Tumor initiation and progression are highly intricate biolog-ical processes,and mutation-driven tumorigenesis is a pri-mary underlying cause.Personalized cancer vaccines have been developed to exploit these specific m...Tumor initiation and progression are highly intricate biolog-ical processes,and mutation-driven tumorigenesis is a pri-mary underlying cause.Personalized cancer vaccines have been developed to exploit these specific mutations,particu-larly in the form of tumor neoantigens,to induce immune responses,particularly the activation of CD8+T cells,which can attack malignant cells.Since tumor mutations result in protein sequence alterations distinct from those in normal tissues,therapies that precisely target these alterations could,in principle,confer effective tumor control while minimizing off-target effects.展开更多
Immunotherapy,particularly immune checkpoint inhibitors(ICIs)programmed death-ligand 1/programmed death-1(PD-L1/PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),has heralded a new era of tumor treatment.Al...Immunotherapy,particularly immune checkpoint inhibitors(ICIs)programmed death-ligand 1/programmed death-1(PD-L1/PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),has heralded a new era of tumor treatment.Although ICIs have clinical benefits,their complex heterogeneity and diverse resistance mechanisms critically limit their efficacy.Neoantigens,arising from tumor-specific alterations,offer novel targets for individualized immunotherapy,because of their high immunogenicity and tumor specificity.In the past decade,neoantigen-based tumor vaccines have been demonstrated to be a promising immunotherapy strategy to prime the tumor-specific immune response.These therapeutic vaccines include peptide vaccines,nucleic acid vaccines,and dendritic cell(DC)vaccines,and are categorized according to the neoantigen source and delivery method.In vivo,neoantigens are processed and presented by antigen-presenting cells(APCs)via the peptide-Major Histocompatibility Complex(pMHC)for T cell recognition,thereby triggering specific immune responses.Because DCs,the most potent APCs,play crucial roles in antitumor immunity,neoantigen-based DC vaccines provide a promising therapeutic strategy.A series of global clinical trials are exploring the safety,feasibility,and efficacy of neoantigen-based DC vaccines in tumors.This review focuses on current progress in clinical research on neoantigen-based DC vaccines in the treatment of solid tumors.展开更多
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 hyp...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.展开更多
Objective: Neoantigens derived from tumor-specific genomic alterations have demonstrated great potential for immunotherapeutic interventions in cancers. However, the comprehensive profile of hepatocellular carcinoma(H...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.展开更多
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 ...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.展开更多
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...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.展开更多
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 withi...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.展开更多
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 amo...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展开更多
Neoantigen vaccines and oncolytic viruses are emerging immunotherapies that can reshape the tumor microenvironment(TME).However,tumors with low mutation burdens often respond poorly to immunotherapies because of their...Neoantigen vaccines and oncolytic viruses are emerging immunotherapies that can reshape the tumor microenvironment(TME).However,tumors with low mutation burdens often respond poorly to immunotherapies because of their limited immunogenicity.Developing effective immunotherapy strategies for these types of tumors remains a significant challenge.In this study,we engineered oncolytic adenoviruses to accurately amplify neoantigen expression within tumor cells,which demonstrated superior efficacy compared to synthetic long peptide vaccines and showed enhanced effectiveness in a low mutation burden intrahepatic cholangiocarcinoma model.Building on this,we further developed NeoViron,which coexpresses neoantigens and Flt3L,a dendritic cell growth factor,to promote antigen presentation and T-cell infiltration simultaneously.NeoViron significantly inhibited tumor growth and prevented metastasis in intrahepatic cholangiocarcinoma animal models.Mechanistically,NeoViron enhanced the cytotoxicity of CD8+T cells and promoted the expansion of CD69+CD8+tissue-resident memory T cells and TCF1+CD8+stem-like T cells to promote anti-tumor immunity and immune memory.When combined with anti-PD-1,it further enhances the cytotoxicity of tissue-resident memory T cells to eradicate solid tumors.These findings demonstrate that NeoViron can effectively sensitize lowmutation tumors to immunotherapy by increasing neoantigen expression and antigen-presentation efficacy,offering a promising strategy for cancer treatment,particularly for tumors with scarce neoantigens.展开更多
