Repeated dose (14days) rat intramuscular toxicology study of Her1 vaccine

Mancebo, A.; Casacó, Á.; Sánchez, Belinda; González, B.; Gomez, Daniel E.; León, Avelina; Bada, A.M.; Arteaga, M.E.; González, Y.; González, Cristóbal; Pupo, Mônica Tallarico; Fuentes, Dasha

doi:10.1016/j.yrtph.2012.10.002

Cited by 6 publications

(4 citation statements)

References 54 publications

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“…However, it has also been found that there is poor interspecies concordance with respect to injection site reactions for biological drugs and that the occurrence of haemorrhage, oedema and/or inflammatory cells infiltrates with or without fibroplasia/fibrosis in animal studies should be regarded as only a signal for potential effects in the clinic (Engelhardt, ). Of note for vaccine use, inflammatory signs have been reported at the injection site in clinical trials with various adjuvanted vaccines in development (for example, Mancebo et al ., ; Garçon et al ., ; Segal et al ., ). Furthermore, the long history of the human use of vaccines using aluminium‐containing adjuvants has shown local inflammatory reactions, although these are usually mild and of a short duration (Hogenesch, ; Lindblad, ).…”

Section: Discussionmentioning

confidence: 99%

Dose site reactions and related findings after vaccine administration in safety studies

Baldrick

2016

J of Applied Toxicology

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Potential new human vaccines undergo toxicology testing to evaluate local reactogenicity and systemic toxicity. A review of 30 recently published and in-house repeat dose toxicity studies with a variety of vaccines was performed. Species tested were generally rat or rabbit, usually by intramuscular (although occasionally subcutaneous) injection. Results showed no unexpected findings indicating vaccine toxicity, but classic signs of enhanced acute and/or chronic inflammation at the dose site compared with that seen in injected control animals, often accompanied by changes in draining lymph nodes and the spleen (lymphoid hyperplasia and/or increased weight). Other associated signs of a response to vaccine dosing were altered clinical pathology parameters (commonly raised blood neutrophil count and altered globulin level). No obvious difference in dose site or systemic reaction was seen across vaccine, species or the dose route used. A non-dose recovery period of 2 to 4 weeks was sufficient to show evidence of reversibility of dose site effects. Injection site, lymphoid tissue and clinical pathological changes can be interpreted as related to an expected reaction after vaccine dosing, with generation of an immune response largely as a result of the presence of adjuvant, although direct vaccine antigen involvement was also occasionally demonstrated by the presence of a slightly increased inflammatory response seen over adjuvant treatment only. Overall, the need for toxicity testing of vaccines is in line with current regulatory guideline requirements and has proven to be a valuable part of the safety evaluation process prior to human use. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Dose site reactions and related findings after vaccine administration in safety studies

Baldrick

2016

J of Applied Toxicology

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“…This potential toxicity was the cause by which the initial dose of the vaccine was 100 μg. This dose was the half of the dose evaluated in monkeys (Barro et al, 2012; Mancebo et al, 2012), and it demonstrated antitumor effect in mice (Ramirez et al, 2006, 2008). Then, the dose was increased up to 800 μg without find any important toxic effect.…”

Section: Discussionmentioning

confidence: 99%

“…Regarding to vaccine safety, immune response induced in vaccinated mice did not have a deleterious effect in wound healing process (Fuentes et al, 2014) and reproduction-associated side effect was absent (Ramirez et al, 2006). Besides, toxicity studies in rats and monkeys demonstrated that vaccine was immunogenic and well tolerated with only local reactions at administration site (Barro et al, 2012; Mancebo et al, 2012). Based on these findings, a first -in- human phase I clinical trial was approved in 2009 by the Cuban Regulatory Agency (CECMED).…”

