Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Immunology
Published in: BMC Immunology 1/2020

Open Access 01-12-2020 | Bevacizumab | Research article

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

Authors: Javier Sánchez Ramírez, Yanelys Morera Díaz, Mónica Bequet-Romero, Francisco Hernández-Bernal, Yenima Martín Bauta, Katty-Hind Selman-Housein Bernal, Ana Victoria de la Torre Santos, Mariela Pérez de la Iglesia, Lian Trimiño Lorenzo, Marta Ayala Avila, Team of Investigators of Compassionate use Program

Published in: BMC Immunology | Issue 1/2020

Login to get access

Abstract

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-to-day clinical practice and treatment settings for these diseases in Cuban medical institutions.

Conclusions

The CIGB-247 CUP has demonstrated that immunization and follow-up of a variety of cancer patients, under day-to-day clinical practice conditions in several Cuban medical institutions, replicate our previous findings in clinical trials: CIGB-247 is safe and immunogenic.
Appendix
Available only for authorised users
Literature
1.
Ferrara N. The role of VEGF in the regulation of physiological and pathological angiogenesis. EXS. 2005;94:209–31.
2.
3.
4.
Lapeyre-Prost A, Terme M, Pernot S, Pointet AL, Voron T, Tartour E, Taieb J. Immunomodulatory activity of VEGF in Cancer. Int Rev Cell Mol Biol. 2017;330:295–342.CrossRefPubMed
5.
Papadopoulos N, Martin J, Ruan Q, Rafique A, Rosconi MP, Shi E, Pyles EA, Yancopoulos GD, Stahl N, Wiegand SJ. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF trap, ranibizumab and bevacizumab. Angiogenesis. 2012;15(2):171–85.CrossRefPubMedPubMedCentral
6.
Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab plus FOLFOX4 as second-line treatment of colorectal cancer. Oncologist. 2007;12(3):356–61.CrossRefPubMed
7.
Cohen MH, Gootenberg J, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer. Oncologist. 2007;12(6):713–8.CrossRefPubMed
8.
Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009;14(11):1131–8.CrossRefPubMed
9.
Summers J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma. Oncologist. 2010;15(1):104–11.CrossRefPubMedPubMedCentral
10.
Tewari KS, Sill MW, Long HJ, Penson RT, Huang H, Ramondetta LM, Landrum LM, Oaknin A, Reid TJ, Leitao MM, et al. Improved survival with Bevacizumab in advanced cervical Cancer. N Engl J Med. 2014;370(8):734–43.CrossRefPubMedPubMedCentral
11.
Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, Sorio R, Vergote I, Witteveen P, Bamias A, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302–8.CrossRefPubMed
12.
Wick W, Brandes AA, Gorlia T, Bendszus M, Sahm F, Taal W, Taphoorn MJB, Domont J, Idbaih A, Campone M, et al. EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine in patients with first progression of a glioblastoma. J Clin Oncol. 2016;34(15_suppl):2001.CrossRef
13.
Morera-Díaz Y, Gavilondo JV, Bequet-Romero M, Sánchez Ramírez J, Hernández-Bernal F, Selman-Housein K-H, Perez L, Ayala-Ávila M. Specific active immunotherapy with the HEBERSaVax VEGF-based cancer vaccine: from bench to bedside. Semin Oncol. 2018;45(1):68–74.CrossRefPubMed
14.
15.
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
16.
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
17.
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
18.
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
19.
Sánchez Ramírez J, Morera Díaz Y, Bequet-Romero M, Hernández-Bernal F, Selman-Housein Bernal K-H, de la Torre Santos A, Santiesteban Álvarez ER, Martín Bauta Y, Bermúdez Badell CH, de la Torre PJ, et al. 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. BMC Immunol. 2017;18(1):39.CrossRefPubMedPubMedCentral
20.
Wentink MQ, Hackeng TM, Tabruyn SP, Puijk WC, Schwamborn K, Altschuh D, Meloen RH, Schuurman T, Griffioen AW, Timmerman P. Targeted vaccination against the bevacizumab binding site on VEGF using 3D-structured peptides elicits efficient antitumor activity. Proc Natl Acad Sci U S A. 2016;113(44):12532–7.CrossRefPubMedPubMedCentral
21.
Wentink MQ, Verheul HMW, Griffioen AW, Schafer KA, McPherson S, Early RJ, van der Vliet HJ, de Gruijl TD. A safety and immunogenicity study of immunization with hVEGF26-104/RFASE in cynomolgus monkeys. Vaccine. 2018;36(15):2025–32.CrossRefPubMed
22.
Wentink MQ, van der Vliet HJ, De Gruijl TD, Griffioen AW, Verheul HMW. A phase I open-label clinical trial, evaluating the therapeutic vaccine hVEGF26–104/RFASE in patients with advanced solid tumors; 2019. p. 134–47.