Neoantigen-based immunotherapy has demonstrated long-lasting antitumor activity.The recognition of neoantigens by T cell receptors(TCRs)is considered a trigger for antitumor responses.Due to the overwhelming number of...Neoantigen-based immunotherapy has demonstrated long-lasting antitumor activity.The recognition of neoantigens by T cell receptors(TCRs)is considered a trigger for antitumor responses.Due to the overwhelming number of TCR repertoires in the human genome,pinpointing neoantigen-specific TCRs is a formidable challenge.Recent studies have identified a number of functional neoantigen-specific TCRs,but the corresponding information is scattered across published literature and is difficult to retrieve.To improve access to these data,we developed an immunoinformatic database(NeoTCR)containing a unified description of publicly available neoantigen-specific TCR sequences,as well as relevant information on targeted neoantigens,from experimentally-supported studies across 17 cancer subtypes.A user-friendly web interface allows interactive browsing and running of complex database queries.To facilitate rapid identification of neoantigen-specific TCRs from raw sequencing data,NeoTCR offers a one-stop analysis for annotation and visualization of TCR clonotypes,discovery of existing neoantigen-specific TCRs,and exclusion of bystander virus-associated TCRs.NeoTCR represents a unique tool to expedite future studies of neoantigen-specific TCRs and the development of neoantigen-based immunotherapy.NeoTCR is available at http://neotcrdb.bioxai.cn/and https://github.com/lyot vincent/NeoTCR.展开更多
Recently,T cells expressing engineered T cell receptor(TCR-T cells)have become recognized as a promising tumor cell therapy for solid tumors because of their ability to selectively kill tumor cells with less destructi...Recently,T cells expressing engineered T cell receptor(TCR-T cells)have become recognized as a promising tumor cell therapy for solid tumors because of their ability to selectively kill tumor cells with less destruction of other cells and their high safety when used as autologous T cells.Several studies and clinical tests have been conducted to demonstrate its potential as a novel therapy.However,previous research has mainly focused on antigens;these common targets for TCR-T are tumor-associated antigens,which exhibit expression not only in tumor cells but also in normal cells,resulting in off-target risk and not considering the heterogeneity of different patients.In contrast,neoantigens offer superior specificity as they are uniquely expressed on tumor cells due to genomic alterations.Given the frequent occurrence and notable role of genetic mutations in tumorigenesis and tumor progression,identification and targeting of neoantigens is a valuable therapeutic direction.This perspective delves into various antigen classifications,including their characteristics and advantages,as well as strategies for identifying and validating neoantigens that have emerged from numerous research studies.These insights are crucial for guiding the search for new neoantigens.We also review significant and representative studies involving TCR-T and other immunotherapies that target neoantigens to assess the therapeutic effectiveness of TCR-T therapy.Moreover,we discuss the challenges and complexities inherent in TCR-T therapy and propose potential solutions for these issues.In this perspective,we aim to provide fresh perceptions and strategies for cancer treatment by highlighting the potential of TCR-T and exploring its challenges and future directions.It also seeks to propel the development of precision medicine and personalized therapy,offering hope for more effective and targeted cancer treatments in the future.展开更多
