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BMC Immunology
Published in: BMC Immunology 1/2017

Open Access 01-12-2017 | Research article

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

Authors: Javier Sánchez Ramírez, Yanelys Morera Díaz, Mónica Bequet-Romero, Francisco Hernández-Bernal, Katty-Hind Selman-Housein Bernal, Ana de la Torre Santos, Eduardo Rafael Santiesteban Álvarez, Yenima Martín Bauta, Cimara H. Bermúdez Badell, Josué de la Torre Pupo, Jorge V. Gavilondo, Marta Ayala Avila, CENTAURO-2 Team of Investigators

Published in: BMC Immunology | Issue 1/2017

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Abstract

Background

CIGB-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.

Results

The 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.

Conclusions

Vaccination 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 registration

Trial registration number: RPCEC00000155. Cuban Public Clinical Trial Registry. Date of registration: June 06, 2013. Available from: http://​registroclinico.​sld.​cu/​.
Appendix
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Literature
1.
Wentink MQ, Huijbers EJ, de Gruijl TD, Verheul HM, Olsson AK, Griffioen AW. Vaccination approach to anti-angiogenic treatment of cancer. Biochim Biophys Acta. 2015;1855(2):155–71.PubMed
2.
3.
Morera Y, Bequet M, Ayala M, Lamdán H, Agger EM, Andersen P, Gavilondo JV. Anti-tumoral effect of active immunotherapy in C57BL/6 mice using a recombinant human VEGF protein as antigen and three chemically unrelated adjuvants. Angiogenesis. 2008;11(4):381–93.CrossRefPubMed
4.
Estévez F, Carr A, Solorzano L, Valiente O, Mesa C, Barroso O, Sierra GV, Fernández LE. Enhancement of the immune response to poorly immunogenic gangliosides after incorporation into very small size proteoliposomes (VSSP). Vaccine. 1999;18(1-2):190–7.CrossRefPubMed
5.
Morera Y, Bequet M, Ayala M, Velazco JC, Pérez PP, Alba JS, Ancízar J, Rodríguez M, Cosme K, Gavilondo JV. Immunogenicity and some safety features of a VEGF-based cancer therapeutic vaccine in rats, rabbits and non-human primates. Vaccine. 2010;28(19):3453–61.CrossRefPubMed
6.
Bequet M, Morera Y, Ayala M, Ancízar J, Soria Y, Blanco A, Suárez-Alba J, Gavilondo JV. CIGB-247: a VEGF-based therapeutic vaccine that reduces experimental and spontaneous lung metastasis of C57Bl/6 and BALB/c mouse tumors. Vaccine. 2012;30(10):1790–9.CrossRef
7.
Morera Y, Bequet M, Ayala M, Pérez PP, Castro J, Sánchez J, Alba JS, Ancízar J, Cosme K, Gavilondo JV. Antigen dose escalation study of a VEGF-based therapeutic cancer vaccine in non human primates. Vaccine. 2012;30(2):368–77.CrossRefPubMed
8.
Gavilondo JV, Hernández F, Ayala M, de la Torre AV, de la Torre J, Morera Y, Bequet M, Sánchez J, Valenzuela CM, Martin Y, et al. Specific active immunotherapy with a VEGF vaccine in patients with advanced solid tumors. results of the CENTAURO antigen dose escalation phase I clinical trial. Vaccine. 2014;32(19):2241–50.CrossRefPubMed
9.
Mesa C, De Leon J, Rigley K, Fernandez LE. Very small size proteoliposomes derived from Neisseria meningitidis: an effective adjuvant for Th1 induction and dendritic cell activation. Vaccine. 2004;22(23-24):3045–52.CrossRefPubMed
