中的关键作用。抗血管生成抗体贝伐单抗联合化疗除能提高抗肿瘤治疗抗体的活性外，还能提高抗血管生成抗体对卵巢癌和非小细胞肺癌移植瘤的抗肿瘤作用[33-34]。
多种治疗方式联合治疗骨肉瘤一定程度上改善了早期患者的UPS和OSR[35-38]，但复发和转移性疾病患者的预后仍然很差，5年总生存率在10-30%之间，无论使用手术、化疗，分子靶向治疗和放疗[39-45]。这种临床方案需要对新的治疗策略进行研究努力，包括探索具有显著改善黑素瘤患者预后的免疫治疗，目前正在其他实体瘤中探索。最近使用检查点抑制剂没有观察到在最初的肉瘤试验中临床显著效果。这很可能是由于它们相对较小的Neo-抗原负载和在肿瘤微环境中存在重要的免疫抑制元件 [46-47] 。在这个领域中，有希望的免疫治疗方法是基于抗肿瘤免疫效应物的过继输注，其重要结果最近报告了用抗NY-ESOO1工程T淋巴细胞治疗的肉瘤的选择病例 [48-52] 。
肿瘤免疫环境
重新规划肿瘤免疫环境，使免疫检查点抑制剂有效结合，揭示了其多种活性，为其与免疫检查点抑制剂的联合应用提供了坚实的理论基础。化疗可以导致肿瘤的凋亡，凋亡肿瘤细胞释放大量的抗原，这些抗原物质可以促使免疫微环境的改变，通过T细胞免疫效应杀伤肿瘤细胞。其次，化疗可以去除部分免疫抑制活性的功能细胞，如髓样来源的抑制性细胞(myeloid-derived suppressor cells, MDSC)和调节性T细胞，化疗通过细胞毒作用抑制这些细胞的免疫力，从而改善机体抗肿瘤免疫效应，达到免疫化疗的协同效果。CXCL 12的表观遗传调控在骨肉瘤的肿瘤进展和免疫应答中起重要作用 [53-56] 。 为了最大限度地提高抗肿瘤药物的治疗效果，降低有效剂量和全身毒性，已开发出不同的给药系统。实现这些目标的理想方法是开发一种药物，其活性仅限于恶性细胞，具有有限且可耐受的副作用。免疫共轭是朝这个方向发展的重要工具。这些分子由载体部分组成，通常是一种单克隆抗体(MAb)，其功能是向特定的肿瘤靶点传递毒性分子。然而，随着嵌合的、人化的、然后是完全人类抗体的发展，免疫原性随之降低[57]。有三种不同类型的细胞毒性物质被经典地用于产生免疫结合物：药理剂、放射性核素和毒素(细菌和植物)[58-60]。载体和治疗单元主要由一种化学连接剂连接在一起。
临床上，大多数骨肉瘤在IIB或III期已诊断为隐匿性微转移，与仅手术治疗后6个月内的高死亡率一致。寻找潜在的新的治疗途径可能包括操纵肿瘤的微环境和它的免疫浸润[61]。然而，关于骨肉瘤中肿瘤免疫细胞相互作用的研究却很少。例如，尽管肿瘤相关巨噬细胞在几种肿瘤类型[62]中表现出预后较差的原发瘤，但一项单一的骨肉瘤研究显示，它们与高级别骨肉瘤的转移抑制呈正相关，而不论其表现型为M1或M2。骨贝丁(Trabectedin)是一种海洋来源的化疗药物，在欧洲已被批准用于作为软组织肉瘤[65]的二线单剂治疗。骨贝丁通过影响肿瘤细胞和免疫浸润细胞，明显抑制骨肉瘤原发肿瘤的生长和转移，并与Pd-1阻断抗体联合应用，显示出更高的治疗效果。
免疫治疗被证明是一种很有前途的治疗人类恶性肿瘤的方法。逃避免疫监视被认为是恶性进展的主要因素。抑制性受体，尤其是CTLA-4和Pd-1，在抗肿瘤免疫效应的调节中起着关键作用。骨肉瘤是高度恶性的，目前的治疗仍然是一个挑战，尤其是那些有转移的患者。尽管对骨肉瘤的无论化疗还是免疫治疗中的一种治疗手段的取得了一些成就，效果仍然不能令人满意，但免疫治疗对骨肉瘤化疗协同机制给我们提供了新的策略，以供进一步探索。
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