Probiotics are natural systems bridging synthetic biology,physical biotechnology,and immunology,initiating innate and adaptive anti-tumor immune activity.We previously constructed an all-inone engineered food-grade pr...Probiotics are natural systems bridging synthetic biology,physical biotechnology,and immunology,initiating innate and adaptive anti-tumor immune activity.We previously constructed an all-inone engineered food-grade probiotic Lactococcus lactis(FOLactis)which could boost the crosstalk among different immune cells such as dendritic cells(DCs),natural killer cells,and T cells.Herein,considering the limited clinical efficacy of naked personalized neoantigen peptide vaccines,we decorate FOLactis with tumor antigens by employing a Plug-and-Display system comprising membrane-inserted peptides.Intranodal injection of FOLactis coated with neoantigen peptides(Ag-FOLactis)induces robust DCs presentation and neoantigen-specific cellular immunity.Notably,Ag-FOLactis not only triggers a 45-fold rise in the quantity of locally reactive neoantigen-specific T cells but also induces epitope spreading in both subcutaneous and metastatic tumor-bearing models,leading to potent inhibition of tumor growth.These findings imply that Ag-FOLactis represents a powerful platform to rapidly and easily display antigens,facilitating the development of a bio-activated platform for personalized therapy.展开更多
Cancer immunotherapy faces challenges in achieving durable antitumor immunity due to poor immunogenicity of tumor antigens and inadequate immune activation.In this study,we developed a self-assembling neoantigen nanop...Cancer immunotherapy faces challenges in achieving durable antitumor immunity due to poor immunogenicity of tumor antigens and inadequate immune activation.In this study,we developed a self-assembling neoantigen nanoparticle vaccine(Neo-NV)integrating charge-modified Kirsten rat sarcoma viral oncogene homologue(KRAS)G12V-derived multi-epitope peptides with dual adjuvants—hydrophilic CpG oligonucleotides(ODNs)and hydrophobic R848.Neo-NV demonstrated enhanced antigen uptake by dendritic cells(DCs)in vitro,promoting DC maturation and M1 macrophage polarization,while stimulating robust neoantigen-specific CD8+T cell responses.Additionally,Neo-NV enhanced the activation of antigen-specific T cells from human peripheral blood mononuclear cells(PBMCs)and their proliferation in immunodeficient NSG mice.Moreover,it significantly increased CD4+and CD8+T cell proliferation in the spleen and PBMCs of mice,while promoting the activation and aggregation of CD4+and CD8+T cells in the draining lymph nodes.In murine KRAS G12V melanoma models,Neo-NV significantly suppressed tumor growth and prolonged survival without systemic toxicity,as evidenced by stable body weight and normal hepatic/renal biomarkers.Mechanistically,Neo-NV enhanced tumor-infiltrating lymphocyte(TIL)activation and memory precursor T cell formation.This study establishes Neo-NV as a modular platform for personalized immunotherapy,highlighting the synergy of dual adjuvants and self-assembled nanoparticle in overcoming neoantigen immunogenicity barriers.展开更多
Neoantigens exhibit high immunogenic potential and confer a uniqueness to tumor cells,making them ideal targets for personalized cancer immunotherapy.Neoantigens originate from tumor-specific genetic alterations,abnor...Neoantigens exhibit high immunogenic potential and confer a uniqueness to tumor cells,making them ideal targets for personalized cancer immunotherapy.Neoantigens originate from tumor-specific genetic alterations,abnormal viral infections,or other biological mechanisms,including atypical RNA splicing events and post-translational modifications(PTMs).These neoantigens are recognized as foreign by the immune system,eliciting an immune response that largely bypasses conventional mechanisms of central and peripheral tolerance.Advances in next-generation sequencing(NGS),mass spectrometry(MS),and artificial intelligence(AI)have greatly expedited the rapid detection and forecasting of neoantigens,markedly propelling the development of diverse immunotherapeutic strategies,including cancer vaccines,adoptive cell therapy,and antibody treatment.In this review,we comprehensively explore the discovery and characterization of neoantigens and their clinical use within promising immunotherapeutic frameworks.Additionally,we address the current landscape of neoantigen research,the intrinsic challenges of the field,and potential pathways for clinical application in cancer treatment.展开更多
Neoantigens,also known as tumor-specific antigens(TSAs),represent a current research hotspot in the field of tumor immunology,offering immense potential for cancer treatment.Adoptive cell therapy(ACT),an emerging and ...Neoantigens,also known as tumor-specific antigens(TSAs),represent a current research hotspot in the field of tumor immunology,offering immense potential for cancer treatment.Adoptive cell therapy(ACT),an emerging and rapidly evolving treatment modality,provides novel insights into oncological treatment strategies.Traditional ACT has primarily targeted tumor-associated antigens(TAAs),with chimeric antigen receptor-T cell(CAR-T)therapy demonstrating promising clinical benefits in hematological malignancies,but it exhibits limited efficacy in solid tumors.In contrast to TAAs,neoantigens can be more specifically targeted on tumor cells,which render ACT targeting TSAs an innovative and optimized therapeutic approach.This review commences with an exploration of the sources of neoantigens,elaborates on the identification processes,and subsequently summarizes the preclinical and clinical trials of ACT targeting neoantigens in solid tumors.Ultimately,we also discuss the related challenges and offer prospects for future research in this field.展开更多
