A safety and immunogenicity study of immunization with hVEGF26-104/RFASE in cynomolgus monkeys

Wentink, Madelon Q.; Verheul, Henk M.W.; Schafer, Kenneth A; McPherson, Susan; Early, R.; Vliet, Hans J. van der; Gruijl, Tanja D. de

doi:10.1016/j.vaccine.2018.02.066

Cited by 8 publications

(6 citation statements)

References 29 publications

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“…These mutations create a local conformational perturbation within the receptor binding domain of the antigen. Despite this, the polyclonal antibody response elicited after immunization blocks the receptor binding domain on natural VEGF as well as the binding site for antigen and RFASE as adjuvant [16]. This VEGF therapeutic vaccine has shown antiangiogenic and antitumor activity in pre-clinical models [15], but discrete results in terms of immunogenicity have been observed in the first cancer patients treated with the vaccine [17].…”

Section: Discussionmentioning

confidence: 99%

“…This antigen sequence represents the complete Bevacizumab binding site and using RFASE as adjuvant, the vaccine (hVEGF 26-104 /RFASE) induces an immune response with VEGF neutralizing activity and anti-tumor effect [15]. Elicited polyclonal antibody response in addition to its cross-reactivity with human VEGF, have also demonstrated in rats and monkeys its capacity to impair the binding of Bevacizumab to VEGF [15,16], indicating the presence of antibodies that block binding sites on VEGF which have shown to be clinically relevant. This vaccine is being investigated in a phase I open-label clinical trial (NCT02237638), and preliminary results of the first included patients indicated that hVEGF 26-104 /RFASE has a good safety profile.…”

Section: Introductionmentioning

confidence: 99%

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Specific humoral response in cancer patients treated with a VEGF therapeutic vaccine under a compassionate use program

Ramírez¹,

Díaz²,

Bequet-Romero³

et al. 2019

Preprint

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Background: CIGB-247 is a cancer therapeutic vaccine that uses as antigen a variant of human vascular endothelial growth factor (VEGF) mixed with the bacterial-derived adjuvant VSSP. This VEGF vaccine has been evaluated in phase I clinical trials CENTAURO and CENTAURO-2, showing to be safe and immunogenic in advanced cancer patients selected under well-defined and controlled clinical conditions. Surviving patients were submitted to monthly re-immunizations and some of them showed objective clinical benefits. These observations led us to initiate a compassionate use program of CIGB-247 in patients who do not meet entry criteria applied for CENTAURO and CENTAURO-2 clinical trials. Results: This report shows the characterization of the humoral response elicited after vaccination with 400 µg of antigen combined with 200 µg of VSSP in cancer patients representative of the Cuban real clinical practice setting. Polyclonal antibody response was specific to VEGF, and showed no cross reactivity with other VEGF family members like VEGF-C and VEGF-D. Specific IgM, IgA and IgG antibodies detected in the serum of vaccinated patients were able to block the binding of VEGF to its receptors VEGFR1 and VEGFR2. Serum-purified IgG fraction exhibited all these properties. For the first time, there is experimental evidence of the presence of polyclonal antibodies directed to clinically relevant epitopes on VEGF. These elicited antibodies impaired the high affinity interaction between VEGF and monoclonal antibody Bevacizumab, an antiangiogenic drug approved in combination with chemotherapy for the treatment of different tumors. This investigation also shows preliminary evidences of safety and immunogenicity of CIGB-247 in cancer patients under clinical conditions not yet explored. Conclusions: CIGB-247 was immunogenic in a broader patient population, and induced Bevacizumab-like polyclonal antibodies, indicating that the VEGF-specific antibody response could have a potentially relevant clinical activity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Specific humoral response in cancer patients treated with a VEGF therapeutic vaccine under a compassionate use program

Ramírez¹,

Díaz²,

Bequet-Romero³

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…The finding of the presence of bevacizumab-blocking antibodies within the polyclonal response elicited by CIGB-247 indicates that the specific humoral response is directed to relevant domains on VEGF. The induction of bevacizumab-blocking antibodies by active immunization has been also developed by Wentink et al This approach is based on vaccination against the bevacizumab binding site on VEGF using a truncated protein (human VEGF 26-104 ) as antigen and RFASE as adjuvant [21]. This VEGF therapeutic vaccine has shown antiangiogenic and antitumor activity in pre-clinical models [20], but discrete results in terms of immunogenicity have been observed in the first cancer patients treated with the vaccine [22].…”

