14 augustus 2017: Bron: Frontiers in immunology (en met dank aan Marina)

(Voor onze donateurs hebben we de adresgegevens beschikbaar om dit vaccin te kopen of mee te doen aan een studie)

Meer dan 4000 mensen met kanker zouden zijn geholpen door het Cubaanse virus CIMAvax. Dat inmiddels goedgekeurd is om te gebruiken bij longkanker en daarmee ook uitstekende resultaten heeft laten zien. Nu blijkt uit een aanvullende fase IV studie na een fase III studie dat  het vaccin CIMAvax-EGF wanneer gegeven in combinatie na vier chemokuren bijzonder extra goede resultaten geeft. Vooral bij patienten met een EGFR mutatie. En belangrijk om te weten dat ook andere vormen van kanker vaak een EGFR mutatie hebben, zoals tumoren van darmkanker, baarmoederhalskanker, eierstokkanker, prostaatkanker  enz. Eigenlijk komt een EGFR mutatie voor bij bijna alle vormen van kanker met solide tumoren. (Tekst gaat verder onder afbeelding)

CIMAvax vaccin

CIMAvax-EGF composition. CIMAvax-EGF therapeutic vaccine consist on a chemical conjugate of the EGF with the P64K protein derived from Neisseria meningitidis.
er zijn al veel studies gedaan met CIMAvax (zie referentielijst onderaan dit artikel) maar geen gerandomiseerde studies. Al zijn er wel fase III studies gedaan. Zoals deze fase III open label studie bij longkanker: 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

en deze reviewstudie vorige week gepubliceerd: CIMAvax-EGF: A New Therapeutic Vaccine for Advanced Non-Small Cell Lung Cancer Patients. Zie meer gegevens daarvan verderop in dit artikel.

Ook is er een nieuwe fase III studie  (WHO-validated public registry; http://www.who.int/ictrp/network/rpcec/en, trial number RPCEC00000208) opengesteld waarin CIMAvax-EGF wordt gegeven als belangrijkste medicijn na vier chemokuren waarbij de EGF concentratie hoger is dan 870 pg/ml .

Hieronder de resultaten in een grafiek, waarin de mediane overall overleving bij longkanker is aangegeven.

Table 2

CIMAvax-EGF in the treatment of patients with advanced NSCLC (Phase III clinical trial).

Patient populationCIMAvax-EGF armControl armMST
CIMAvax arm (months)Control arm (months)
Stage IIIB/IV NSCLC patients, with at least stable disease after CTP (ITT) CIMAvax-EGF BSC 10.83 8.86
Stage IIIB/IV NSCLC patients, with at least stable disease after CTP (PP) CIMAvax-EGF BSC 12.43 9.43
Stage IIIB/IV NSCLC patients, with at least stable disease after CTP. Patients with (EGF) > 870 pg/ml CIMAvax-EGF BSC 14.66 8.63

NSCLC, non-small cell lung cancer; MST, median survival time; PD, progressive disease; CTP, chemotherapy; BSC, best supportive care.

CIMAvax vaccin werkingsmechanisme CIMAvax werkingsmechanisme

Het vaccin wordt al 16 jaar onderzocht en heeft goede resultaten gegeven blijkt uit verschillende studies, zelfs bij patiënten met gevorderde uitgezaaide vormen van kanker. Het bijzondere aan dit vaccin is dat het weinig tot geen bijwerkingen geeft. Wat nog indrukwekkender is, is dat in een land als Cuba met weinig budget zo'n vaccin kan worden ontwikkeld zonder hulp van farmaceutische bedrijven.

Het vaccin werkt door een eiwit bekend als EGF (epidermale groeifactor) aan te vallen. EGF zorgt voor groei van longkankercellen maar ook van andere tumorcellen. Het CIMAvax vaccin versterkt het immuunsysteem en versnelt de productie van antilichamen die zich binden aan EGF, waardoor het kankercellen niet voedt en de ziekte zich niet verder kan verspreiden. Dit verbetert de levensduur van de patiënt en voorkomt de ziekte effectief. De toediening van het vaccin verlicht ook de symptomen van kanker en vermindert de pijn.  Het vaccin wordt al gebruikt in landen zoals Bosnië en Herzegovina, Paraguay, Colombia en Peru.

Uit het studierapport: CIMAvax-EGF vaccine exerts its anti-cancer activity by targeting the immune system, inducing anti-EGF antibodies that result in the decline of the circulating EGF in sera (23, 24). This, in turn, significantly decreases the probability that the remaining EGF binds to its receptor (EGFR) on the surface of cancer cells. EGF withdrawal results in the loss of a key pro-proliferation and pro-survival signal for the neoplastic cells (23, 24). The vaccine has demonstrated to be safe and immunogenic in more than 5,000 advanced NSCLC patients (23, 24).