23.
Selman-Housein KH, de la Torre A, Hernández-Bernal F, Martín Y, Garabito A, Piñero J, Morera, 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;1216.
24.
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
25.
Al-Baimani K, Jonker H, Zhang T, Goss GD, Laurie SA, Nicholas G, Wheatley-Price P. Are clinical trial eligibility criteria an accurate reflection of a real-world population of advanced non-small-cell lung cancer patients? Curr Oncol. 2018;25(4):e291–7.CrossRefPubMedPubMedCentral
26.
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
27.
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
28.
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
29.
Guidance Development Review Committee, 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. 2015 Guidance on cancer immunotherapy development in early-phase clinical studies. Cancer Sci. 2015;106(12):1761–71.CrossRef
30.
Kyogoku N, Ikeda H, Tsuchikawa T, Abiko T, Fujiwara A, Maki T, Yamamura Y, Ichinokawa M, Tanaka K, Imai N, et al. Time-dependent transition of the immunoglobulin G subclass and immunoglobulin E response in cancer patients vaccinated with cholesteryl pullulan-melanoma antigen gene-A4 nanogel. Oncol Lett. 2016;12(6):4493–504.CrossRefPubMedPubMedCentral
31.
Platzer B, Elpek KG, Cremasco V, Baker K, Stout MM, Schultz C, Dehlink E, Shade KT, Anthony RM, Blumberg RS, et al. IgE/FcepsilonRI-mediated antigen cross-presentation by dendritic cells enhances anti-tumor immune responses. Cell Rep. 2015;10:1487–95.CrossRefPubMedPubMedCentral
32.
Fu SL, Pierre J, Smith-Norowitz TA, Hagler M, Bowne W, Pincus MR, Mueller CM, Zenilman ME, Bluth MH. Immunoglobulin E antibodies from pancreatic cancer patients mediate antibody-dependent cell-mediated cytotoxicity against pancreatic cancer cells. Clin Exp Immunol. 2008;153(3):401–9.CrossRefPubMedPubMedCentral
33.
Wiesmann C, Fuh G, Christinger HW, Eigenbrot C, Wells JA, de Vos AM. Crystal structure at 1.7 a resolution of VEGF in complex with domain 2 of the Flt-1 receptor. Cell. 1997;91(5):695–704.CrossRefPubMed
34.
Markovic-Mueller S, Stuttfeld E, Asthana M, Weinert T, Bliven S, Goldie KN, Kisko K, Capitani G, Ballmer-Hofer K. Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A. Structure. 2017;25(2):341–52.CrossRefPubMed
35.
Muller YA, Li B, Christinger HW, Wells JA, Cunningham BC, de Vos AM. Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc Natl Acad Sci U S A. 1997;94(14):7192–7.CrossRefPubMedPubMedCentral
36.
Brozzo MS, Bjelic S, Kisko K, Schleier T, Leppanen VM, Alitalo K, Winkler FK, Ballmer-Hofer K. Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization. Blood. 2012;119(7):1781–8.CrossRefPubMed
37.
Muller YA, Chen Y, Christinger HW, Li B, Cunningham BC, Lowman HB, de Vos AM. VEGF and the Fab fragment of a humanized neutralizing antibody: crystal structure of the complex at 2.4 A resolution and mutational analysis of the interface. Structure. 1998;6(9):1153–67.CrossRefPubMed
38.
Keyt BA, Nguyen HV, Berleau LT, Duarte CM, Park J, Chen H, Ferrara N. Identification of vascular endothelial growth factor determinants for binding KDR and FLT-1 receptors. Generation of receptor-selective VEGF variants by site-directed mutagenesis. J Biol Chem. 1996;271(10):5638–46.CrossRefPubMed
39.
Hosseini Ghatar R, Soltantoyeh T, Bahadori M, Khoshnoodi J, Golsaz Shirazi F, Jeddi Tehrani M, Amiri MM, Shokri F. Polyclonal antibody against different extracellular subdomains of HER2 induces tumor growth inhibition in vitro. Iran J Immunol. 2017;14(3):200–14.PubMed
40.
Clay TM, Osada T, Hartman ZC, Hobeika A, Devi G, Morse MA, Lyerly HK. Polyclonal immune responses to antigens associated with cancer signaling pathways and new strategies to enhance cancer vaccines. Immunol Res. 2011;49(1–3):235–47.CrossRefPubMedPubMedCentral
41.
Caballero I, Aira LE, Lavastida A, Popa X, Rivero J, Gonzalez J, Mesa M, Gonzalez N, Coba K, Lorenzo-Luaces P, et al. 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. Front Pharmacol. 2017;8:263.CrossRefPubMedPubMedCentral
42.
Junco JA, Rodríguez R, Fuentes F, Baladrón I, Castro MD, Calzada L, Valenzuela C, Bover E, Pimentel E, Basulto R, et al. Safety and Therapeutic Profile of a GnRH-Based Vaccine Candidate Directed to Prostate Cancer. A 10-year follow-up of patients vaccinated with Heberprovac. Front Oncol. 2019;9:49.CrossRefPubMedPubMedCentral
43.
44.
