Very small size proteoliposomes derived from Neisseria meningitidis: An effective adjuvant for antigen-specific cytotoxic T lymphocyte response stimulation under leukopenic conditions

Oliver, Liliana; Fernández, Audry; Raymond, Judith; López‐Requena, Alejandro; Fernández, Luis E.; Mesa, Circe

doi:10.1016/j.vaccine.2012.02.054

Cited by 11 publications

(13 citation statements)

References 47 publications

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“…As experimental basis for this matter, our group achieved satisfactory results in non-human primates by increasing the amount of antigen in combination with VSSP as adjuvant and using a weekly vaccination scheme [7]. VSSP has shown immunopotentiating properties on the humoral and cellular responses [9–11], however, it has not yet been explored whether increasing the amount of VSSP in the vaccine lead to higher antibody titers specific to VEGF.…”

Section: Introductionmentioning

confidence: 99%

Characteristics of the specific humoral response in patients with advanced solid tumors after active immunotherapy with a VEGF vaccine, at different antigen doses and using two distinct adjuvants

et al. 2017

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BackgroundCIGB-247, a VSSP-adjuvanted VEGF-based vaccine, was evaluated in a phase I clinical trial in patients with advanced solid tumors (CENTAURO). Vaccination with the maximum dose of antigen showed an excellent safety profile, exhibited the highest immunogenicity and was the only one showing a reduction on platelet VEGF bioavailability. However, this antigen dose level did not achieve a complete seroconversion rate in vaccinated patients. These clinical results led us to the question whether a “reserve” of untapped immune response potential against VEGF could exist in cancer patients. To address this matter, CENTAURO-2 clinical trial was conducted where antigen and VSSP dose scale up were studied, and also incorporated the exploration of aluminum phosphate as adjuvant. These changes were made with the aim to increase immune response against VEGF.ResultsThe present study reports the characterization of the humoral response elicited by CIGB-247 from the combining of different antigen doses and adjuvants. Cancer patients were immunologically monitored for approximately 1 year. Vaccination with different CIGB-247 formulations exhibited a very positive safety profile. Cancer patients developed IgM, IgG or IgA antibodies specific to VEGF. Elicited polyclonal antibodies had the ability to block the interaction between VEGF and its receptors, VEGFR1 and VEGFR2. The highest humoral response was detected in patients immunized with 800 μg of antigen + 200 μg of VSSP. Off-protocol long-term vaccination did not produce negative changes in humoral response.ConclusionsVaccination with a human VEGF variant molecule as antigen in combination with VSSP or aluminum phosphate is immunogenic. The results of this study could contribute to the investigation of this vaccine therapy in an adequately powered efficacy trial.Trial registrationTrial registration number: RPCEC00000155. Cuban Public Clinical Trial Registry. Date of registration: June 06, 2013. Available from: http://registroclinico.sld.cu/.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-017-0222-z) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Characteristics of the specific humoral response in patients with advanced solid tumors after active immunotherapy with a VEGF vaccine, at different antigen doses and using two distinct adjuvants

et al. 2017

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“…This adjuvant induces DCs maturation and antigen cross-presentation to CD8 + T cells in tumor-free mice [27,28]. More recently, we demonstrated that VSSP protects CTL responses specific for the nominal antigen not only in TB mice but also in the context of severe leukopenia [24,29]. Currently four therapeutic cancer vaccines using this product as adjuvant are in clinical research.…”

Section: Introductionmentioning

confidence: 99%

Very small size proteoliposomes abrogate cross-presentation of tumor antigens by myeloid-derived suppressor cells and induce their differentiation to dendritic cells

Fernández¹,

Oliver²,

Alvarez³

et al. 2014

j. immunotherapy cancer

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Background: Myeloid-derived suppressor cells (MDSCs) are among the major obstacles that adjuvants for cancer vaccines have to overcome. These cells cross-present tumor-associated antigens (TAA) to naive T lymphocytes with a tolerogenic outcome. Very Small Size Proteoliposomes (VSSP) is used as adjuvant by four therapeutic cancer vaccines currently in Phase I and II clinical trials. We previously found that VSSP reduces the suppressive function of MDSCs, then activating antigen-specific CTL responses in tumor-bearing (TB) mice, with the consequent reduction of tumor growth. However the mechanistic explanation for the immunomodulatory effect of this adjuvant in TB hosts has not been addressed before. Methods: TB mice were inoculated with VSSP and MDSCs isolated and characterized by their expression of Arg1 and Nos2 genes by RT-PCR. The effect of VSSP on antigen cross-presentation by MDSCs, regulatory T cells (Tregs) expansion and MDSCs differentiation towards dendritic cells (DCs) was analyzed by FACS. Student's t test or ANOVA and Tukey's tests were used for statistical analyses.

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“…Experiments with antigen-specific transgenic T cells demonstrated that VSSP-treated DCs induced a Th1 phenotype in stimulated naïve CD4+ T cells (Mesa et al, 2004). Furthermore, VSSP expanded CD8+ T cells specific for the co-injected antigen and promoted an effective in vivo cytotoxic T lymphocytes (CTL) response (Oliver et al, 2012). On the other hand, anti-HER1 monoclonal antibodies, which have been demonstrated good clinical results in cancer patients, are IgG1 antibodies (Dechant et al, 2008; Garrido et al, 2011; You and Chen, 2012) since IgG1 subclasses potently triggers effector mechanisms such as complement activation and antibody dependent cellular cytotoxicity (Garrido et al, 2011).…”

Section: Discussionmentioning

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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Very small size proteoliposomes derived from Neisseria meningitidis: An effective adjuvant for antigen-specific cytotoxic T lymphocyte response stimulation under leukopenic conditions

Cited by 11 publications

References 47 publications

Characteristics of the specific humoral response in patients with advanced solid tumors after active immunotherapy with a VEGF vaccine, at different antigen doses and using two distinct adjuvants

Characteristics of the specific humoral response in patients with advanced solid tumors after active immunotherapy with a VEGF vaccine, at different antigen doses and using two distinct adjuvants

Very small size proteoliposomes abrogate cross-presentation of tumor antigens by myeloid-derived suppressor cells and induce their differentiation to dendritic cells

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

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