Phase I and II randomized clinical trial of an oral therapeutic vaccine targeting human papillomavirus for treatment of cervical intraepithelial neoplasia 2 and 3

Article

作者: Schust, Danny J ; Kawana-Tachikawa, Ai ; Satoh, Toyomi ; Hori-Hirose, Yumiko ; Igimi, Shizunobu ; Yahata, Hideaki ; Nakajima, Takahiro ; Tomita, Naoko ; Katoh, Yuki ; Akiyama, Azusa ; Taguchi, Ayumi ; Maeda, Daichi ; Ikeda, Yuji ; Kawana, Kei ; Kobayashi, Osamu ; Uemura, Yukari ; Iwata, Takashi ; Asai-Sato, Mikiko ; Aoki, Daisuke ; Nakayama-Hosoya, Kaori ; Kato, Kiyoko ; Katoh, Kanoko ; Komatsu, Atsushi

AbstractBackgroundAlthough many human papillomavirus (HPV)–targeted therapeutic vaccines have been examined for efficacy in clinical trials, none have been translated into clinical use. These previous agents were mostly administered by intramuscular or subcutaneous injection to induce systemic immunity. We investigated the safety and therapeutic efficacy of an HPV-16 E7-expressing lacticaseibacillus-based oral vaccine.MethodsIn a double-blind, placebo-controlled, randomized trial, a total of 165 patients with HPV-16–positive high-grade cervical intraepithelial neoplasia 2 and 3 were assigned to orally administered placebo or low, intermediate, or high doses of IGMKK16E7 (lacticaseibacillus paracasei expressing cell surface, full-length HPV-16 E7). In the 4 groups, IGMKK16E7 or placebo was administered orally at weeks 1, 2, 4, and 8 postenrollment. The primary outcomes included histopathological regression and IGMKK16E7 safety.ResultsIn per-protocol analyses, histopathological regression to normal (complete response) occurred in 13 (31.7%) of 41 high-dose recipients and in 5 (12.5%) of 40 placebo recipients (rate difference = 19.2, 95% confidence interval [CI] = 0.5 to 37.8). In patients positive for HPV-16 only, the clinical response rate was 40.0% (12 of 30) in high-dose recipients and 11.5% (3 of 26) in recipients of placebo (rate difference = 28.5, 95% CI = 4.3 to 50.0). There was no difference in adverse events that occurred in the high-dose and placebo groups (P = .83). The number of HPV-16 E7–specific interferon-γ producing cells within peripheral blood increased with level of response (stable disease, partial, and complete responses; P = .004). The regression to normal (complete response) rates among recipients with high levels of immune response were increased in a dose-dependent manner.ConclusionThis trial demonstrates safety of IGMKK16E7 and its efficacy against HPV-16–positive cervical intraepithelial neoplasia 2 and 3. IGMKK16E7 is the first oral immunotherapeutic vaccine to show antineoplastic effects.Trial registrationjRCT2031190034.

2021-08-01·Journal for ImmunoTherapy of Cancer2区 · 医学

HPV-16 E6/E7 DNA tattoo vaccination using genetically optimized vaccines elicit clinical and immunological responses in patients with usual vulvar intraepithelial neoplasia (uVIN): a phase I/II clinical trial

2区 · 医学

ArticleOA

作者: Zijlmans, Henry J Maa ; van Trommel, Nienke E ; de Gruijl, Tanja D ; Bakker, Noor Alida Maria ; Nuijen, Bastiaan ; van Ruiten, Maartje ; Rotman, Jossie ; Jordanova, Ekaterina S ; van den Berg, Joost H ; van Beurden, Marc ; Samuels, Sanne ; Beijnen, Jos ; Kenter, Gemma G ; Schumacher, Ton ; De Visser, Karin ; Haanen, John