In a recent study published in Nature,1 Kwok et al.identified tumor-wide antigens that derived from tumor-specific splicing events,known as neojunctions(NJs)(Fig.1a).The study identified two distinct neopeptide-encodi...In a recent study published in Nature,1 Kwok et al.identified tumor-wide antigens that derived from tumor-specific splicing events,known as neojunctions(NJs)(Fig.1a).The study identified two distinct neopeptide-encoding NJs(NEJs)that were spatially and temporally conserved in glioblastoma(GBM)patients and induced an HLA-dependent T cell response.The discovery of these NEJs,as well as the pipeline used for their identification,harbors significant potential for the development of tumor vaccines and adoptive cell therapies that might be effective across various cancer entities.展开更多
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 neoa...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).展开更多
Tumor-specific neoantigens have attracted much attention since they can be used as biomarkers to predict therapeutic effects of immune checkpoint blockade therapy and as potential targets for cancer immunotherapy. In ...Tumor-specific neoantigens have attracted much attention since they can be used as biomarkers to predict therapeutic effects of immune checkpoint blockade therapy and as potential targets for cancer immunotherapy. In this study, we developed a comprehensive tumor-specific neoantigen database （TSNAdb v1.0）, based on pan-cancer immunogenomic analyses of somatic mutation data and human leukocyte antigen （HLA） allele information for 16 tumor types with 7748 tumor samples from The Cancer Genome Atlas （TCGA） and The Cancer Immunome Atlas （TCIA）. We predicted binding affinities between mutant/wild-type peptides and HLA class I molecules by NetMHCpan v2.8/v4.0, and presented detailed information of 3,707,562/1,146,961 potential neoantigens generated by somatic mutations of all tumor samples. Moreover, we employed recurrent mutations in combination with highly frequent HLA alleles to predict potential shared neoantigens across tumor patients,which would facilitate the discovery of putative targets for neoantigen-based cancer immunotherapy.TSNAdb is freely available at http：//biopharm.zju.edu.cn/tsnadb.展开更多
Immunotherapies targeting cancer neoantigens are safe,effective,and precise.Neoantigens can be identified mainly by genomic techniques such as next-generation sequencing and high-throughput single-cell sequencing;prot...Immunotherapies targeting cancer neoantigens are safe,effective,and precise.Neoantigens can be identified mainly by genomic techniques such as next-generation sequencing and high-throughput single-cell sequencing;proteomic techniques such as mass spectrometry;and bioinformatics tools based on high-throughput sequencing data,mass spectrometry data,and biological databases.Neoantigen-related therapies are widely used in clinical practice and include neoantigen vaccines,neoantigen-specific CD8+and CD4+T cells,and neoantigen-pulsed dendritic cells.In addition,neoantigens can be used as biomarkers to assess immunotherapy response,resistance,and prognosis.Therapies based on neoantigens are an important and promising branch of cancer immunotherapy.Unremitting efforts are needed to unravel the comprehensive role of neoantigens in anti-tumor immunity and to extend their clinical application.This review aimed to summarize the progress in neoantigen research and to discuss its opportunities and challenges in precision cancer immunotherapy.展开更多
基金supported by the National Natural Science Foundation of China(82341042 and 32270993)the PhD program of the Interdisciplinary Research Center,Sun Yat-sen University.
文摘Tumor initiation and progression are highly intricate biolog-ical processes,and mutation-driven tumorigenesis is a pri-mary underlying cause.Personalized cancer vaccines have been developed to exploit these specific mutations,particu-larly in the form of tumor neoantigens,to induce immune responses,particularly the activation of CD8+T cells,which can attack malignant cells.Since tumor mutations result in protein sequence alterations distinct from those in normal tissues,therapies that precisely target these alterations could,in principle,confer effective tumor control while minimizing off-target effects.
