Objectives A xenogeneic human tyrosinase DNA vaccine was developed for treatment of dogs with oral malignant melanoma (Oncept; Merial). No studies have evaluated the safety or efficacy of this vaccine in cats. The purpose of this study was to evaluate the safety of the canine melanoma vaccine in cats diagnosed with melanoma. Methods Medical records were reviewed from cats diagnosed with malignant melanoma and treated with the canine melanoma DNA vaccine (Oncept). Data regarding signalment, melanoma location, treatments received, vaccine adverse effects and cause of death were collected. Results A total of 114 melanoma vaccines were administered to 24 cats. Seven cats (11.4%) had clinical adverse effects from a total of 13 vaccines classified as grade 1 or 2 based on the Veterinary Cooperative Oncology Group’s common terminology criteria for adverse events v1.1. These included pain on vaccine administration, brief muscle fasciculation, transient inappetence, depression, nausea and mild increase in pigmentation at the injection site. Nineteen cats were deceased at study close. The most common cause of death was melanoma (14 cats). Hematological and biochemical changes were observed in six cats, five of which had concurrent disease or treatments that likely caused or greatly contributed to the laboratory abnormalities found. Therefore, these adverse events were considered unlikely to be caused by the melanoma vaccine. One cat had transient grade 1 hypoalbuminemia, which was possibly caused by the vaccination but not thoroughly evaluated. Conclusions and relevance The canine melanoma DNA vaccine can be safely administered to cats, with minimal risk of adverse effects.

2014-10-01·Cancer Immunology Research1区 · 医学

Adjuvant Vaccine Immunotherapy of Resected, Clinically Node-Negative Melanoma: Long-term Outcome and Impact of HLA Class I Antigen Expression on Overall Survival

1区 · 医学

Article

作者: Sondak, Vernon K. ; Othus, Megan ; Porter, Mark J. ; Carson, William E. ; Sosman, Jeffrey A. ; Ribas, Antoni ; Unger, Joseph M. ; Kempf, Raymond A. ; Tuthill, Ralph J. ; Thompson, John A. ; Flaherty, Lawrence E.

AbstractAssociations between HLA class I antigen expression and the efficacy of a melanoma vaccine (Melacine; Corixa Corp.) were initially described in stage IV melanoma. Similar associations were observed in S9035, a phase III adjuvant trial evaluating Melacine for 2 years compared with observation in patients with stage II melanoma. This report provides long-term results. The effects of treatment on relapse-free survival (RFS) and overall survival (OS) were evaluated, and prespecified analyses investigated associations between treatment and HLA expression. Multivariable analyses were adjusted for tumor thickness, ulceration and site, method of nodal staging, and sex. P = 0.01 was considered statistically significant in subset analyses to account for multiple comparisons. For the entire study population of 689 patients, there were no significant differences in RFS or OS by treatment arm. HLA serotyping was performed on 553 (80%) patients (vaccine, 294; observation, 259). Among the subpopulation with HLA-A2 and/or HLA-Cw3 serotype, vaccine arm patients (n = 178) had marginally improved RFS (adjusted P = 0.02) and significantly improved OS compared with observation arm patients (n = 145), with 10-year OS of 75% and 63%, respectively [hazard ratio (HR), 0.62; 99% confidence interval (CI), 0.37–1.02; P = 0.01]. There was no impact of HLA-A2 and/or HLA-Cw3 expression on observation arm patients. An analysis of mature data from S9035 indicates a significant OS benefit from adjuvant vaccine therapy for patients with HLA-A2– and/or HLA-Cw3–expressing melanoma. The possibility of interactions between HLA type and outcome should be considered in future immunotherapy trials. Further investigations of melanoma-associated antigens present in Melacine and presented by HLA-A2 and HLA-Cw3 may be warranted. Cancer Immunol Res; 2(10); 981–7. ©2014 AACR.