10.
Fernandez A, Mesa C, Marigo I, Dolcetti L, Clavell M, Oliver L, Fernandez LE, Bronte V. Inhibition of tumor-induced myeloid-derived suppressor cell function by a nanoparticulated adjuvant. J Immunol. 2011;186(1):264–74.CrossRefPubMed
11.
Oliver L, Fernandez A, Raymond J, Lopez-Requena A, Fernandez LE, Mesa C. Very small size proteoliposomes derived from Neisseria meningitidis: an effective adjuvant for antigen-specific cytotoxic T lymphocyte response stimulation under leukopenic conditions. Vaccine. 2012;30(19):2963–72.CrossRefPubMed
12.
13.
Pérez Sánchez L, Morera Diaz Y, Bequet-Romero M, Ramses Hernández G, Rodríguez Y, Castro Velazco J, Puente Pérez P, Ayala Avila M, Gavilondo JV. Experimental studies of a vaccine formulation of recombinant human VEGF antigen with aluminum phosphate. Hum Vaccin Immunother. 2015;11(8):2030–7.CrossRefPubMedPubMedCentral
14.
Morera Y, Lamdán H, Bequet M, Ayala M, Rojas G, Muñoz Y, Gavilondo JV. Biologically active vascular endothelial growth factor as a bacterial recombinant glutathione S-transferase fusion protein. Biotechnol Appl Biochem. 2006;44(Pt 1):45–53.PubMed
15.
Sánchez Ramírez J, Morera Díaz Y, Musacchio Lasa A, Bequet-Romero M, Muñoz Pozo Y, Pérez Sánchez L, Hernández-Bernal F, Mendoza Fuentes O, Selman-Housein KH, Gavilondo Cowley JV, et al. Indirect and competitive enzyme-linked immunosorbent assays for monitoring the humoral response against human VEGF. J Immunoassay Immunochem. 2016;37(6):636–58.CrossRefPubMed
16.
Danziger-Isakov L, Cherkassky L, Siegel H, McManamon M, Kramer K, Budev M, Sawinski D, Augustine JJ, Hricik DE, Fairchild R, et al. Effects of influenza immunization on humoral and cellular alloreactivity in humans. Transplantation. 2010;89(7):838–44.CrossRefPubMedPubMedCentral
17.
Adams J, Carder PJ, Downey S, Forbes MA, MacLennan K, Allgar V, Kaufman S, Hallam S, Bicknell R, Walker JJ, et al. Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen. Cancer Res. 2000;60(11):2898–905.PubMed
18.
Recchia F, Candeloro G, Necozione S, Bisegna R, Bratta M, Rea S. Immunotherapy in patients with less than complete response to chemotherapy. Anticancer Res. 2009;29(2):567–72.PubMed
19.
Zhang Z, Neiva KG, Lingen MW, Ellis LM, Nor JE. VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ. 2010;17(3):499–512.CrossRefPubMed
20.
Shah MA, Wainberg ZA, Catenacci DV, Hochster HS, Ford J, Kunz P, Lee FC, Kallender H, Cecchi F, Rabe DC, et al. Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS One. 2013;8(3):e54014.CrossRefPubMedPubMedCentral
21.
Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol. 2009;27(18):3027–35.CrossRefPubMedPubMedCentral
22.
Boige V, Malka D, Bourredjem A, Dromain C, Baey C, Jacques N, Pignon JP, Vimond N, Bouvet-Forteau N, De Baere T, et al. Efficacy, safety, and biomarkers of single-agent bevacizumab therapy in patients with advanced hepatocellular carcinoma. Oncologist. 2012;17(8):1063–72.CrossRefPubMedPubMedCentral
23.
Willett CG, Duda DG, di Tomaso E, Boucher Y, Ancukiewicz M, Sahani DV, Lahdenranta J, Chung DC, Fischman AJ, Lauwers GY, et al. Efficacy, safety, and biomarkers of neoadjuvant bevacizumab, radiation therapy, and fluorouracil in rectal cancer: a multidisciplinary phase II study. J Clin Oncol. 2009;27(18):3020–6.CrossRefPubMedPubMedCentral