文摘Immunotherapy,particularly immune checkpoint inhibitors(ICIs)programmed death-ligand 1/programmed death-1(PD-L1/PD-1)and cytotoxic T-lymphocyte-associated antigen-4(CTLA-4),has heralded a new era of tumor treatment.Although ICIs have clinical benefits,their complex heterogeneity and diverse resistance mechanisms critically limit their efficacy.Neoantigens,arising from tumor-specific alterations,offer novel targets for individualized immunotherapy,because of their high immunogenicity and tumor specificity.In the past decade,neoantigen-based tumor vaccines have been demonstrated to be a promising immunotherapy strategy to prime the tumor-specific immune response.These therapeutic vaccines include peptide vaccines,nucleic acid vaccines,and dendritic cell(DC)vaccines,and are categorized according to the neoantigen source and delivery method.In vivo,neoantigens are processed and presented by antigen-presenting cells(APCs)via the peptide-Major Histocompatibility Complex(pMHC)for T cell recognition,thereby triggering specific immune responses.Because DCs,the most potent APCs,play crucial roles in antitumor immunity,neoantigen-based DC vaccines provide a promising therapeutic strategy.A series of global clinical trials are exploring the safety,feasibility,and efficacy of neoantigen-based DC vaccines in tumors.This review focuses on current progress in clinical research on neoantigen-based DC vaccines in the treatment of solid tumors.
基金Supported by Ministerium für Wirtschaft,Arbeit und Gesundheit Mecklenburg-Vorpommern,No.TBI-V-1-241-VBW-084
文摘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.
基金supported by the National Science and Technology Major Project of China (No. 2018ZX 10302205)the Scientific Foundation of Fujian Province (No. 2018J01145, No. 2020J011171)+1 种基金the Scientific Foundation of Fujian Health and family planning Department (No. 2019-ZQN-87)the Joint Funds for the Innovation of Science and Technology of Fujian Province (No. 2018Y9121)。
文摘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.
文摘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.
基金National Key Sci-Tech Special Project of China,No.2018ZX10302207。
文摘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.
基金supported by grants from the National Clinical Research Center Cancer Fundthe Haihe Laboratory of Synthetic Biology(22HHSWSS00004)。
文摘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.
基金supported by a grant from the Chinese Academy of Medical Sciences (CAMS) Initiative for Innovative Medicine(CAMS-2017-I2M-4-002)
文摘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
基金supported by the National Natural Science Foundation of China(82303776 to YHS,81930074 to LXQ)the National Key R&D Program of China(2018YFA0900902 to CQS).
文摘Neoantigen vaccines and oncolytic viruses are emerging immunotherapies that can reshape the tumor microenvironment(TME).However,tumors with low mutation burdens often respond poorly to immunotherapies because of their limited immunogenicity.Developing effective immunotherapy strategies for these types of tumors remains a significant challenge.In this study,we engineered oncolytic adenoviruses to accurately amplify neoantigen expression within tumor cells,which demonstrated superior efficacy compared to synthetic long peptide vaccines and showed enhanced effectiveness in a low mutation burden intrahepatic cholangiocarcinoma model.Building on this,we further developed NeoViron,which coexpresses neoantigens and Flt3L,a dendritic cell growth factor,to promote antigen presentation and T-cell infiltration simultaneously.NeoViron significantly inhibited tumor growth and prevented metastasis in intrahepatic cholangiocarcinoma animal models.Mechanistically,NeoViron enhanced the cytotoxicity of CD8+T cells and promoted the expansion of CD69+CD8+tissue-resident memory T cells and TCF1+CD8+stem-like T cells to promote anti-tumor immunity and immune memory.When combined with anti-PD-1,it further enhances the cytotoxicity of tissue-resident memory T cells to eradicate solid tumors.These findings demonstrate that NeoViron can effectively sensitize lowmutation tumors to immunotherapy by increasing neoantigen expression and antigen-presentation efficacy,offering a promising strategy for cancer treatment,particularly for tumors with scarce neoantigens.