2013-07-01·Cancer Immunology, Immunotherapy2区 · 医学

Activation, dysfunction and retention of T cells in vaccine sites after injection of incomplete Freund’s adjuvant, with or without peptide

2区 · 医学

Article

作者: Mark E. Smolkin ; Chantel McSkimming ; Walter C. Olson ; Sofia M. Shea ; Craig L. Slingluff ; Elise P. Salerno ; Gina R. Petroni ; Kimberly A. Chianese-Bullock

We conducted a randomized clinical trial in 45 patients with resected AJCC stage IIB-IV melanoma to characterize cellular and molecular events at sites of immunization with incomplete Freund's adjuvant (IFA) alone, or a melanoma vaccine in IFA. At a primary vaccine site, all patients received a multi-peptide melanoma vaccine in IFA. At a replicate vaccine site, which was biopsied, group 1 received IFA only; group 2 received vaccine in IFA. Lymphocytes isolated from replicate vaccine site microenvironments (VSME) were compared to time-matched peripheral blood mononuclear cells (PBMC) in ELISpot and flow cytometry assays. Compared to PBMC, the VSME had fewer naïve and greater proportions of effector memory CD8(+) T cells (TCD8). The vast majority of TCD8 within the VSME were activated (CD69(+)), with a concentration of antigen-specific (tetramer(pos)) cells in the VSME, particularly in vaccine sites with peptide (group 2). CXCR3(+) lymphocytes were concentrated in the VSME of all patients, suggesting IFA-induced chemokine recruitment. TCD8 expression of retention integrins αEβ7 and α1β1 was elevated in VSME, with the highest levels observed in antigen-specific cells in VSME containing peptide (group 2). TCD8 retained in the VSME of both groups were strikingly dysfunctional, with minimal IFN-γ production in response to peptide stimulation and few tetramer(pos) cells producing IFN-γ. These data suggest that vaccine-induced selective retention and dysfunction of antigen-specific TCD8 within VSME may represent a significant mechanism underlying transient immune responses and low clinical response rates to peptide vaccines administered in IFA.