24.
Guidance Development Review C, Working Group for Clinical Studies of Cancer I, Working Group for Effector Cell T, Working Group for CMCNcS, Working Group for Cancer V, Adjuvants, Working Group for Anti‐immune Checkpoint T, Comprehensive Cancer I, Biostatistics S, Arato T, et al. Guidance on cancer immunotherapy development in early‐phase clinical studies. Cancer Sci. 2015;106(12):1761–71.CrossRef
25.
Gonzalez G, Crombet T, Neninger E, Viada C, Lage A. Therapeutic vaccination with epidermal growth factor (EGF) in advanced lung cancer: analysis of pooled data from three clinical trials. Hum Vaccin. 2007;3(1):8–13.CrossRefPubMed
26.
Ullenhag GJ, Frodin JE, Jeddi-Tehrani M, Strigard K, Eriksson E, Samanci A, Choudhury A, Nilsson B, Rossmann ED, Mosolits S, et al. Durable carcinoembryonic antigen (CEA)-specific humoral and cellular immune responses in colorectal carcinoma patients vaccinated with recombinant CEA and granulocyte/macrophage colony-stimulating factor. Clin Cancer Res. 2004;10(10):3273–81.CrossRefPubMed
27.
Staff C, Magnusson CG, Hojjat-Farsangi M, Mosolits S, Liljefors M, Frodin JE, Wahren B, Mellstedt H, Ullenhag GJ. Induction of IgM, IgA and IgE antibodies in colorectal cancer patients vaccinated with a recombinant CEA protein. J Clin Immunol. 2012;32(4):855–65.CrossRefPubMed
28.
Gonzalez G, Crombet T, Catala M, Mirabal V, Hernandez JC, Gonzalez Y, Marinello P, Guillen G, Lage A. A novel cancer vaccine composed of human-recombinant epidermal growth factor linked to a carrier protein: report of a pilot clinical trial. Ann Oncol. 1998;9(4):431–5.CrossRefPubMed
29.
Alfonso S, Valdés-Zayas A, Santiesteban ER, Flores YI, Areces F, Hernández M, Viada CE, Mendoza IC, Guerra PP, García E, et al. A randomized, multicenter, placebo-controlled clinical trial of racotumomab-alum vaccine as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Cancer Res. 2014;20(14):3660–71.CrossRefPubMed
30.
Osorio M, Gracia E, Reigosa E, Hernandez J, de la Torre A, Saurez G, Perez K, Viada C, Cepeda M, Carr A, et al. Effect of vaccination with N-glycolyl GM3/VSSP vaccine by subcutaneous injection in patients with advanced cutaneous melanoma. Cancer Manage Res. 2012;4:341–5.CrossRef
31.
de la Torre A, Hernandez J, Ortiz R, Cepeda M, Perez K, Car A, Viada C, Toledo D, Guerra PP, Garcia E, et al. NGlycolylGM3/VSSP Vaccine in Metastatic Breast Cancer Patients: Results of Phase I/IIa Clinical Trial. Breast Cancer: Basic Clin Res. 2012;6:151–7.
32.
Kim YT, Merrifield N, Zarchy T, Brody NI, Siskind GW. Studies on antigenic competition. 3. Effect on antigenic competition on antibody affinity. Immunology. 1974;26(5):943–55.PubMedPubMedCentral
33.
Dagan R, Eskola J, Leclerc C, Leroy O. Reduced response to multiple vaccines sharing common protein epitopes that are administered simultaneously to infants. Infect Immun. 1998;66(5):2093–8.PubMedPubMedCentral
34.
Ragupathi G, Liu NX, Musselli C, Powell S, Lloyd K, Livingston PO. Antibodies against tumor cell glycolipids and proteins, but not mucins, mediate complement-dependent cytotoxicity. J Immunol. 2005;174(9):5706–12.CrossRefPubMed
