Neoantigen cancer vaccines:a new star on the horizon

Immunotherapy represents a promising strategy for cancer treatment that utilizes immune cells or drugs to activate the patient's own immune system and eliminate cancer cells.One of the most exciting advances within this field is the targeting of neoantigens,which are peptides derived from non-synonymous somatic mutations that are found exclusively within cancer cells and absent in normal cells.Although neoantigen-based therapeutic vaccines have not received approval for standard cancer treatment,early clinical trials have yielded encouraging outcomes as standalone monotherapy or when combined with checkpoint inhibitors.Progress made in high-throughput sequencing and bioinformatics have greatly facilitated the precise and efficient identification of neoantigens.Consequently,personalized neoantigen-based vaccines tailored to each patient have been developed that are capable of eliciting a robust and long-lasting immune response which effectively eliminates tumors and prevents recurrences.This review provides a concise overview consolidating the latest clinical advances in neoantigen-based therapeutic vaccines,and also discusses challenges and future perspectives for this innovative approach,particularly emphasizing the potential of neoantigen-based therapeutic vaccines to enhance clinical efficacy against advanced solid tumors.

Identifying Comprehensive Genomic Alterations and Potential Neoantigens for Cervical Cancer Immunotherapy in a Cohort of Chinese Squamous Cell Carcinoma of the Cervix

Objective Genomic alterations and potential neoantigens for cervical cancer immunotherapy were identified in a cohort of Chinese patients with cervical squamous cell carcinoma(CSCC).Methods Whole-exome sequencing was used to identify genomic alterations and potential neoantigens for CSCC immunotherapy.RNA Sequencing was performed to analyze neoantigen expression.Results Systematic bioinformatics analysis showed that C>T/G>A transitions/transversions were dominant in CSCCs.Missense mutations were the most frequent types of somatic mutation in the coding sequence regions.Mutational signature analysis detected signature 2,signature 6,and signature 7 in CSCC samples.PIK3CA,FBXW7,and BICRA were identified as potential driver genes,with BICRA as a newly reported gene.Genomic variation profiling identified 4,960 potential neoantigens,of which 114 were listed in two neoantigen-related databases.Conclusion The present findings contribute to our understanding of the genomic characteristics of CSCC and provide a foundation for the development of new biotechnology methods for individualized immunotherapy in CSCC.

Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens

Therapeutic options for the treatment of colorectal cancer(CRC) are diverse but still not always satisfying. Recent success of immune checkpoint inhibition treatment for the subgroup of CRC patients suffering from hypermutated tumors suggests a permanent role of immune therapy in the clinical management of CRC. Substantial improvement in treatment outcome could be achieved by development of efficient patient-individual CRC vaccination strategies. This mini-review summarizes the current knowledge on the two general classes of targets: tumor-associated antigens(TAAs) and tumorspecific antigens. TAAs like carcinoembryonic antigen and melanoma associated antigen are present in and shared by a subgroup of patients and a variety of clinical studies examined the efficacy of different TAA-derived peptide vaccines. Combinations of several TAAs as the next step and the development of personalized TAA-based peptide vaccines are discussed. Improvements of peptidebased vaccines achievable by adjuvants and immunestimulatory chemotherapeutics are highlighted. Finally, we sum up clinical studies using tumor-specific antigens-in CRC almost exclusively neoantigens-which revealed promising results; particularly no severe adverse events were reported so far. Critical progress for clinical outcomes can be expected by individualizing neoantigen-based peptide vaccines and combining them with immunestimulatory chemotherapeutics and immune checkpoint inhibitors. In light of these data and latest developments, truly personalized neoantigen-based peptide vaccines can be expected to fulfill modern precision medicine's requirements and will manifest as treatment pillar for routine clinical management of CRC.

Profiling of hepatocellular carcinoma neoantigens reveals immune microenvironment and clonal evolution related patterns