基金supported by the National Natural Science Foundation of China(Grant No.81890994)the National Key R&D Program of China(Grant No.2019YFA0905902)+2 种基金the Guangdong Basic and Applied Basic Research Foundation,China(Grant Nos.2019A1515010299 and 2023A1515030298)the Science and Technology Program of Guangzhou,China(Grant No.202102020727)the Innovative Research Team of High-level Local Universities in Shanghai,and the Dean’s fund of Zhujiang Hospital of Southern Medical University,China(Grant No.yzjj2019qn05).
文摘Neoantigen-based immunotherapy has demonstrated long-lasting antitumor activity.The recognition of neoantigens by T cell receptors(TCRs)is considered a trigger for antitumor responses.Due to the overwhelming number of TCR repertoires in the human genome,pinpointing neoantigen-specific TCRs is a formidable challenge.Recent studies have identified a number of functional neoantigen-specific TCRs,but the corresponding information is scattered across published literature and is difficult to retrieve.To improve access to these data,we developed an immunoinformatic database(NeoTCR)containing a unified description of publicly available neoantigen-specific TCR sequences,as well as relevant information on targeted neoantigens,from experimentally-supported studies across 17 cancer subtypes.A user-friendly web interface allows interactive browsing and running of complex database queries.To facilitate rapid identification of neoantigen-specific TCRs from raw sequencing data,NeoTCR offers a one-stop analysis for annotation and visualization of TCR clonotypes,discovery of existing neoantigen-specific TCRs,and exclusion of bystander virus-associated TCRs.NeoTCR represents a unique tool to expedite future studies of neoantigen-specific TCRs and the development of neoantigen-based immunotherapy.NeoTCR is available at http://neotcrdb.bioxai.cn/and https://github.com/lyot vincent/NeoTCR.
文摘Recently,T cells expressing engineered T cell receptor(TCR-T cells)have become recognized as a promising tumor cell therapy for solid tumors because of their ability to selectively kill tumor cells with less destruction of other cells and their high safety when used as autologous T cells.Several studies and clinical tests have been conducted to demonstrate its potential as a novel therapy.However,previous research has mainly focused on antigens;these common targets for TCR-T are tumor-associated antigens,which exhibit expression not only in tumor cells but also in normal cells,resulting in off-target risk and not considering the heterogeneity of different patients.In contrast,neoantigens offer superior specificity as they are uniquely expressed on tumor cells due to genomic alterations.Given the frequent occurrence and notable role of genetic mutations in tumorigenesis and tumor progression,identification and targeting of neoantigens is a valuable therapeutic direction.This perspective delves into various antigen classifications,including their characteristics and advantages,as well as strategies for identifying and validating neoantigens that have emerged from numerous research studies.These insights are crucial for guiding the search for new neoantigens.We also review significant and representative studies involving TCR-T and other immunotherapies that target neoantigens to assess the therapeutic effectiveness of TCR-T therapy.Moreover,we discuss the challenges and complexities inherent in TCR-T therapy and propose potential solutions for these issues.In this perspective,we aim to provide fresh perceptions and strategies for cancer treatment by highlighting the potential of TCR-T and exploring its challenges and future directions.It also seeks to propel the development of precision medicine and personalized therapy,offering hope for more effective and targeted cancer treatments in the future.
基金supported by the National Natural Science Foundation of China(81930080 and 82272811)the Fund for Distinguished Young Scholars of Jiangsu Province(BK20230001,China)the Key Project Foundation of Nanjing for the Development of Medical Technology(ID:ZKX20024,China).
