Xiuli Zhang, S Peter Goedegebuure, Michael Y Chen, Rashmi Mishra, Felicia Zhang, Yik Yeung Yu, Kartik Singhal, Lijin Li, Feng Gao, Nancy B Myers, Tammi Vickery, Jasreet Hundal, Michael D McLellan, Mark A Sturmoski, Samuel W Kim, Ina Chen, Jesse T Davidson, Narendra V Sankpal, Stephanie Myles, Rama Suresh, Cynthia X Ma, Ademuyiwa Foluso, Andrea Wang-Gillam, Sherri Davies, Ian S Hagemann, Elaine R Mardis, Obi Griffith, Malachi Griffith, Christopher A Miller, Ted H Hansen, Timothy P Fleming, Robert D Schreiber, William E Gillanders
{"title":"Neoantigen DNA vaccines are safe, feasible, and induce neoantigen-specific immune responses in triple-negative breast cancer patients.","authors":"Xiuli Zhang, S Peter Goedegebuure, Michael Y Chen, Rashmi Mishra, Felicia Zhang, Yik Yeung Yu, Kartik Singhal, Lijin Li, Feng Gao, Nancy B Myers, Tammi Vickery, Jasreet Hundal, Michael D McLellan, Mark A Sturmoski, Samuel W Kim, Ina Chen, Jesse T Davidson, Narendra V Sankpal, Stephanie Myles, Rama Suresh, Cynthia X Ma, Ademuyiwa Foluso, Andrea Wang-Gillam, Sherri Davies, Ian S Hagemann, Elaine R Mardis, Obi Griffith, Malachi Griffith, Christopher A Miller, Ted H Hansen, Timothy P Fleming, Robert D Schreiber, William E Gillanders","doi":"10.1186/s13073-024-01388-3","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence.</p><p><strong>Methods: </strong>Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing.</p><p><strong>Results: </strong>Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4-20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7-100%) in the cohort of vaccinated patients.</p><p><strong>Conclusion: </strong>Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses.</p><p><strong>Clinical trial registration number: </strong>NCT02348320.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"131"},"PeriodicalIF":10.4000,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562513/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Medicine","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13073-024-01388-3","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence.
Methods: Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing. The pVACtools software suite of neoantigen prediction algorithms was used to identify and prioritize cancer neoantigens and facilitate vaccine design for manufacture in an academic GMP facility. Neoantigen DNA vaccines were administered via electroporation in the adjuvant setting (i.e., following surgical removal of the primary tumor and completion of standard of care therapy). Vaccines were monitored for safety and immune responses via ELISpot, intracellular cytokine production via flow cytometry, and TCR sequencing.
Results: Eighteen subjects received three doses of a neoantigen DNA vaccine encoding on average 11 neoantigens per patient (range 4-20). The vaccinations were well tolerated with relatively few adverse events. Neoantigen-specific T cell responses were induced in 14/18 patients as measured by ELISpot and flow cytometry. At a median follow-up of 36 months, recurrence-free survival was 87.5% (95% CI: 72.7-100%) in the cohort of vaccinated patients.
Conclusion: Our study demonstrates neoantigen DNA vaccines are safe, feasible, and capable of inducing neoantigen-specific immune responses.
背景:新抗原疫苗可诱导或增强高度特异性的抗肿瘤免疫反应,同时将自身免疫风险降至最低。我们开发了一种新抗原 DNA 疫苗平台,该平台能够有效呈现 HLA I 类和 II 类表位,并在新辅助化疗后手术病理结果显示疾病持续存在的三阴性乳腺癌患者(疾病复发风险较高的患者群体)中进行了一期临床试验:通过肿瘤/正常外显子组测序和肿瘤 RNA 测序确定表达的体细胞突变。新抗原预测算法的 pVACtools 软件套件用于识别和优先处理癌症新抗原,并促进疫苗设计,以便在学术界的 GMP 工厂生产。新抗原 DNA 疫苗通过电穿孔技术在佐剂环境下接种(即手术切除原发肿瘤并完成标准治疗后)。通过 ELISpot 监测疫苗的安全性和免疫反应,通过流式细胞术监测细胞内细胞因子的产生,并进行 TCR 测序:18名受试者接种了三剂新抗原DNA疫苗,平均每名患者接种11个新抗原(4-20个不等)。受试者对疫苗的耐受性良好,不良反应相对较少。通过 ELISpot 和流式细胞术测定,14/18 名患者诱导了新抗原特异性 T 细胞应答。中位随访36个月后,接种疫苗的患者无复发生存率为87.5%(95% CI:72.7-100%):我们的研究表明,新抗原 DNA 疫苗是安全、可行的,而且能够诱导新抗原特异性免疫反应:临床试验注册号:NCT02348320。
期刊介绍:
Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.