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

Abstract

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.

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

“…Additionally, this work shows now that the polyclonal antibody response elicited by CIGB-247 is able to block the binding of bevacizumab to VEGF, adding this property to other previously described for the interaction of VEGF with VEGFR2 and VEGFR1 [19].…”

“…The immune response elicited by CIGB-247 has been extensively investigated in two phase I clinical trials (CENTAURO and CENTAURO-2), with follow up studies in long-term surviving patients [18,19,24], with documented clinical benefits in the latter Although IgE has been pointed out as a mediator of anti-tumor effect [31,32], the generation of IgE antibodies by active immunization is probably the result of the specific antigen, adjuvants or schedules, or a combination of these.…”

“…To achieve a clinically relevant effect using a cancer vaccine, it is not only important to generate a robust immune response, but also to sustain this response over time with booster vaccinations. On this regard, patients recruited for the CENTAURO and CENTAURO-2 clinical trials received off-trial monthly re-immunizations until death, intolerance, marked disease progression or patient's withdrawal of consent [18,19]. This re-immunization phase was important to sustain the VEGF- Despite the fact that since 2011 a thoroughly characterization of the humoral response elicited by CIGB-247 in cancer patients has been performed [18,19,24], no data about a possible cross-reactivity of the VEGF-specific polyclonal response with other VEGF family members had been done.…”

“…CIGB-247 has shown anti-tumor and anti-metastatic effects in mice, stimulating the development of VEGF-blocking antibodies and specific T cell responses [15,17]. CIGB-247 has been already evaluated in two phase I clinical trials known as CENTAURO and CENTAURO-2, where safety and immunogenicity were studied in patients with advanced solid tumors [18,19] The results obtained from these two trials demonstrated the excellent safety profile of CIGB-247, and also indicated that it is possible to induce a polyclonal antibody response against human VEGF, characterized by the presence of specific IgG, IgM and IgA antibodies. This specific polyclonal antibody response was able to inhibit the interaction between VEGF and its receptors and reduce VEGF bioavailability within platelets [18,19].…”

“…In these individuals we have been able to show an excellent safety profile and sustained specific immune responses [23,24]. As immunizations have increased over the years, anti-VEGF IgG polyclonal antibody response shifts gradually in some patients from IgG1 to IgG4 [19,24]. Objective clinical benefits have been documented in a number of surviving CENTAURO patients [23,24] All the aforementioned led us to propose to the Cuban Regulatory Authority (CECMED), the initiation of a compassionate use program (CUP) for CIGB-247 in cancer 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 CIGB-247.…”