文摘Probiotics are natural systems bridging synthetic biology,physical biotechnology,and immunology,initiating innate and adaptive anti-tumor immune activity.We previously constructed an all-inone engineered food-grade probiotic Lactococcus lactis(FOLactis)which could boost the crosstalk among different immune cells such as dendritic cells(DCs),natural killer cells,and T cells.Herein,considering the limited clinical efficacy of naked personalized neoantigen peptide vaccines,we decorate FOLactis with tumor antigens by employing a Plug-and-Display system comprising membrane-inserted peptides.Intranodal injection of FOLactis coated with neoantigen peptides(Ag-FOLactis)induces robust DCs presentation and neoantigen-specific cellular immunity.Notably,Ag-FOLactis not only triggers a 45-fold rise in the quantity of locally reactive neoantigen-specific T cells but also induces epitope spreading in both subcutaneous and metastatic tumor-bearing models,leading to potent inhibition of tumor growth.These findings imply that Ag-FOLactis represents a powerful platform to rapidly and easily display antigens,facilitating the development of a bio-activated platform for personalized therapy.
基金supported by Joint Funds of the National Natural Science Foundation of China(No.U20A20409).
文摘Cancer immunotherapy faces challenges in achieving durable antitumor immunity due to poor immunogenicity of tumor antigens and inadequate immune activation.In this study,we developed a self-assembling neoantigen nanoparticle vaccine(Neo-NV)integrating charge-modified Kirsten rat sarcoma viral oncogene homologue(KRAS)G12V-derived multi-epitope peptides with dual adjuvants—hydrophilic CpG oligonucleotides(ODNs)and hydrophobic R848.Neo-NV demonstrated enhanced antigen uptake by dendritic cells(DCs)in vitro,promoting DC maturation and M1 macrophage polarization,while stimulating robust neoantigen-specific CD8+T cell responses.Additionally,Neo-NV enhanced the activation of antigen-specific T cells from human peripheral blood mononuclear cells(PBMCs)and their proliferation in immunodeficient NSG mice.Moreover,it significantly increased CD4+and CD8+T cell proliferation in the spleen and PBMCs of mice,while promoting the activation and aggregation of CD4+and CD8+T cells in the draining lymph nodes.In murine KRAS G12V melanoma models,Neo-NV significantly suppressed tumor growth and prolonged survival without systemic toxicity,as evidenced by stable body weight and normal hepatic/renal biomarkers.Mechanistically,Neo-NV enhanced tumor-infiltrating lymphocyte(TIL)activation and memory precursor T cell formation.This study establishes Neo-NV as a modular platform for personalized immunotherapy,highlighting the synergy of dual adjuvants and self-assembled nanoparticle in overcoming neoantigen immunogenicity barriers.
基金supported by grants from National Key Research & Development Program of China(Nos.2023YFC3402100,2020YFA0509400)Guangdong Basic and Applied Basic Research Foundation(No.2019B030302012)+2 种基金National Natural Science Foundation of China(Nos.81821002,82130082,and 81790251)1·3·5 projects for disciplines of excellence,West China Hospital,Sichuan University(Nos.ZYGD22007 and ZYJC21004)Sichuan Science and Technology Program(No.2023YFS0073).
文摘Neoantigens exhibit high immunogenic potential and confer a uniqueness to tumor cells,making them ideal targets for personalized cancer immunotherapy.Neoantigens originate from tumor-specific genetic alterations,abnormal viral infections,or other biological mechanisms,including atypical RNA splicing events and post-translational modifications(PTMs).These neoantigens are recognized as foreign by the immune system,eliciting an immune response that largely bypasses conventional mechanisms of central and peripheral tolerance.Advances in next-generation sequencing(NGS),mass spectrometry(MS),and artificial intelligence(AI)have greatly expedited the rapid detection and forecasting of neoantigens,markedly propelling the development of diverse immunotherapeutic strategies,including cancer vaccines,adoptive cell therapy,and antibody treatment.In this review,we comprehensively explore the discovery and characterization of neoantigens and their clinical use within promising immunotherapeutic frameworks.Additionally,we address the current landscape of neoantigen research,the intrinsic challenges of the field,and potential pathways for clinical application in cancer treatment.
基金supported by the National Natural Science Foundation of China(82373230,82373289,82172765)National High-Level Hospital Clinical Research Funding(2022-PUMCH-D-001)+1 种基金Peking Union Medical College Hospital Outstanding Young Talent Development Program(No.UBJ11020)CAMS Innovation Fund for Medical Sciences(CIFMS,2023-I2M-C&T-B-024).
文摘Neoantigens,also known as tumor-specific antigens(TSAs),represent a current research hotspot in the field of tumor immunology,offering immense potential for cancer treatment.Adoptive cell therapy(ACT),an emerging and rapidly evolving treatment modality,provides novel insights into oncological treatment strategies.Traditional ACT has primarily targeted tumor-associated antigens(TAAs),with chimeric antigen receptor-T cell(CAR-T)therapy demonstrating promising clinical benefits in hematological malignancies,but it exhibits limited efficacy in solid tumors.In contrast to TAAs,neoantigens can be more specifically targeted on tumor cells,which render ACT targeting TSAs an innovative and optimized therapeutic approach.This review commences with an exploration of the sources of neoantigens,elaborates on the identification processes,and subsequently summarizes the preclinical and clinical trials of ACT targeting neoantigens in solid tumors.Ultimately,we also discuss the related challenges and offer prospects for future research in this field.
文摘In a recent study published in Nature,1 Kwok et al.identified tumor-wide antigens that derived from tumor-specific splicing events,known as neojunctions(NJs)(Fig.1a).The study identified two distinct neopeptide-encoding NJs(NEJs)that were spatially and temporally conserved in glioblastoma(GBM)patients and induced an HLA-dependent T cell response.The discovery of these NEJs,as well as the pipeline used for their identification,harbors significant potential for the development of tumor vaccines and adoptive cell therapies that might be effective across various cancer entities.
基金National Key R&D Program of China,Grant/Award Number:2021YFF1200900National Natural Science Foundation of China,Grant/Award Numbers:61721003,62250005,62103227。
文摘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).
基金supported by the National Key Research and Development Program of China (Grant No. 2017YFC0908600)the National Natural Science Foundationof China (Grant No. 31501021)the Fundamental Research Funds for the Central Universities of China
文摘Tumor-specific neoantigens have attracted much attention since they can be used as biomarkers to predict therapeutic effects of immune checkpoint blockade therapy and as potential targets for cancer immunotherapy. In this study, we developed a comprehensive tumor-specific neoantigen database （TSNAdb v1.0）, based on pan-cancer immunogenomic analyses of somatic mutation data and human leukocyte antigen （HLA） allele information for 16 tumor types with 7748 tumor samples from The Cancer Genome Atlas （TCGA） and The Cancer Immunome Atlas （TCIA）. We predicted binding affinities between mutant/wild-type peptides and HLA class I molecules by NetMHCpan v2.8/v4.0, and presented detailed information of 3,707,562/1,146,961 potential neoantigens generated by somatic mutations of all tumor samples. Moreover, we employed recurrent mutations in combination with highly frequent HLA alleles to predict potential shared neoantigens across tumor patients,which would facilitate the discovery of putative targets for neoantigen-based cancer immunotherapy.TSNAdb is freely available at http：//biopharm.zju.edu.cn/tsnadb.
基金National Natural Science Foundation of China(Nos. 81925030 and 81821003 to Bo Zhu)
文摘Immunotherapies targeting cancer neoantigens are safe,effective,and precise.Neoantigens can be identified mainly by genomic techniques such as next-generation sequencing and high-throughput single-cell sequencing;proteomic techniques such as mass spectrometry;and bioinformatics tools based on high-throughput sequencing data,mass spectrometry data,and biological databases.Neoantigen-related therapies are widely used in clinical practice and include neoantigen vaccines,neoantigen-specific CD8+and CD4+T cells,and neoantigen-pulsed dendritic cells.In addition,neoantigens can be used as biomarkers to assess immunotherapy response,resistance,and prognosis.Therapies based on neoantigens are an important and promising branch of cancer immunotherapy.Unremitting efforts are needed to unravel the comprehensive role of neoantigens in anti-tumor immunity and to extend their clinical application.This review aimed to summarize the progress in neoantigen research and to discuss its opportunities and challenges in precision cancer immunotherapy.