Objective: Neoantigens derived from tumor-specific genomic alterations have demonstrated great potential for immunotherapeutic interventions in cancers. However, the comprehensive profile of hepatocellular carcinoma(HCC) neoantigens and their complex interplay with immune microenvironment and tumor evolution have not been fully addressed.Methods: Here we integrated whole exome sequencing data, transcriptome sequencing data and clinical information of 72 primary HCC patients to characterize the HCC neoantigen profile, and systematically explored its interactions with tumor clonal evolution, driver mutations and immune microenvironments.Results: We observed that higher somatic mutation/neoantigen load was associated with better clinical outcomes and HCC patients could be further divided into two subgroups with distinct prognosis based on their neoantigen expression patterns. HCC subgroup with neoantigen expression probability high(NEP-H) showed more aggressive pathologic features including increased incidence of tumor thrombus(P=0.038), higher recurrence rate(P=0.029),more inclined to lack tumor capsule(P=0.026) and with more microsatellite instability sites(P=0.006). In addition,NEP-H subgroup was also characterized by higher chance to be involved in tumor clonal evolution [odds ratio(OR)=46.7, P<0.001]. Gene set enrichment analysis revealed that upregulation of MYC and its targets could suppress immune responses, leading to elevated neoantigen expression proportion in tumor cells. Furthermore, we discovered an immune escape mechanism that tumors could become more inconspicuous by evolving subclones with less immunogenicity. We observed that smaller clonal mutation clusters with higher immunogenicity in tumor were more likely to involve in clonal evolution. Based on identified neoantigen profiles, we also discovered series of neoantigenic hotspot genes, which could serve as potential actionable targets in future.Conclusions: Our results revealed the landscape of HCC neoantigens and discovered two clinically relevant subgroups with distinct neoantigen expression patterns, suggesting the neoantigen expression should be fully considered in future immunotherapeutic interventions.

Neoantigen vaccine:An emerging immunotherapy for hepatocellular carcinoma

Tumor-specific neoantigens,which are expressed on tumor cells,can induce an effective antitumor cytotoxic T-cell response and mediate tumor regression.Among tumor immunotherapies,neoantigen vaccines are in early human clinical trials and have demonstrated substantial efficiency.Compared with more neoantigens in melanoma,the paucity and inefficient identification of effective neoantigens in hepatocellular carcinoma(HCC)remain enormous challenges in effectively treating this malignancy.In this review,we highlight the current development of HCC neoantigens in its generation,screening,and identification.We also discuss the possibility that there are more effective neoantigens in hepatitis B virus(HBV)-related HCC than in non-HBV-related HCC.In addition,since HCC is an immunosuppressive tumor,strategies that reverse immunosuppression and enhance the immune response should be considered for the practical exploitation of HCC neoantigens.In summary,this review offers some strategies to solve existing problems in HCC neoantigen research and provide further insights for immunotherapy.

Prediction of neoantigens and their application in cancer treatment

Tumor antigens can be divided into tumor-associated antigens and tumor-specific antigens according to their specificity. Tumorassociated antigens are not unique to tumor cells, and can also be synthesized in small amounts by normal cells. Tumor-specific antigens, also called neoantigens, are formed by peptides that are entirely absent from the normal human genome [1]. Neoantigens are

NeoHunter:Flexible software for systematically detecting neoantigens from sequencing data

Complicated molecular alterations in tumors generate various mutant peptides.Some of these mutant peptides can be presented to the cell surface and then elicit immune responses,and such mutant peptides are called neoantigens.Accurate detection of neoantigens could help to design personalized cancer vaccines.Although some computational frameworks for neoantigen detection have been proposed,most of them can only detect SNV-and indel-derived neoantigens.In addition,current frameworks adopt oversimplified neoantigen prioritization strategies.These factors hinder the comprehensive and effective detection of neoantigens.We developed NeoHunter,flexible software to systematically detect and prioritize neoantigens from sequencing data in different formats.NeoHunter can detect not only SNV-and indel-derived neoantigens but also gene fusion-and aberrant splicing-derived neoantigens.NeoHunter supports both direct and indirect immunogenicity evaluation strategies to prioritize candidate neoantigens.These strategies utilize binding characteristics,existing biological big data,and T-cell receptor specificity to ensure accurate detection and prioritization.We applied NeoHunter to the TESLA dataset,cohorts of melanoma and non-small cell lung cancer patients.NeoHunter achieved high performance across the TESLA cancer patients and detected 79%(27 out of 34)of validated neoantigens in total.SNV-and indel-derived neoantigens accounted for 90%of the top 100 candidate neoantigens while neoantigens from aberrant splicing accounted for 9%.Gene fusion-derived neoantigens were detected in one patient.NeoHunter is a powerful tool to‘catch all’neoantigens and is available for free academic use on Github(XuegongLab/NeoHunter).

TSNAdb v2.0:The Updated Version of Tumor-specific Neoantigen Database

In recent years,neoantigens have been recognized as ideal targets for tumor immunotherapy.With the development of neoantigen-based tumor immunotherapy,comprehensive neoantigen databases are urgently needed to meet the growing demand for clinical studies.We have built the tumor-specific neoantigen database(TSNAdb)previously,which has attracted much attention.In this study,we provide TSNAdb v2.0,an updated version of the TSNAdb.TSNAdb v2.0 offers several new features,including(1)adopting more stringent criteria for neoantigen identification,(2)providing predicted neoantigens derived from three types of somatic mutations,and(3)collecting experimentally validated neoantigens and dividing them according to the experimental level.