Lavinder JJ, Wine Y, Giesecke C, Ippolito GC, Horton AP, Lungu OI, Hoi KH, DeKosky BJ, Murrin EM, Wirth MM, et al. Identification and characterization of the constituent human serum antibodies elicited by vaccination. Proc Natl Acad Sci U S A. 2014;111(6):2259–64.CrossRefPubMedPubMedCentral
45.
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9(6):669–76.CrossRefPubMed
46.
Ogawa S, Oku A, Sawano A, Yamaguchi S, Yazaki Y, Shibuya M. A novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding domain. J Biol Chem. 1998;273(47):31273–82.CrossRefPubMed
47.
Yamazaki Y, Matsunaga Y, Tokunaga Y, Obayashi S, Saito M, Morita T. Snake venom vascular endothelial growth factors (VEGF-Fs) exclusively vary their structures and functions among species. J Biol Chem. 2009;284(15):9885–91.CrossRefPubMedPubMedCentral
48.
Rauniyar K, Jha SK, Jeltsch M. Biology of vascular endothelial growth factor C in the morphogenesis of lymphatic vessels. Front Bioeng Biotechnol. 2018;6:7.CrossRefPubMedPubMedCentral
49.
Yeh J, Yeh YC. Transforming growth factor-alpha and human cancer. Biomed Pharmacother. 1989;43(9):651–9.CrossRefPubMed
50.
Garcia B, Neninger E, de la Torre A, Leonard I, Martinez R, Viada C, Gonzalez G, Mazorra Z, Lage A, Crombet T. Effective inhibition of the epidermal growth factor/epidermal growth factor receptor binding by anti-epidermal growth factor antibodies is related to better survival in advanced non-small-cell lung cancer patients treated with the epidermal growth factor cancer vaccine. Clin Cancer Res. 2008;14(3):840–6.CrossRefPubMed
51.
Samanta D, Park Y, Ni X, Li H, Zahnow CA, Gabrielson E, Pan F, Semenza GL. Chemotherapy induces enrichment of CD47(+)/CD73(+)/PDL1(+) immune evasive triple-negative breast cancer cells. Proc Natl Acad Sci U S A. 2018;115(6):E1239–e1248.CrossRefPubMedPubMedCentral
52.
Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell. 2015;28(6):690–714.CrossRefPubMed
53.
54.
Zhang H, Huang Z, Zou X, Liu T. Bevacizumab and wound-healing complications: a systematic review and meta-analysis of randomized controlled trials. Oncotarget. 2016;7(50):82473–81.PubMedPubMedCentral
55.
Sánchez Ramírez J, Bequet-Romero M, Morera Díaz Y, Hernández-Bernal F, Ayala Avila M. Does VEGF-targeted active immunotherapy induce complete abrogation of platelet VEGF levels? BMC Res Notes. 2019;12(1):323.CrossRefPubMedPubMedCentral
56.
CECMED: Requirements for the authorization of the expanded clinical use program for products subject to research. 2012.
57.
Sánchez Ramírez J, Bequet-Romero M, Morera Díaz Y, Hernández-Bernal F, de la Torre SA, Selman-Housein Bernal K-H, Martín Bauta Y, Bermúdez Badell CH, Limonta Fernández M, Ayala Avila M. Evaluation of methodologies to determine the effect of specific active immunotherapy on VEGF levels in phase I clinical trial patients with advanced solid tumors. Heliyon. 2018;4(11):e00906.CrossRefPubMedPubMedCentral
58.
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
Metadata
Title
Specific humoral response in cancer patients treated with a VEGF-specific active immunotherapy procedure within a compassionate use program
Authors
Javier Sánchez Ramírez
Yanelys Morera Díaz
Mónica Bequet-Romero
Francisco Hernández-Bernal
Yenima Martín Bauta
Katty-Hind Selman-Housein Bernal
Ana Victoria de la Torre Santos
Mariela Pérez de la Iglesia
Lian Trimiño Lorenzo
Marta Ayala Avila
Team of Investigators of Compassionate use Program
Publication date
01-12-2020
Publisher
BioMed Central
Keyword
Bevacizumab
Published in
BMC Immunology / Issue 1/2020
Electronic ISSN: 1471-2172
DOI
https://doi.org/10.1186/s12865-020-0338-4

Other articles of this Issue 1/2020

BMC Immunology 1/2020 Go to the issue

Research article

Comparison of personal and shared frameshift neoantigen vaccines in a mouse mammary cancer model

Research article

Cytokine profile in the sputum of subjects with post-tuberculosis airflow obstruction and in those with tobacco related chronic obstructive pulmonary disease

Research article

Increased Interleukin-35 suppresses peripheral CD14+ monocytes function in patients with Kawasaki disease

Research

Extracellular signal-regulated kinase 1/2 is required for complement component C1q and fibronectin dependent enhancement of Fcγ- receptor mediated phagocytosis in mouse and human cells

Software

A software package for immunologists to learn simulation modeling

Research article

Elevated expansion of follicular helper T cells in peripheral blood from children with acute measles infection

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits