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肿瘤疫苗（tumor vaccine）通过将抗原辅以佐剂或通过树突状细作为递送载体，制备成疫苗制剂导入患者体内，激活抗原特异性细胞毒性T细胞从而发挥杀伤肿瘤细胞的作用。由于大部分宫颈癌与HPV E6和E7蛋白的持续表达密切相关，目前宫颈癌中研究较多的肿瘤疫苗均为治疗性HPV疫苗。临床上使用的治疗性HPV疫苗不同的技术来传递HPV相关抗原以及不同的佐剂来刺激免疫反应，按照载体不同分为活载体疫苗、肽/蛋白质疫苗、核酸疫苗和树突状细胞疫苗。
活载体疫苗选择细菌和病毒作为载体，诱导产生较强的细胞和体液免疫反应。同时，活载体疫苗也存在一些问题，首先是可能引起机体针对载体而非编码抗原的免疫反应，其次不适用于免疫低下或免疫缺陷的人群。
常见的细菌载体有李斯特菌和干酪乳杆菌等，将携带的E7蛋白以MHC依赖的方式呈递给T细胞。LmLLOE7（ADXS11001）为HPV-16 E7与LLO融合的李斯特菌疫苗，临床试验显示可引起晚期宫颈癌肿瘤缩小及外周血中HPV-16 E7特异性T细胞增加，目前该疫苗已进入Ⅲ期临床试验（NCT02853604）。
常见的病毒载体疫苗通常靶向E6和E7抗原，包括腺病毒、腺相关病毒、甲病毒和牛痘病毒等。目前，表达HPV 16/18型E6/E7的重组痘苗病毒TA-HPV、含牛乳头瘤病毒E2蛋白的基于安卡拉病毒的重组疫苗MVA E2、含 HPV 16 E6 / E7 和 IL - 2 基因的改良安卡拉病毒载体的tipapkinogen sovacivec疫苗，以及基于HPV-16 E6/E7的arenavirus病毒疫苗都已进入临床试验阶段，均能诱导HPV特异性细胞毒性T细胞免疫反应、较高病毒清除率和HPV相关CIN 2/3病变清除作用 ［129］ 。2022年ASCO会议报道了一项HB-201和HB-202治疗HPV 16+HNSCC的临床研究，安全性方面总体耐受性良好，未观察到剂量限制性毒性。无论是HB-201单药还是HB-201和HB-202联用均表现出了较好的抗肿瘤活性。HB-202/HB-201组和HB-201组中，出现靶病灶缩小的患者比例分别为56%和38%；出现内脏病变缩小的患者比例分别为59%和18%。
基于肽/蛋白质的疫苗较活载体疫苗具有更好的安全性和稳定性，但免疫原性较差，常需佐剂/脂质增强。源自HPV抗原的肽/蛋白质被树突状细胞吸收后以MHC依赖方式提呈给T细胞发挥作用。一项HPV 16-SLP（ISA101）治疗转移/复发宫颈癌的Ⅰ/Ⅱ临床试验中观察到T细胞应答和临床组织学应答 ［130］ 。TA-CIN疫苗即组织抗原-宫颈上皮内瘤变疫苗是一种靶向HPV-16 E6/E7和L2蛋白的疫苗，用于治疗高级别鳞状上皮内病变（highgrade squamous intraepithelial lesion，HSIL）和低级别鳞状上皮内病变（lowgrade squamous intraepithelial lesion，LSIL）是安全有效的，并观察到HPV-16 E6/E7特异性T细胞增多，目前评估其用于HPV相关宫颈癌的临床研究（NCT02405221）正在进行中。