35.
Snijdewint FG, von Mensdorff-Pouilly S, Karuntu-Wanamarta AH, Verstraeten AA, Livingston PO, Hilgers J, Kenemans P. Antibody-dependent cell-mediated cytotoxicity can be induced by MUC1 peptide vaccination of breast cancer patients. Int J Cancer. 2001;93(1):97–106.CrossRefPubMed
36.
Wen YM, Mu L, Shi Y. Immunoregulatory functions of immune complexes in vaccine and therapy. 2016;8(10):1120-1133.
37.
de Jong JM, Schuurhuis DH, Ioan-Facsinay A, Welling MM, Camps MG, van der Voort EI, Huizinga TW, Ossendorp F, Verbeek JS, Toes RE. Dendritic cells, but not macrophages or B cells, activate major histocompatibility complex class II-restricted CD4+ T cells upon immune-complex uptake in vivo. Immunology. 2006;119(4):499–506.CrossRefPubMedPubMedCentral
38.
den Haan JM, Bevan MJ. Constitutive versus activation-dependent cross-presentation of immune complexes by CD8(+) and CD8(-) dendritic cells in vivo. J Exp Med. 2002;196(6):817–27.CrossRef
39.
Hamano Y, Arase H, Saisho H, Saito T. Immune complex and Fc receptor-mediated augmentation of antigen presentation for in vivo Th cell responses. J Immunol. 2000;164(12):6113–9.CrossRefPubMed
40.
Shen L, van Egmond M, Siemasko K, Gao H, Wade T, Lang ML, Clark M, van De Winkel JG, Wade WF. Presentation of ovalbumin internalized via the immunoglobulin-A Fc receptor is enhanced through Fc receptor gamma-chain signaling. Blood. 2001;97(1):205–13.CrossRefPubMed
41.
Shibuya A, Honda S. Molecular and functional characteristics of the Fcalpha/muR, a novel Fc receptor for IgM and IgA. Springer Semin Immunopathol. 2006;28(4):377–82.CrossRefPubMed
42.
Voron T, Marcheteau E, Pernot S, Colussi O, Tartour E, Taieb J, Terme M. Control of the immune response by pro-angiogenic factors. Front Oncol. 2014;4:70.CrossRefPubMedPubMedCentral
43.
González G, Crombet T, Lage A. Chronic vaccination with a therapeutic EGF-based cancer vaccine: a review of patients receiving long lasting treatment. Curr Cancer Drug Targets. 2011;11(1):103–10.CrossRefPubMed
44.
Selman-Housein KH, de la Torre A, Hernández-Bernal F, Martin Y, Garabito A, Piñero J, Morera Diaz Y, Sánchez Ramírez J, Bequet-Romero M, Bermúdez C, et al. Clinical benefits in patients with advanced solid tumors after long-term immunization with a VEGF therapeutic vaccine. Open J Clin Med Case Rep. 2017, 3(2).
45.
Almand B, Clark JI, Nikitina E, van Beynen J, English NR, Knight SC, Carbone DP, Gabrilovich DI. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166(1):678–89.CrossRefPubMed
46.
Gross S, Walden P. Immunosuppressive mechanisms in human tumors: why we still cannot cure cancer. Immunol Lett. 2008;116(1):7–14.CrossRefPubMed
47.
Morera Y, Sánchez J, Bequet-Romero M, Selman-Housein KH, de la Torre A, Hernández-Bernal F, Martin Y, Garabito A, Pinero J, Bermúdez C, et al. Specific humoral and cellular immune responses in cancer patients undergoing chronic immunization with a VEGF-based therapeutic vaccine. Vaccine. 2017;35(28):3582–90.CrossRefPubMed
48.
Ullenhag GJ, Frodin JE, Strigard K, Mellstedt H, Magnusson CG. Induction of IgG subclass responses in colorectal carcinoma patients vaccinated with recombinant carcinoembryonic antigen. Cancer Res. 2002;62(5):1364–9.PubMed