Section: Uc-ha14mentioning

confidence: 99%

“…Using RFASE as adjuvant, the vaccine (hVEGF 26-104 /RFASE) induces an immune response with VEGF neutralizing activity and anti-tumor effect [20]. In rats and monkeys immunized with this vaccine candidate, the VEGFspecific polyclonal antibody response has also demonstrated its capacity to impair the binding of bevacizumab to VEGF, suggesting the presence of antibodies that target the same VEGF epitope as bevacizumab [20,21]. This vaccine is being investigated in a phase I open-label clinical trial (NCT02237638), and preliminary results of the first included patients indicated that hVEGF 26-104 / RFASE has a good safety profile.…”

Section: Introductionmentioning

confidence: 99%

Specific humoral response in cancer patients treated with a VEGF-specific active immunotherapy procedure within a compassionate use program

et al. 2020

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Background: CIGB-247 is a cancer therapeutic vaccine that uses as antigen a variant of human vascular endothelial growth factor (VEGF) mixed with the bacterially-derived adjuvant VSSP. CIGB-247 has been already evaluated in two phase I clinical trials (CENTAURO and CENTAURO-2), showing to be safe and immunogenic in advanced cancer patients selected under well-defined and controlled clinical conditions. Surviving patients were submitted to monthly re-immunizations and some of them showed objective clinical benefits. Based on these results, a compassionate use program (CUP) with CIGB-247 was initiated for patients that did not meet the strict entry criteria applied for the CENTAURO and CENTAURO-2 clinical trials, but could potentially benefit from the application of this cancer therapeutic vaccine. Results: Polyclonal IgM, IgA and IgG antibodies specific for VEGF were detected by ELISA in serum samples from patients vaccinated with 400 μg of antigen combined with 200 μg of VSSP. Polyclonal antibody response showed no cross reactivity for other VEGF family member molecules like VEGF-C and VEGF-D. Serum from immunized individuals was able to block the binding of VEGF to its receptors VEGFR2 and VEGFR1. IgG fraction purified from immune sera shared the aforementioned characteristics and also inhibited the interaction between VEGF and the therapeutic recombinant antibody bevacizumab, an anti-angiogenic drug approved for the treatment of different tumors. No serious adverse events attributable to CIGB-247 have been documented yet in participants of the CIGB-247 CUP. The present paper is a first report of our findings concerning the humoral response and safety characteristics in treated CIGB-247 CUP cancer patients. The study has provided the unique opportunity of not only testing CIGB-247 in a broader clinical spectrum sample of Cuban cancer patients, but also within the context of the day-today clinical practice and treatment settings for these diseases in Cuban medical institutions.

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“…It would offer the advantage of continuous and a potentially more pronounced inhibition of VEGF without the need for repeated antibody administrations. Here, we describe the results of a phase-I trial of the novel therapeutic vaccine hVEGF 26-104 /RFASE 1,2 in patients with advanced solid malignancies.…”

mentioning

confidence: 99%

A Phase I Open-Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies

et al. 2020

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The novel therapeutic vaccine hVEGF 26-104 /RFASE was found to be safe and well tolerated in cancer patients. • hVEGF 26-104 /RFASE failed to induce seroconversion against native hVEGF 165 and, accordingly, neither a decrease in circulating VEGF levels nor clinical benefit was observed. • Remarkably, hVEGF 26-104 /RFASE induced VEGF 165-neutralizing antibodies in a non-human primate model. • The absence of seroconversion in man calls for caution in the interpretation of efficacy of human vaccines in non-human primates.

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A safety and immunogenicity study of immunization with hVEGF26-104/RFASE in cynomolgus monkeys

Abstract: These data show that hVEGF/RFASE can be safely administered in cynomolgus monkeys, induces the desired immune response and therefore support the clinical development of this vaccine.

Cited by 8 publications

References 29 publications

Specific humoral response in cancer patients treated with a VEGF therapeutic vaccine under a compassionate use program

Specific humoral response in cancer patients treated with a VEGF therapeutic vaccine under a compassionate use program

Specific humoral response in cancer patients treated with a VEGF-specific active immunotherapy procedure within a compassionate use program

A Phase I Open-Label Clinical Trial Evaluating the Therapeutic Vaccine hVEGF26–104/RFASE in Patients with Advanced Solid Malignancies

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