BackgroundUsual vulvar intraepithelial neoplasia (uVIN) is a premalignancy caused by persistent infection with high-risk types of human papillomavirus (HPV), mainly type 16. Even though different treatment modalities are available (eg, surgical excision, laser evaporation or topical application of imiquimod), these treatments can be mutilating, patients often have recurrences and 2%–8% of patients develop vulvar carcinoma. Therefore, immunotherapeutic strategies targeting the pivotal oncogenic HPV proteins E6 and E7 are being explored to repress carcinogenesis.MethodIn this phase I/II clinical trial, 14 patients with HPV16+ uVIN were treated with a genetically enhanced DNA vaccine targeting E6 and E7. Safety, clinical responses and immunogenicity were assessed. Patients received four intradermal HPV-16 E6/E7 DNA tattoo vaccinations, with a 2-week interval, alternating between both upper legs. Biopsies of the uVIN lesions were taken at screening and +3 months after last vaccination. Digital photography of the vulva was performed at every check-up until 12 months of follow-up for measurement of the lesions. HPV16-specific T-cell responses were measured in blood over time in ex vivo reactivity assays.ResultsVaccinations were well tolerated, although one grade 3 suspected unexpected serious adverse reaction was observed. Clinical responses were observed in 6/14 (43%) patients, with 2 complete responses and 4 partial responses (PR). 5/14 patients showed HPV-specific T-cell responses in blood, measured in ex vivo reactivity assays. Notably, all five patients with HPV-specific T-cell responses had a clinical response.ConclusionsOur results indicate that HPV-16 E6/E7 DNA tattoo vaccination is a biologically active and safe treatment strategy in patients with uVIN, and suggest that T-cell reactivity against the HPV oncogenes is associated with clinical benefit.Trial registration numberNTR4607.

2020-11-01·New Biotechnology2区 · 工程技术

Enhancement of a biotechnological platform for the purification and delivery of a human papillomavirus supercoiled plasmid DNA vaccine

2区 · 工程技术

Article

作者: Almeida, Ana M ; Costa, Diana ; Sousa, Fani ; Simões, Ana R ; Sousa, Ângela ; Queiroz, João A

New biotechnological strategies are being explored, aimed at rapid and economic manufacture of large quantities of DNA vaccines with the required purity for therapeutic applications, as well as their correct delivery as biopharmaceuticals to target cells. This report describes the purification of supercoiled (sc) HPV-16 E6/E7 plasmid DNA (pDNA) vaccine from a bacterial lysate, using an arginine-based monolith, presenting a spacer arm in its configuration. To enhance the performance of the purification process, monolith modification with the spacer arm can improve accessibility of the arginine ligand. By using a low NaCl concentration at pH 7.0, a condition to eliminate the RNA impurity directly in the flow through was established. The pH increase to 7.5 allowed the elimination of non-functional pDNA isoforms, the sc pDNA being recovered by increasing the ionic strength. As well as a binding capacity of 2.53 mg/mL obtained with a pre-purified sc pDNA sample, the column also purified sc pDNA from high lysate loading, with capacities above 1 mg/mL. Due to the sample displacement phenomena, non-functional pDNA isoforms were eliminated throughout column loading, favoring the degree of purity of final sc pDNA of 93.3%-98.5%. Thereafter, purified sc pDNA was successfully encapsulated into CaCO₃-gelatin nano-complexes. Delivery of the pDNA-carriers to THP-1 cells was assessed through pDNA cellular uptake evaluation and correct E6 expression was verified by mRNA and protein detection. A biotechnological platform was established for sc pDNA purification and delivery to dendritic cells, stimulating further in vivo studies.

100 项与 HPV 16 E7/HSP70 fused DNA vaccine(The Johns Hopkins University) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
卵巢癌	临床2期	-	The Johns Hopkins University	-
头颈部鳞状细胞癌	临床2期	-	The Johns Hopkins University	-
子宫颈发育不良	临床2期	-	The Johns Hopkins University	-