49.
50.
Prechl J. A generalized quantitative antibody homeostasis model: antigen saturation, natural antibodies and a quantitative antibody network. bioRxiv. 2016.
51.
Cunningham SA, Tran TM, Arrate MP, Brock TA. Characterization of vascular endothelial cell growth factor interactions with the kinase insert domain-containing receptor tyrosine kinase. A real time kinetic study. J Biol Chem. 1999;274(26):18421–7.CrossRefPubMed
52.
Seifert M, Przekopowitz M, Taudien S, Lollies A, Ronge V, Drees B, Lindemann M, Hillen U, Engler H, Singer BB, et al. Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions. Proc Natl Acad Sci U S A. 2015;112(6):E546–555.CrossRefPubMedPubMedCentral
53.
Banks RE, Forbes MA, Kinsey SE, Stanley A, Ingham E, Walters C, Selby PJ. Release of the angiogenic cytokine vascular endothelial growth factor (VEGF) from platelets: significance for VEGF measurements and cancer biology. Br J Cancer. 1998;77(6):956–64.CrossRefPubMedPubMedCentral
54.
Sabrkhany S, Griffioen AW, Oude Egbrink MG. The role of blood platelets in tumor angiogenesis. Biochim Biophys Acta. 2011;1815(2):189–96.PubMed
55.
Rodríguez PC, Popa X, Martínez O, Mendoza S, Santiesteban E, Crespo T, Amador RM, Fleytas R, Acosta SC, Otero Y, et al. A Phase III Clinical Trial of the Epidermal Growth Factor Vaccine CIMAvax-EGF as Switch Maintenance Therapy in Advanced Non-Small Cell Lung Cancer Patients. Clin Cancer Res. 2016.
56.
Dror Michaelson M, Regan MM, Oh WK, Kaufman DS, Olivier K, Michaelson SZ, Spicer B, Gurski C, Kantoff PW, Smith MR. Phase II study of sunitinib in men with advanced prostate cancer. Ann Oncol. 2009;20(5):913–20.CrossRefPubMedPubMedCentral
57.
Sleijfer S, Gorlia T, Lamers C, Burger H, Blay JY, Le Cesne A, Scurr M, Collin F, Pandite L, Marreaud S, et al. Cytokine and angiogenic factors associated with efficacy and toxicity of pazopanib in advanced soft-tissue sarcoma: an EORTC-STBSG study. Br J Cancer. 2012;107(4):639–45.CrossRefPubMedPubMedCentral
58.
Kopetz S, Hoff PM, Morris JS, Wolff RA, Eng C, Glover KY, Adinin R, Overman MJ, Valero V, Wen S, et al. Phase II trial of infusional fluorouracil, irinotecan, and bevacizumab for metastatic colorectal cancer: efficacy and circulating angiogenic biomarkers associated with therapeutic resistance. J Clin Oncol. 2010;28(3):453–9.CrossRefPubMed
59.
Loupakis F, Cremolini C, Fioravanti A, Orlandi P, Salvatore L, Masi G, Di Desidero T, Canu B, Schirripa M, Frumento P, et al. Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer. Br J Cancer. 2011;104(8):1262–9.CrossRefPubMedPubMedCentral
Metadata
Title
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
Authors
Javier Sánchez Ramírez
Yanelys Morera Díaz
Mónica Bequet-Romero
Francisco Hernández-Bernal
Katty-Hind Selman-Housein Bernal
Ana de la Torre Santos
Eduardo Rafael Santiesteban Álvarez
Yenima Martín Bauta
Cimara H. Bermúdez Badell
Josué de la Torre Pupo
Jorge V. Gavilondo
Marta Ayala Avila
CENTAURO-2 Team of Investigators
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Immunology / Issue 1/2017
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/s12865-017-0222-z

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