Ionizable polymeric nanocarriers for the codelivery of bi-adjuvant and neoantigens in combination tumor immunotherapy

Ionizable lipid nanocarriers have made historical contribution to COVID-19 mRNA vaccines.Here,we report ionizable polymeric nanoparticles that co-deliver bi-adjuvant and neoantigen peptides for cancer immunotherapy in combination with immune checkpoint blockade(ICB).Current cancer ICB benefits only a small subset of patients,largely due to a lack of pre-existing target cells and checkpoint targets for ICB,tumor antigenic heterogeneity,and tumor immunosuppression.Therapeutic vaccines hold the potential to enhance ICB therapeutic efficacy by expanding antitumor cell repertoires,upregulating immune checkpoint levels and hence sensitizing ICB,and reducing tumor immunosuppression.Chemically defined peptide vaccines are attractive,but their current therapeutic efficacy has been limited due to 1)poor vaccine delivery to immunomodulatory lymph nodes(LNs)and antigen(Ag)-presenting cells(APCs),2)poor immunostimulant adjuvant efficacy with restricted target cell subsets in humans,3)limited adjuvant/Ag codelivery to enhance Ag immunogenicity,and 4)limited ability to overcome tumor antigenic heterogeneity.Here,we developed nanovaccines(NVs)using pH-responsive polymeric micellular nanoparticles(NPs)for the codelivery of bi-adjuvant[Toll-like receptor(TLR)7/8 agonist R848 and TLR9 agonist CpG]and peptide neoantigens(neoAgs)to draining LNs for efficient Ag presentation in a broad range of APC subsets.These NVs potentiated the immunogenicity of peptide Ags and elicits robust antitumor T cell responses with memory,and remodeled the tumor immune milium with reduced tumor immunosuppression.As a result,NVs significantly enhanced ICB therapeutic efficacy for murine colorectal tumors and orthotopic glioblastoma multiforme(GBM).These results suggest marked potential of bi-adjuvant/neoAg-codelivering NVs for combination cancer immunotherapy.

共表达IL-7/CCL19的新抗原反应性T细胞对小鼠肺癌的抗肿瘤研究

背景与目的新抗原反应性T细胞(neoantigen reactive T cell,NRT)具有抑制表达特异性新抗原的肿瘤生长的能力。然而,由于免疫浸润困难和肿瘤微环境的抑制,NRT在实体瘤中的治疗效果有限。本研究针对小鼠肺癌细胞设计出可以同时表达白细胞介素7(interleukin 7,IL-7)和趋化因子19(chemokine C-C motif ligand 19,CCL19)的NRT细胞(7×19 NRT),并对7×19 NRT细胞和常规NRT细胞的抗肿瘤效果差异进行了评估。方法针对小鼠Lewis肺癌细胞(Lewis lung carcinoma,LLC)进行了新一代测序和新抗原预测,制备了RNA疫苗,培养了NRT细胞,构建了编码IL-7和CCL19的逆转录病毒载体,转导NRT细胞并成功表达IL-7和CCL19,成功获得了7×19 NRT,并在小鼠体内外对其抗肿瘤效果进行了评估。结果7×19 NRT细胞通过分泌IL-7和CCL19显著增强T细胞的增殖和侵袭能力,在小鼠肺癌中实现了显著的抑瘤作用,延长了小鼠的生存期。经7×19 NRT治疗后,T细胞浸润肿瘤组织及肿瘤组织坏死显著增加。此外,7×19 NRT治疗与常规NRT治疗均安全。结论通过IL-7和CCL19的表达,NRT细胞的抗实体瘤能力显著增强,这是一种对NRT安全有效的基因修饰。

肿瘤抗原肽的HLA限制性确认和诱导反应性T细胞杀瘤能力评估

目的了解肿瘤抗原肽的HLA限制性以及其诱导的T细胞能否杀伤肿瘤细胞,探索无关供者来源细胞用于过继性抗肿瘤T细胞治疗。方法使用16个肿瘤抗原肽诱导18名无关供者外周血单个核细胞(PBMC)分化为反应性T细胞,并分析HLA型别;利用NetMHC数据库预测肽和HLA分子亲和力;选择HLA-A2限制性的肿瘤抗原肽诱导第二组17名无关供者的PBMC进行杀瘤实验,反应性T细胞作为效应细胞,T2细胞及肿瘤抗原肽同源的肿瘤细胞作为靶细胞,测量LDH(乳酸脱氢酶)释放量或者RTCA(实时无标记细胞分析仪)检测效应细胞杀瘤效率,比较HLA-A2+和A2-T细胞杀瘤效率。结果筛出和HLA-A2具有高亲和力的肿瘤抗原肽LM7,可诱导5/11 HLA-A2+为反应性T细胞,其中HLA-A2+纯合子则为3/3,而HLA-A2-者则为2/7。LM7诱导反应性T细胞杀伤肿瘤百分比A2+组明显强于A2-组(60.72±11.28 vs 47.2±4.46,P=0.03)。结论本研究显示NetMHC预测对于纯合子样品更有帮助,肿瘤抗原肽LM7具有HLA-A2限制性,可诱导部分HLAA2+PBMC分化为反应性T细胞,可杀伤肿瘤,应对供者进行HLA筛选并分析其细胞功能,其诱导的反应性T细胞可作为过继性T细胞抗肿瘤治疗的细胞来源。

肿瘤新抗原在肿瘤免疫治疗中的应用研究进展

肿瘤新抗原是由肿瘤特异性突变基因编码产生的抗原,具有高度特异性、显著外源性、突变随机性、分布集落性和基因突变相关性。这类抗原由于未受胸腺的阴性筛选,被T细胞识别为“异类”,不易受免疫耐受机制的影响且具有强免疫原性,是较好的免疫治疗靶点。肿瘤新抗原可用于制备治疗性疫苗,诱导培养靶向性更强的T淋巴细胞,用于肿瘤生存预后和免疫检查点封锁疗法应答的预测,在肿瘤诊断和治疗中的应用前景广阔。本文综述了近年来基于肿瘤新抗原免疫治疗的临床应用研究进展,并展望了未来的相关研究方向。

黑色素瘤个体化治疗策略:基于新抗原的特异性免疫治疗

免疫检查点抑制剂显著改善黑色素瘤患者预后,但原发及继发性耐药使治疗进入瓶颈期。T细胞受体与肿瘤抗原的结合是免疫治疗发挥作用的关键。肿瘤新抗原(neoantigen)由肿瘤特异性蛋白编码突变产生,在肿瘤细胞中特异表达,在正常组织不表达,不受中枢免疫耐受影响,是免疫治疗的理想靶点。靶向肿瘤新抗原的疫苗、过继性细胞回输及抗体药物等能有效加强和扩大肿瘤特异性免疫反应,促进T细胞识别并清除肿瘤,突破当前治疗瓶颈。本文就黑色素瘤新抗原的个性化治疗现状、最新进展、临床困境及未来发展方向进行讨论分析。

合成生物学在肿瘤疫苗设计中的应用进展

根据中心法则和细胞免疫学原则,利用合成生物学设计和生产新型肿瘤疫苗代表了癌症免疫治疗中的一个重要途径。本文概述了利用合成生物学针对两个主要方面(抗原选择和疫苗设计)的创新治疗性肿瘤疫苗的最新研究进展。针对肿瘤相关或特定抗原,开发更精确和有效的肿瘤疫苗引起了广泛关注。传统方法在抗原选择中主要针对肿瘤中的特定基因,而以高通量测序及质谱为基础筛选新抗原的方法明显改善了疫苗的靶向性及免疫原性。在疫苗类别方面,与传统多肽疫苗相比,通过对DNA、mRNA、病毒/细菌、细胞的工程化修饰而成的新型疫苗显著扩大了肿瘤疫苗的范围,从而大幅增强了不同肿瘤疫苗的免疫效果。合成生物学的快速发展将加速对肿瘤疫苗的实验研究进度,最终导致临床治疗效果的持续增强。

新抗原脉冲树突状细胞疫苗在肿瘤免疫治疗中的作用

新抗原脉冲树突状细胞疫苗(Neo-DCVac)是一种新型肿瘤免疫治疗手段。新抗原是指肿瘤细胞突变产生的具有较强免疫原性和肿瘤特异性的肽段。Neo-DCVac是基于新抗原被树突状细胞摄取、加工后递呈并激活T细胞引发机体免疫反应,从而发挥抗肿瘤作用。在高通量测序基础上发展而来的个体化Neo-DCVac有望成为肿瘤精准免疫治疗的新方向。本文从个体化Neo-DCVac构建、在实体瘤中联合治疗的临床应用、适宜接种人群和目前存在的局限性等方面进行综述,旨在为肿瘤免疫治疗的相关研究提供参考。

Wilm′s tumor gene1肽疫苗Galinpepimut-S在肿瘤免疫治疗中的应用

目的为Wilm′s tumor gene1(WT1)肽疫苗Galinpepimut-S(GPS)用于肿瘤免疫治疗的后续研究提供参考。方法采用计算机检索中国知网、PubMed等数据库自建库起至2022年12月的肿瘤免疫治疗相关文献,总结GPS在肿瘤免疫治疗中的应用现状。结果GPS能激发自身免疫系统,对WT1抗原产生强烈免疫反应而发挥抗肿瘤作用,在卵巢癌、恶性胸膜间皮瘤、急性髓系白血病、多发性骨髓瘤的治疗中均显示出较好的疗效。结论以GPS为代表的肿瘤疫苗是未来肿瘤治疗的重要方向,需进一步进行临床研究,以获取更多数据。

结肠直肠癌肿瘤疫苗研究现状及展望

结肠直肠癌(CRC)是全球发病率排名第3、但死亡率排名第2的恶性肿瘤。肿瘤疫苗是一种新型免疫治疗方式,向机体递呈肿瘤抗原,诱导抗肿瘤免疫应答,以形成长期免疫记忆。本文综述不同类型CRC疫苗近5年代表性临床/基础研究进展并展望未来。

PD-1抑制剂帕博利珠单抗用于宫颈癌治疗效果的影响因素研究

目的探讨程序性死亡受体1(PD-1)抑制剂帕博利珠单抗用于宫颈癌治疗效果的影响因素。方法回顾性分析2020年1月至2023年10月安徽省妇女儿童医学中心妇产科收治的使用帕博利珠单抗宫颈癌患者临床资料,根据疗效分为无效组和有效组。比较两组患者的临床资料[年龄、肿瘤类型、病理类型、病灶大小、分化程度、妊娠次数、生产次数、流产次数、绝经情况、肿瘤突变负荷(TMB)、DNA修复基因突变情况、PD-L1表达情况、糖尿病、高血压、治疗模式、体质量指数、肿瘤侵润淋巴细胞(TIL)表达情况、新抗原瘤内异质性(ITH)情况、有无肝病、家族史],采用Logistic回归分析确定影响宫颈癌患者帕博利珠单抗疗效的危险因素。结果研究共纳入60例患者,有效组42例,无效组18例。无效组TMB<143/Mb、DNA修复基因未突变、PD-L1低表达、单纯免疫治疗、TIL阴性、ITH高的患者占比均高于有效组(P<0.05)。多因素Logistic回归分析显示,TMB<143/Mb、DNA修复基因未突变、PD-L1低表达、单纯免疫治疗、TIL阴性、ITH高均是影响宫颈癌患者帕博利珠单抗疗效的危险因素(P<0.05)。结论宫颈癌患者PD-1抑制剂帕博利珠单抗疗效受TMB、DNA修复基因突变、PD-L1表达、治疗模式、TIL、ITH等因素的影响。

新抗原在结直肠癌中的研究进展

目前,结直肠癌有多种治疗策略,包括手术、化疗、放疗和靶向治疗。最新的研究发现,新抗原是一类肿瘤特异性抗原,被视为许多癌症免疫治疗的新靶点。基于新抗原的免疫治疗策略包括肿瘤疫苗和过继细胞疗法,其目的是通过增强宿主T细胞对新抗原的免疫反应来消除肿瘤细胞。该文总结了目前发现的结直肠癌新抗原及其免疫原性,并列举了基于新抗原治疗结直肠癌的临床试验,最后对当前研究面临的问题与挑战提出思考。

肿瘤新抗原疫苗的设计与优化策略

随着免疫检查点抑制剂和嵌合抗原受体T细胞疗法在不同适应证中的研究和临床应用,免疫治疗已经彻底改变了多种肿瘤的治疗方式。肿瘤新抗原疫苗作为一种前景广阔的免疫治疗方法,旨在激发针对新抗原的特异性T细胞反应。新抗原具有高度特异性,能够诱导和扩展肿瘤特异性T细胞库,即表位扩展。初步临床研究表明,通过快速、经济、高效的合成生物学技术,新抗原肿瘤疫苗已经展现出强大的肿瘤特异性免疫原性和抗肿瘤活性的初步证据。本文详细探讨了肿瘤新抗原的来源、发现与鉴定,以及新抗原疫苗的分类和免疫接种方案。还总结了肿瘤新抗原疫苗的优化策略,包括对预测算法、疫苗结构、免疫原性、给药方式和递送系统等方面的优化,以及联合佐剂、放化疗、免疫检查点抑制剂等方式,为个性化免疫疗法的发展提供了新的思路。