Section: Introductionmentioning

confidence: 99%

Safety and Immunogenicity of a Human Epidermal Growth Factor Receptor 1 (HER1)-Based Vaccine in Prostate Castration-Resistant Carcinoma Patients: A Dose-Escalation Phase I Study Trial

et al. 2017

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Metastatic castration-resistant prostate cancer (CRPC) remains incurable due to the lack of effective therapies. Activation of the human epidermal growth factor receptor 1 (HER1) in prostate cancer contributes to metastatic progression as well as to disease relapse. Here, we determined the toxicity and immunogenicity of a HER1-based cancer vaccine in CRPC patients included in a phase I clinical trial. CRPC patients (n = 24) were intramuscularly vaccinated with HER1 vaccine consisting of the extracellular domain of HER1 molecule (ECD) and very small size proteoliposome from Neisseria meningitidis (VSSP) and Montanide ISA-51 VG as adjuvants. Patients were included in five groups according to the vaccine dose (100, 200, 400, 600, and 800 μg). The primary endpoints were safety and immunogenicity. The anti-HER1 antibodies were measured by an ELISA, the recognition of an HER1 positive tumor cell line and the inhibition of HER1 phosphorylation by sera were determined by flow cytometry and western blot analysis, respectively. The HER1-specific T cell response was assessed by determination of IFN-γ-producing T cells using ELISpot assay. The vaccine was well tolerated. No grade III or IV adverse events were reported. High titers of anti-HER1 antibodies were observed in most of the evaluated patients. There were no significant differences regarding the geometric means of the anti-HER1 titers among the dose groups except the group of 100 μg in which antibody titers were significantly lower. A Th1-type IgG subclasses pattern was predominant in most patients. Only patients receiving the higher doses of vaccine showed significant tumor cell recognition and HER1 phosphorylation inhibition by hyperimmune sera. Forty two percent of the patients showed a specific T cell response against HER1 peptides pool in post-treatment samples. There was a trend toward survival benefit in those patients showing high anti-HER1 specific antibody titers and a significant association between cellular immune response and clinical outcome.

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“…However, our previous studies showed the proof of principle of autologous vaccination, immunizing with murine EGFR adjuvated in VSSP. This vaccine circumvented the tolerance to this self-protein, inducing humoral and cellular immune response, with antimetastatic effect in vivo [ 41 ] without evidences of toxicity [ 42 , 43 ]. Additionally, break of tolerance against the human variant of HER1 using VSSP as adjuvant, has been also evidenced in closest models like monkeys, without any sign of toxicity [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

Anti-proliferative and pro-apoptotic effects induced by simultaneous inactivation of HER1 and HER2 through endogenous polyclonal antibodies

et al. 2017

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The human epidermal growth factor receptor (HER1) and its partner HER2 are extensively described oncogenes and validated targets for cancer therapy. However, the effectiveness of monospecific therapies targeting these receptors is hampered by resistance emergence, which is frequently associated with the upregulation of other members of HER family. Combined therapies using monoclonal antibodies or tyrosine kinase inhibitors have been suggested as a promising strategy to circumvent this resistance mechanism. We propose an alternative approach based on simultaneous inactivation of HER1 and HER2 by multi-epitope blockade with specific polyclonal antibodies induced by vaccination. Elicited antibodies impaired both receptors activation and induced their degradation, which caused the inhibition of down-signaling cascades. This effect was translated into cell cycle arrest and apoptosis induction of human tumor cells. Elicited antibodies were able to reduce the viability of a panel of human tumor lines with differential expression levels of HER1 and HER2. The most significant effects were obtained in the tumor lines with lower expression levels of both receptors. These new insights would contribute to the rational design of HER receptors targeting multivalent vaccines, as an encouraging approach for the treatment of cancer patients.

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Repeated dose (14days) rat intramuscular toxicology study of Her1 vaccine

Cited by 6 publications

References 54 publications

Dose site reactions and related findings after vaccine administration in safety studies

Dose site reactions and related findings after vaccine administration in safety studies

Safety and Immunogenicity of a Human Epidermal Growth Factor Receptor 1 (HER1)-Based Vaccine in Prostate Castration-Resistant Carcinoma Patients: A Dose-Escalation Phase I Study Trial

Anti-proliferative and pro-apoptotic effects induced by simultaneous inactivation of HER1 and HER2 through endogenous polyclonal antibodies

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