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
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
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 amoun...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.展开更多
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...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.展开更多
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...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.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
Molecular-assisted precision oncology gained tremendous ground with high-throughput next-generation sequencing(NGS),supported by robust bioinformatics.The quest for genomicsbased cancer medicine set the foundations fo...Molecular-assisted precision oncology gained tremendous ground with high-throughput next-generation sequencing(NGS),supported by robust bioinformatics.The quest for genomicsbased cancer medicine set the foundations for improved patient stratification,while unveiling a wide array of neoantigens for immunotherapy.Upfront pre-clinical and clinical studies have successfully used tumor-specific peptides in vaccines with minimal off-target effects.However,the low mutational burden presented by many lesions challenges the generalization of these solutions,requiring the diversification of neoantigen sources.Oncoproteogenomics utilizing customized databases for protein annotation by mass spectrometry(MS)is a powerful tool toward this end.Expanding the concept toward exploring proteoforms originated from post-translational modifications(PTMs)will be decisive to improve molecular subtyping and provide potentially targetable functional nodes with increased cancer specificity.Walking through the path of systems biology,we highlight that alterations in protein glycosylation at the cell surface not only have functional impact on cancer progression and dissemination but also originate unique molecular fingerprints for targeted therapeutics.Moreover,we discuss the outstanding challenges required to accommodate glycoproteomics in oncoproteogenomics platforms.We envisage that such rationale may flag a rather neglected research field,generating novel paradigms for precision oncology and immunotherapy.展开更多
The phenomenon of tumor hierarchy and genetic instability can be explained by the“two-hits theory”and results in the occurrence of many somatic mutations.The expression of nonsynonymous mutations results in the prod...The phenomenon of tumor hierarchy and genetic instability can be explained by the“two-hits theory”and results in the occurrence of many somatic mutations.The expression of nonsynonymous mutations results in the production of mutant proteins from tumor cells,namely tumor-specific antigens called neoantigens.Because neoantigens do not exist in healthy cells,they have the potential to stimulate antitumor immune responses by CD4+and CD8+T-cell activation without jeopardizing normal tissues.Immunotherapy has reshaped the cancer treatment paradigm in recent decades with the introduction of immune-checkpoint blockade therapy and transgenic Tcell receptor/chimeric antigen receptor T cells.However,these strategies performed poorly in solid tumors because of the obstacles of the immunosuppressive microenvironment caused by regulatory T cells and other suppressor cells.Therefore,other immunotherapeutic strategies are under development,such as personalized vaccines,to trigger de novo T-cell responses against neoantigens and lead to the amplification of tumorspecific T-cell subclones.Neoantigen epitope prediction algorithms have enabled the detection of neoantigens and the creation of tailored neoantigen vaccines as a result of the fast development of next-generation sequencing and cancer bioinformatics.Here we provide an overview of the current neoantigen cancer vaccines and adoptive T-cell transfer therapy with neoantigen-specific lymphocytes.We also discuss the challenges in developing neoantigentargeted immunotherapeutic strategies for cancer.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
Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immunotherapeutic agents...Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex(MHC)class I and II antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4t and CD8t T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.展开更多
Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) app...Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) approved as first line systemic treatment in HCC. Regorafenib and nivolumab are the only FDA approved second line treatment after progression on sorafenib. We will discuss all potential first and second line options in HCC. In addition, we also will explore sequencing treatment options in HCC, and examine biomarkers that can potentially predict benefits from treatments such as immune checkpoint inhibitor. This minireview summarizes potential treatments in HCC based on clinical trials that have been published in manuscript or abstract format from 1994-2018.展开更多
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.
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 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.
基金supported by the National Natural Science Foundation of China(Grant Nos.31971371 and U20A20409)the Key R&D Program of Zhejiang Province,China(Grant No.2020C03010)+1 种基金the Huadong Medicine Joint Funds of the Zhejiang Provincial Natural Science Foundation of China(Grant No.LHDMZ22H300002)the AlibabaZhejiang University Joint Research Center of Future Digital Healthcare.
文摘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.
基金G.Z.acknowledges funding support from NIH(R01CA266981,R01AI168684,R35GM143014,R21NS114455)DoD CDMRP Breast Cancer Breakthrough Award Level II(BC210931/P1)+3 种基金NIH-NCATS KL2 scholarship(KL2TR002648)via VCU C.Kenneth and Dianne Wright Center for Clinical and Translational Research(UL1TR002649)American Cancer Society Research Scholar Grant(RSG-22-055-01-IBCD)METAvivor Early Career Investigator Award,among others.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.T.S.and F.C.acknowledge the National Natural Science Foundation of China(52103199,82102203)Guangdong Basic and Applied Basic Research Foundation(2020A1515110811).
文摘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.
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.
基金the Portuguese Foundation for Science and Technology(FCT)for the PhD grants(Grant Nos.SFRH/BD/111242/2015 awarded to AP and SFRH/BD/146500/2019 awarded to MRS)the FCT assistant researcher grant(Grant No.CEECIND/03186/2017 awarded to JAF)+8 种基金co-financed by European Social Fund(ESF)under Human Potential Operation Programme(POPH)from National Strategic Reference Framework(NSRF)the FCT funding for CI-IPOP research unit(Grant No.PEst-OE/SAU/UI0776/201)LAQV-REQUIMTE research unit(Grant No.UIDB/50006/2020)the Portuguese Oncology Institute of Porto Research Centre(Grant Nos.CI-IPOP-29-2020,CI-IPOP-58-2020,and CI-IPOP-Proj.70-bolsa2019-GPTE)the PhD Program in Biomedical Sciences of ICBAS-University of Porto in Portugalthe “Early stage cancer treatment,driven by context of molecular imaging(ESTIMA)”framework(Grant No.NORTE-01-0145-FEDER-000027)the IPO-Score(Grant No.DSAIPA/DS/0042/2018)for financial supportfinanced by European Regional Development Fund(ERDF)through the COMPETE 2020–Operational Programme for Competitiveness and Internationalisation(POCI),Portugal 2020by Portuguese funds through FCT/Ministry for Science,Technology and Higher Education(MCTES)
文摘Molecular-assisted precision oncology gained tremendous ground with high-throughput next-generation sequencing(NGS),supported by robust bioinformatics.The quest for genomicsbased cancer medicine set the foundations for improved patient stratification,while unveiling a wide array of neoantigens for immunotherapy.Upfront pre-clinical and clinical studies have successfully used tumor-specific peptides in vaccines with minimal off-target effects.However,the low mutational burden presented by many lesions challenges the generalization of these solutions,requiring the diversification of neoantigen sources.Oncoproteogenomics utilizing customized databases for protein annotation by mass spectrometry(MS)is a powerful tool toward this end.Expanding the concept toward exploring proteoforms originated from post-translational modifications(PTMs)will be decisive to improve molecular subtyping and provide potentially targetable functional nodes with increased cancer specificity.Walking through the path of systems biology,we highlight that alterations in protein glycosylation at the cell surface not only have functional impact on cancer progression and dissemination but also originate unique molecular fingerprints for targeted therapeutics.Moreover,we discuss the outstanding challenges required to accommodate glycoproteomics in oncoproteogenomics platforms.We envisage that such rationale may flag a rather neglected research field,generating novel paradigms for precision oncology and immunotherapy.
基金National Natural Science Foundation of China,Grant/Award Numbers:81972444,82172566。
文摘The phenomenon of tumor hierarchy and genetic instability can be explained by the“two-hits theory”and results in the occurrence of many somatic mutations.The expression of nonsynonymous mutations results in the production of mutant proteins from tumor cells,namely tumor-specific antigens called neoantigens.Because neoantigens do not exist in healthy cells,they have the potential to stimulate antitumor immune responses by CD4+and CD8+T-cell activation without jeopardizing normal tissues.Immunotherapy has reshaped the cancer treatment paradigm in recent decades with the introduction of immune-checkpoint blockade therapy and transgenic Tcell receptor/chimeric antigen receptor T cells.However,these strategies performed poorly in solid tumors because of the obstacles of the immunosuppressive microenvironment caused by regulatory T cells and other suppressor cells.Therefore,other immunotherapeutic strategies are under development,such as personalized vaccines,to trigger de novo T-cell responses against neoantigens and lead to the amplification of tumorspecific T-cell subclones.Neoantigen epitope prediction algorithms have enabled the detection of neoantigens and the creation of tailored neoantigen vaccines as a result of the fast development of next-generation sequencing and cancer bioinformatics.Here we provide an overview of the current neoantigen cancer vaccines and adoptive T-cell transfer therapy with neoantigen-specific lymphocytes.We also discuss the challenges in developing neoantigentargeted immunotherapeutic strategies for cancer.
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supported by Natural Science Foundation of Shaanxi Province(Grant No.:2019ZY-CXPT-03-01)to Ping Zhu and Key Research and Development Program of Shaanxi Province(Grant No.:2020ZDLSF03-02)to Zhi-Nan Chen and Huijie Bian as well as Tricision Biotherapeutics Inc.
文摘Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex(MHC)class I and II antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4t and CD8t T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.
文摘Hepatocellular carcinoma(HCC) is the fifth leading cause of cancer mortality in the United States and the second leading cause of cancer mortality worldwide. Sorafenib is the only food and drug administration(FDA) approved as first line systemic treatment in HCC. Regorafenib and nivolumab are the only FDA approved second line treatment after progression on sorafenib. We will discuss all potential first and second line options in HCC. In addition, we also will explore sequencing treatment options in HCC, and examine biomarkers that can potentially predict benefits from treatments such as immune checkpoint inhibitor. This minireview summarizes potential treatments in HCC based on clinical trials that have been published in manuscript or abstract format from 1994-2018.