TVGV-1疫苗是一种由HPV 16型E7肽序列与铜绿假单胞菌外毒素A和内质网组成的融合蛋白疫苗，临床前研究发现可诱导HPV-16 E7特异性的CD8 + T细胞，目前接种TVGV-1治疗HSIL的Ⅱ期临床试验（NCT02576561）正在开展。2022ASCO会议报道了另一项联合应用PDS0101（脂质体HPV-16 E6/E7多肽疫苗）、M9241和bintrafusp alfa治疗HPV 16+实体瘤的Ⅱ期临床试验，初步数据显示，在既往未接受过ICIs治疗的患者中，ORR达到88%（7/8），既往接受过ICIs治疗的复发患者，ORR达27%（6/22）。
核酸疫苗是将编码某种抗原蛋白的外源基因（DNA和RNA）直接导入细胞内，通过宿主细胞的表达系统合成抗原蛋白，诱导宿主产生对该抗原蛋白的免疫应答，进而达到预防和治疗疾病的目的。根据主要成分的不同，核酸疫苗可主要分为DNA疫苗和mRNA疫苗。
DNA疫苗由编码疫苗抗原的重组真核表达载体组成，能同时激活体液免疫和细胞免疫。许多临床试验表明DNA疫苗治疗实体瘤具有良好的耐受性和特异性 ［131］ 。2022年ASCO会议报道了一项肿瘤新生抗原DNA疫苗及相关抗原疫苗prostvac联合PD-1抗体nivolumab/CTLA-4抗体ipilimumab治疗转移性激素敏感性前列腺癌（metastatic hormone-sensitive prostate cancer，mHSPC）患者的单中心Ⅰ期临床试验（NCT03532217）。试验初步证明了个体化新生抗原DNA疫苗、肿瘤相关抗原疫苗prostvac联合nivolumab/ipilimumab治疗mHSPC患者的安全性、耐受性及抗肿瘤活性。
近年来，DNA疫苗在治疗CIN和宫颈癌中取得了较好的成绩。VGX-3100是编码HPV E6/E7的DNA疫苗，是全球首个开发用于HPV相关癌前病变的治疗性疫苗。VGX-3100的Ⅱ期临床试验显示，部分接受治疗的CIN 2/3患者病变消退 ［132］ ，目前正在宫颈HSIL患者中进行Ⅲ期临床试验。2021年ASCO会议报道了HPV治疗性疫苗GX-188E联合帕博利珠单抗治疗HPV 16/18阳性的经标准治疗后复发的晚期宫颈癌的Ⅱ期临床试验（KEYNOTE-567），试验结果表明与单独使用PD-1单抗相比，联用GX-188E疫苗可以获得更高的疗效应答；且在PD-L1阳性、HPV 16阳性的宫颈鳞癌患者中有更高的应答率。VB10.16是一款潜在“现货型”DNA肿瘤疫苗，用于治疗HPV 16阳性肿瘤表现出良好的抗肿瘤活性。在接受VB10.16单药治疗的宫颈癌中，观察到PD-L1表达水平提高。基于此，Nykode开展了VB10.16联合阿替利珠单抗治疗晚期或复发性、不可切除的HPV 16阳性宫颈癌患者的多中心、单臂、开放标签的Ⅱ期临床研究（VB C-02），其中期结果显示在中位随访时间为6个月时，ORR达21%，包括2名CR的患者和6名PR的患者，疾病控制率（disease control rate，DCR）达64%；且在PD-L1阳性和PD-L1阴性的患者中均观察到了抗肿瘤活性。VB C-02研究表明联合VB10.16治疗性疫苗和PD-1/PD-L1单抗在PD-L1阴性人群中也有潜在的临床获益。