项与 IDD-3 相关的新闻（医药）

2023-02-21

·生物制品圈

新型疫苗佐剂研究进展

在新冠疫情背景下，公众对疫苗的认知度得到了极大的提升。作为疫苗的灵魂伴侣-佐剂，也从幕后走到了台前。佐剂在疫苗免疫机体产生抗体的过程中发挥着关键作用，其主要作用是辅助免疫应答及调节免疫反应。目前，佐剂的作用机制尚未完全研究清楚，且每个佐剂的作用也各不相同。按照佐剂的功能可将其大致分为三类，第一类佐剂具有储存、释放和靶向抗原作用，第二类佐剂具有免疫调节作用，第三类佐剂是兼具以上两种功能的佐剂。其中，铝佐剂的应用范围最为广泛，但会引起注射部位反应，诱导细胞免疫的能力较弱，不能冷冻活冻干，上述缺点在一定程度上限制了它的实际应用。表1 国内外使用铝佐剂的疫苗资料来源：申万宏源研究随着新型疫苗的不断涌现，对疫苗佐剂的要求越来越高。但疫苗佐剂的开发存在很高的技术壁垒，需要兼顾安全性和有效性，同时还要满足规模化生产需求，这些问题限制了新型佐剂的研发进展。二十多年来，FDA批准上市的新型佐剂仅有七款，分别为MF59、AS03、AS01、AS04、CpG 1018，以及新冠紧急使用的Matrix-M佐剂。表2 已获批上市的新型疫苗佐剂资料来源：《已上市人用预防疫苗佐剂的研究进展》，《获批上市疫苗中佐剂的研究进展》从全球研发趋势来看，新型疫苗佐剂向着Toll样受体激活剂、复合佐剂和纳米颗粒等多元化方向发展。Toll样受体（TLR）是天然免疫系统的重要成分，TLR受体激动剂被认为是一类非常有前途的疫苗佐剂。一系列研究证实，TLR4激动剂吡喃葡萄糖基脂质A（GLA-SE）作为H5N1流感疫苗佐剂[1]，在II期临床实验中免疫效果良好，并在结核疫苗[2]、肿瘤抗原疫苗[3]进行了测试。TLR7激动剂Imiquimod作为癌症疫苗佐剂用于头颈基底细胞癌[4]和黑色素瘤[5]的治疗，具有良好的耐受性和免疫原性。此外，TLR9激动剂MGN1703、IC31、SD-101也有望成为候选疫苗佐剂[6-8]。在复合佐剂领域，由磷脂、胆固醇和皂苷组成的复合物ISCOMATRIX能诱导广泛而有效的体液和细胞免疫应答，已在流感疫苗[9]、呼吸道合胞病毒[10]、生殖器疱疹病毒疫苗GEN-003[11]、新冠疫苗[12]等多款疫苗中开展临床研究。另有研究表明，由双链RNA类似物及TLR配体组成的Poly I:C/PIKA佐剂可显著提高狂犬疫苗在成人体内的抗体水平和T细胞反应[13]。近年来，纳米颗粒作为疫苗佐剂和递送系统也发展较快。例如，阳离子脂质体VCL-HB01在DNA登革热疫苗I期临床试验中表现出良好的安全性和耐受性[14]。使用纳米凝胶作为递送系统的肺炎链球菌疫苗[15]，在动物模型中经鼻内免疫，证明纳米凝胶装在的疫苗有效且安全。与此同时，国内也涌现出一批优秀企业，试图突破这一卡脖子领域。例如，瑞科生物对标葛兰素史克的AS01、AS03、AS04研发了三款新型佐剂，分别开展了针对带状疱疹疫苗、新冠疫苗、HPV疫苗的研发。迈科康生物自主研发的复合新型佐剂MA105佐剂系统，已被用于重组带状疱疹疫苗的研发。依生生物开发的皮卡佐剂已经在狂犬疫苗、乙肝疫苗上开展临床研究。此外，华泰诺、华普生物、沃森生物/上海泽润生物、智飞生物、三叶草生物也开始布局新型疫苗佐剂。随着对先天免疫信号通路的认知不断加深，更多潜在的新型疫苗佐剂会不断被发现。我们有理由相信，疫苗佐剂将迎来新的黄金时代。参考文献：1.Pillet S, et al. Humoral and cell-mediated immune responses to H5N1 plant-made virus-like particle vaccine are differentially impacted by alum and GLA-SE adjuvants in a phase 2 clinical trial. NPJ vaccines 2018;3(1):1-92.Penn-Nicholson A, et al. Safety and immunogenicity of the novel tuberculosis vaccine ID93+ GLASE in BCG-vaccinated healthy adults in South Africa: a randomised, double-blind, placebo-controlled phase 1 trial. Lancet Respir Med 2018;6(4):287-298.3.Bakos O, et al. Combining surgery and immunotherapy: turning an immunosuppressive effect into a therapeutic opportunity. J ImmuoTherapy of Cancer 2018; 6(1):1-11.4.Singh S, et al. Topical imiquimod as a neo-adjuvant chemotherapy for cartilage salvage in the treatment of nodular basal cell carcinomas of the head and neck. Indian Journal of Dermatology, Venereology and Leprology 2021;87(3):1-45.Meneveau MO，et al. Immunogenicity in humans of a transdermal multipeptide melanoma vaccine administered with or without a TLR7 agonist. J Immunother Cancer 2021; 9:e002214.6.Burghardt Wittig, et al. MGN1703, an immune-modulator and toll-like receptor 9 (TLR-9) agonist: From bench to bedside. Critical Reviews in Oncology/Hematology 2015; 94(1):31-44.7.Norrby M, et al. Safety and immunogenicity of the novel H4: IC31 tuberculosis vaccine candidate in BCG-vaccinated adults: two phase I dose escalation trials. Vaccine 2017;35(12):1652-1661.8.Suliman S, et al. Dose optimization of H56: IC31 vaccine for tuberculosis-endemic populations. A double-blind, placebo-controlled, dose-selection trial. Am J Respir Crit Care Med 2019;199(2): 220-231.9.Windon RG，et al. Local immune responses to influenza antigen are synergistically enhanced by the adjuvant ISCOMATRIX. Vaccine 2002; 20: 490–497.10.Morelli A,et al. ISCOMATRIX adjuvant in the development of prophylactic and therapeutic vaccines. In:Immunopotentiators in modern vaccines. Elsevier; 2017. p. 311-332.11.Wagoner V, et al. Effects of Different Doses of GEN-003, a Therapeutic Vaccine for Genital Herpes Simplex Virus-2, on Viral Shedding and Lesions: Results of a Randomized Placebo-Controlled Trial. J Infec Diseases 2018; 12:1890-1899.12. Heath PT, et al.Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine. N ENGL J MED 2021; 385(13) :1172-1183.13. Kalimuddin S, et al. A phase II randomized study to determine the safety and immunogenicity of the novel PIKA rabies vaccine containing the PIKA adjuvant using an accelerated regimen. Vaccine 2017;35(51):7127-7132.14.Danko JR, et al. Safety and immunogenicity of a tetravalent dengue DNA vaccine administered with a cationic lipid-based adjuvant in a phase 1 clinical trial. Am J Trop Med Hyg 2018;98(3): 849-856.15. 杨雪华等. 纳米凝胶的研究进展[J]. 食品与药品, 2022年第2期, 183-187.

疫苗临床1期临床2期

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