Non-clinical immuno-toxicological evaluation of HER1 cancer vaccine in non-human primates: a 12-month study

Barro, Ana M. Bada; Rivero, Arianna Iglesias; Goñi, Avelina León; Navarro, Bárbara; Angarica, Meilis Mesa; Ramírez, Belinda Sánchez; Bedoya, Darel Martínez; Triana, Consuelo González; Rodríguez, Axel Mancebo; Parada, Ángel Casacó

doi:10.1016/j.vaccine.2012.10.098

Cited by 5 publications

(5 citation statements)

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“…Finally, in the present study, no evidence of tissue damage was found after histopathological analysis of organs from immunized mice, suggesting the lack of toxicity in this model ( Figure S9 ). Previous studies on non-human primates and castration-resistant prostatic carcinoma patients immunized with the HER1 vaccine demonstrated its immunogenicity without evidence of severe adverse events ( 53 , 60 ). Still, the proposed vaccine candidate adds HER2 as an antigen and trastuzumab-like antibodies can be detected within the PAbs ( Figure 1D ), which might raise concerns regarding cardiotoxicity ( 61 ).…”

Section: Discussionmentioning

confidence: 99%

Polyclonal antibody-induced downregulation of HER1/EGFR and HER2 surpasses the effect of combinations of specific registered antibodies

Bergado-Báez

Suárez²,

García³

et al. 2022

Front. Oncol.

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BackgroundAntitumor therapies targeting HER1/EGFR and HER2, such as monoclonal antibodies (MAbs) and tyrosine-kinase inhibitors (TKIs), have demonstrated a significant clinical benefit, but the emergence of resistance limits long-term efficacy. While secondary HER1 mutations confer tolerance to TKI, compensatory upregulation of HER2 drives resistance to anti-HER1 MAbs, which identifies MAb combinations targeting both receptors as an attractive therapeutic strategy. Nevertheless, toxicity hampers the clinical validation of this approach. Alternatively, cancer vaccines may induce antibodies directed against several antigens with less concern about induced toxicity.MethodsPolyclonal antibodies (PAbs) targeting HER1 and HER2 were induced in mice or rabbits through immunization. Recognition of different epitopes on targets by PAbs was validated by phage-display technology. Receptor downregulation was evaluated by flow cytometry, immunofluorescence, and Western blot. MTT assays assessed cytotoxicity, while the antitumor effect of PAbs was assayed in nude mice.ResultsPAbs promoted degradation of HER1 and HER2 regarding clinical MAbs or their combinations. As a result, inhibition of cytotoxicity on tumor cell lines was improved, even in the presence of oncogenic mutations in HER1, as well as in cetuximab-insensitive cells. Accordingly, the antitumor effect of vaccination-induced PAbs was observed in lung tumor lines representative of sensitivity or resistance to HER1 targeting therapies.ConclusionsImmunization against HER1 and HER2 receptors offers an alternative to passive administration of combinations of MAbs, since vaccination-induced PAbs promote the downregulation of both receptors and they have a higher impact on the survival of tumor cells.

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Section: Discussionmentioning

confidence: 99%

Polyclonal antibody-induced downregulation of HER1/EGFR and HER2 surpasses the effect of combinations of specific registered antibodies

Bergado-Báez

Suárez²,

García³

et al. 2022

Front. Oncol.

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“…This vaccination produced antimetastatic effect in 3LL-D122 Lewis lung carcinoma model (Ramirez et al, 2006, 2008) and did not have a deleterious effect on the healing process in adult mice (Fuentes et al, 2014). In addition, toxicological studies in rats and monkeys demonstrated low toxicity and very safe profile of the HER1 vaccine (Barro et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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“…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 ]. Furthermore, lack of toxicity has been detected in thousands of patients vaccinated with different tumor associated antigens [ 45 ].…”

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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Non-clinical immuno-toxicological evaluation of HER1 cancer vaccine in non-human primates: a 12-month study

Cited by 5 publications

References 28 publications

Polyclonal antibody-induced downregulation of HER1/EGFR and HER2 surpasses the effect of combinations of specific registered antibodies

Polyclonal antibody-induced downregulation of HER1/EGFR and HER2 surpasses the effect of combinations of specific registered antibodies

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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