mRNA疫苗（mRNA vaccine）就是以病原体抗原蛋白对应的mRNA结构为基础，通过不同的递送方式递送至人体细胞内，经翻译后能刺激细胞产生抗原蛋白、引发机体特异性免疫反应的疫苗产品。相比于传统疫苗和DNA疫苗，mRNA疫苗具有研发周期短、相对安全、免疫应答时间长、生产周期短等优势。COVID-19 mRNA疫苗证明了mRNA疗法的前景。随着mRNA疫苗研发技术的成熟，mRNA疫苗用于抗癌症有了越来越强的可行性。目前已有超过20种基于mRNA的免疫疗法进入临床试验，并在实体瘤的治疗中取得了一些有意义的结果。
抗肿瘤mRNA疫苗根据作用机理一般分为两类，即基于树突状细胞给药的mRNA疫苗和直接注射的mRNA疫苗。基于树突状细胞给药的mRNA疫苗是指用体外转录后的mRNA转染树突状细胞，在细胞质中翻译形成抗原，激活树突状细胞，再将已激活的树突状细胞注入人体，激发体内免疫系统应答，从而达到杀死肿瘤细胞的目的。直接注射的mRNA疫苗以粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony stimulating factor，GM-CSF）作为佐剂，将编码相关抗原的mRNA皮下注射入患者体内，从而刺激机体产生抗原抗体，抑制癌细胞的增长 ［133，134］ 。
癌症疫苗可以选择在肿瘤细胞中优先表达的TAA为靶向，目前多个以TAA为靶点的mRNA疫苗正在进行临床研究。BNT111是一种使用lipoplex脂质体纳米颗粒包裹4种黑色素瘤抗原（NY-ESO-1、MAGE-A3、酪氨酸酶和TPTE）的mRNA疫苗。研究表明BNT111单独或联合ICIs治疗晚期黑色素瘤患者具有良好的安全性和抗肿瘤反应，2022年FDA批准BNT111快速通道资格，用于治疗晚期黑色素瘤。多项研究表明靶向TAA的mRNA疫苗可能与其他靶向TAA的CAR-T/NK细胞疗法具有协同作用，表现出“1+1>2”的抗肿瘤免疫效应。2022年AACR会议报道了BNT211（CLDN6 CAR-T + CARVac）治疗复发性或难治性晚期实体瘤患者的安全性和初步疗效，研究表明CLDN6 CAR-T单药或与CARVac联合用药具有良好的耐受性和安全性，在睾丸癌患者表现出令人鼓舞的抗肿瘤活性。肿瘤相关抗原疫苗ADXS-503（A503）是一种以李斯特菌为基础的免疫生物工程减毒活疫苗，包含NSCLC中22种肿瘤相关抗原，能够诱导NSCLC患者体内产生特异性T细胞反应。2022年ASCO会议报道，A503疫苗联合帕博利珠单抗治疗转移性NSCLC的疾病控制率高，且安全可控。2022年ASCO会议还报道了一种TAA疫苗Nous-209联合PD-1抗体帕博利珠单抗用于DNA错配修复功能缺陷（DNA mismatch repair，dMMR）/微卫星不稳定（MSI）肿瘤患者治疗具有较好的安全性和抗肿瘤活性 ［135］ 。
靶向TAA的mRNA疫苗在黑色素瘤、非小细胞肺癌等多种实体瘤中取得了一定的成绩，但在宫颈癌治疗中仍缺乏相关报道。目前存在一些问题限制编码TAA的直接注射mRNA疫苗的临床运用：①对于某些实体瘤，仅鉴定出有限的TAA，导致其应用受到了限制；②患者的TAA具有广泛的变异性，导致其可以逃避免疫效应物的识别；③TAA也存在于正常组织中，因此针对TAA的疫苗可能会引发中枢和外周耐受反应，从而降低疫苗接种效率或者产生针对正常组织的自身免疫。
肿瘤在发展的过程中不断积累突变和基因组变化，产生新抗原。这些新抗原特异性存在于癌细胞中，且具有免疫原性。大多数新抗原产生于个体患者所独有的突变，这使得靶向新抗原的免疫疗法成为一种完全个体化的治疗方法。个性化癌症疫苗的开发策略是识别肿瘤特异性突变的基因序列，预测肿瘤新抗原，从而设计个性化肿瘤疫苗以重新激活肿瘤特异性T细胞。这些抗原只在肿瘤中表达，因此不会引起由于T细胞对健康组织的攻击而产生的毒副作用 ［136］ 。目前针对新抗原已经开发了各种个性化肿瘤疫苗，其中，mRNA疫苗凭借在免疫原性、安全性及工业化生产方面的突出优势，已经在个性化癌症疫苗领域占据了重要地位。
编码肿瘤新抗原的mRNA疫苗是一种真正的个性化疫苗，目前有多项评估其安全性和有效性的临床试验正在进行中。BNT122是一种可以靶向20种新抗原的mRNA癌症疫苗。BNT122在治疗转移性黑色素瘤、胰腺导管腺癌的Ⅰ期临床试验中显示出良好的抗肿瘤活性，且激发新抗原特异性T细胞反应。TG4050疫苗是一种个性化设计的以修饰的痘苗病毒——安卡拉病毒（MVA）为载体的新生抗原疫苗，每个TG4050疫苗可编码30个新生抗原位点，2022年ASCO会议报道了TG4050疫苗用于卵巢癌复发患者，以及接受根治手术的鳞状细胞癌患者的安全性、耐受性及部分抗肿瘤活性（NCT03839524，NCT04183166）。mRNA-4157疫苗是一种封装在脂质纳米颗粒个性化的新生抗原癌症疫苗，可编码34种新生抗原。2019年ASCO会议报道了mRNA-4157和keytruda联合用药的Ⅰ期临床研究，疫苗是安全可耐受的。后续研究进一步表明mRNA-4157联合keytruda疗法能够缩小多种晚期实体肿瘤病灶。mRNA-5671，编码了4种最常见的 KRAS 突变（G12D、G12V、G13D和G12C）的多肽序列，目前正在携带 KRAS 基因突变的晚期或转移性非小细胞肺癌、结肠直肠癌及胰腺癌中进行Ⅰ期临床试验。
个性化mRNA肿瘤疫苗的研发基于患者特异性的新抗原的发现，有望实现肿瘤精准治疗，目前多款靶向TSA的mRNA疫苗已进入临床阶段。尽管目前尚无靶向TSA的mRNA疫苗治疗宫颈癌的临床研究报道，但通过其在多种实体瘤中的成功，我们相信个性化mRNA宫颈癌疫苗是可期待的。但这种个性化mRNA肿瘤疫苗的临床推广仍面临一系列挑战，包括新抗原选择困难、疫苗制备时间长、载体选择和成本高等。简而言之，从抗原筛选到疫苗制备，再到疫苗递送至人体，个性化肿瘤疫苗制备的每个环节都存在着巨大的挑战。
基于树突状细胞的mRNA疫苗使用确定的TAA/TSA的mRNA转染树突状细胞，体外激活扩增后回输到患者体内发挥抗肿瘤能力。自1996年首次报道了用电穿孔转染mRNA的树突状细胞可以引发针对肿瘤抗原的有效免疫反应后，许多研究和临床试验都证实了这种方法的可行性和有效性。目前已经在转移性前列腺癌、转移性肺癌、肾细胞癌、脑癌、黑色素瘤、急性髓系白血病、胰腺癌等多种癌症中验证了这种疫苗的潜力。此外，还有多项临床试验显示，树突状细胞mRNA癌症疫苗与传统化疗药物或免疫检查点抑制剂联用可能具有更好的改善效果 ［137-139］ 。
尽管目前尚无mRNA肿瘤疫苗治疗宫颈癌的临床前和临床研究报道，但mRNA疫苗作为一种个性化、安全有效的癌症治疗方法，在宫颈癌中仍是可期待的。首先，宫颈癌是明确的HPV相关肿瘤，多种免疫疗法靶向病毒特异性抗原——HPV E6和E7癌蛋白均已取得一定成绩，因此，靶向HPV癌蛋白制备mRNA疫苗可能是一个潜在方向。其次，宫颈癌是一种TMB相对较高的肿瘤类型，可能产生更多免疫原性肿瘤新抗原。最后，目前已有靶向HPV的预防性mRNA疫苗正在研制中。
树突状细胞（DC）是唯一能够激活初始型T细胞的专职抗原递呈细胞。DC疫苗属于全细胞疫苗的变体，DC作为抗原呈递细胞发挥作用，充当先天免疫和适应性免疫之间的桥梁。自2010年批准第一个DC疫苗用于前列腺癌治疗以来 ［140］ ，以DC为基础的肿瘤免疫治疗在国内外取得了较大进展，在黑色素瘤、脑胶质瘤、肾癌、乳腺癌和卵巢癌等实体瘤中均显示出良好的抗肿瘤作用。临床前研究发现，用HPV-16/18 E7刺激DC并与IL-2联合回输患者或用全长HPV-16/18 E7和匙孔血蓝蛋白（keyhole limpet hemocyanin，KLH）共同刺激DC成熟后能有效治疗宫颈肿瘤。Ⅰ期临床试验表明靶向HPV的宫颈癌DC疫苗可激发E7特异性抗肿瘤免疫，DC疫苗在宫颈癌治疗中的前景是可期待的。
溶瘤病毒（oncolytic virus，OV）是一类可以选择性地感染和杀死癌细胞，但不伤害正常细胞的天然或重组DNA或RNA病毒。溶瘤病毒通过直接杀伤或激活免疫反应发挥抗肿瘤活性。溶瘤病毒早在20世纪中期就开始被尝试用于肿瘤治疗。随着肿瘤免疫治疗的发展，溶瘤病毒类药物在多种恶性肿瘤等中的治疗潜力得到越来越多的关注。目前常见的溶瘤药物所属病毒包括以下4种：单纯疱疹病毒（herpes simplex virus，HSV）、牛痘病毒（vaccinia virus，VV）、腺病毒（adenovirus，Adeno）和呼肠孤病毒（reovirus，REO） ［141］ 。到目前为止，全球已有5种溶瘤病毒药物被批准用于鼻咽癌、黑色素瘤、HNSCC和脑胶质瘤的治疗。以单纯疱疹病毒1型（herpes simplex virus-1，HSV-1）为载体的T-VEC单药或联用ICI治疗复发不可切除的黑色素瘤表现出良好的耐受性、安全性和抗肿瘤活 ［142，143］ ，T-VEC是首个FDA批准用于治疗复发不可切除的黑色素瘤的溶瘤病毒药物。2021年日本批准teserpaturev用于治疗胶质母细胞瘤等脑癌。重组人5型腺病毒注射液（H101）是首个国家药品监督管理局批准的用于治疗晚期鼻咽癌的基因编辑溶瘤病毒药物，在结直肠癌肝转移、恶性黑色素瘤中也具有良好抗肿瘤活性。此外，溶瘤病毒ONCOS-102（Ad5/3-D24-GMCSF）联合培美曲塞/顺铂治疗不可切除的恶性胸膜间皮瘤的临床试验结果表明ONCOS-102能够刺激局部和全身免疫应答并重新调节肿瘤微环境。
溶瘤病毒在妇科肿瘤治疗中也取得了一定疗效。在一些复发/难治妇科肿瘤的小样本研究中，联合溶瘤病毒和放化疗能有效控制肿瘤进展，总体有效率达70% ［144］ 。H101瘤体注射联合放疗治疗难治性及复发转移性妇科肿瘤的临床研究（NCT05051696）正在进行中。
近年来，随着对病毒基因功能和结构的认识不断深入，优化设计和操作病毒基因组以产生非致病性病毒已成为溶瘤病毒研究的方向，极大推动了溶瘤病毒疗法的进步。然而，溶瘤病毒药物作为单一疗法疗效有限。许多研究表明溶瘤病毒与化疗或免疫治疗药物联合治疗，甚至多种溶瘤病毒药物联合应用，可能会更有效地控制肿瘤进展。
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