Cubaanse wetenschappers verwachten dat het vaccin borstkanker, baarmoederkanker en prostaattumoren kan genezen, terwijl er ook studies naar andere vormen van kanker lopen. Het vaccin is gratis voor Cubanen, terwijl mensen uit andere delen van de wereld wel moeten betalen maar wordt hun niet onthouden en is tegen betaling verkrijgbaar.

Voor onze donateurs hebben we de adresgegevens beschikbaar om dit vaccin te kopen of mee te doen aan een studie.

Deze reviewstudie is gratis in te zien: CIMAvax-EGF: A New Therapeutic Vaccine for Advanced Non-Small Cell Lung Cancer Patients.

Hier het abstract en referentielijst:

CIMAvax-EGF: A new therapeutic vaccine for advanced non-small cell lung cancer patients and other tumors with EGFR mutation (epidermal growth factor)

Front. Immunol., 13 March 2017 | https://doi.org/10.3389/fimmu.2017.00269

CIMAvax-EGF: A New Therapeutic Vaccine for Advanced Non-Small Cell Lung Cancer Patients

  • Center of Molecular Immunology, Havana, Cuba

Lung cancer is the common fatal illness with the highest incidence and mortality globally. Epidermal growth factor receptor overexpression by tumor cells is associated with uncontrolled proliferation, angiogenesis, anti-apoptotic signals, metastization, and invasiveness. CIMAvax-EGF vaccine consists of a chemical conjugate of the EGF with the P64 protein derived from the Meningitis B bacteria and Montanide ISA 51, as adjuvant. The vaccine is projected to induce antibodies against EGF that results in EGF withdrawal. CIMAvax-EGF demonstrated to be safe and immunogenic in advanced non-small cell lung cancer (NSCLC) patients. The efficacy study was an open-label, multicentric Phase III clinical trial, which enrolled 405 advanced NSCLC patients. Patients with proven stage IIIB/IV NSCLC, who had completed four to six cycles of chemotherapy (CTP) were randomized to receive CIMAvax-EGF or best supportive care. CIMAvax-EGF resulted in a significantly larger overall survival in patients receiving at least four doses. High EGF concentration at baseline was a good predictive biomarker of the vaccine activity and a poor prognostic biomarker for the non-treated population. The proportion of CD8+CD28− cells, CD4 cells, and the CD4/CD8 ratio after first-line CTP was also associated with CIMAvax-EGF clinical benefit. After completing the Phase III, a Phase IV trial was done where the vaccine was administered in primary care units. Administering the vaccine at primary care institutions granted better access and treatment compliance. Safety was confirmed. Several clinical trials are currently ongoing to validate EGF as a predictive biomarker of CIMAvax-EGF efficacy.

CIMAvax-EGF in Primary Care Units and Future Perspectives

After completing the Phase III, a Phase IV trial was launched where the family medicine physicians administered CIMAvax-EGF in primary health care units (policlinics). In total, 45 primary level units together with 24 secondary level units (hospitals) participated in the study that enrolled more than 1,000 patients in 3 years. This study was registered in the National Public Registry of Clinical Trials (http://www.who.int/ictrp/network/rpcec/en, trial number RPCEC00000181). Administering the vaccine at primary care institutions granted better access and treatment compliance. Safety was confirmed; the most frequently reported adverse events were pain at the site of injection followed by fever, headache, chills, nausea, and dyspnea (22).

Overall survival of those patients that received at least one vaccine dose was 13.9 months (mean) and 7.0 months (median). Survival rate at 12 and 24 months was 34.8 of 18.1%, respectively. On the other hand, the overall survival of patients receiving at least the induction doses was 16.93 months (mean) and 9.9 months (median). The 12 and 24 months survival rate was of 44.1 and 23.3%, respectively.

In summary, CIMAvax-EGF was safe in patients with NSCLC at advanced stages treated in primary care facilities. The safety profile coincided with the previously described in controlled studies. CIMAvax-EGF also showed benefit in terms of survival, mainly in those subjects that completed four vaccine doses. Treatment with CIMAvax-EGF resulted in preliminary evidences of improvement in the quality of life, which was significant for the emotional functioning and the fatigue symptom. The use of medications to control pain was stable during vaccination (22).

Several clinical trials are currently ongoing. A new Phase III trial (WHO-validated public registry; http://www.who.int/ictrp/network/rpcec/en, trial number RPCEC00000208) is open for enrollment, where CIMAvax-EGF is used as switch maintenance in patients completing front-line CTP that has EGF concentration higher than 870 pg/ml (enrichment design). The main goal of the trial is to prospectively validate EGF as a predictive biomarker. In this scenario, the randomization is unbalanced (3:1) given the previous evidences of the clinical benefit of the vaccine. In addition, a new Phase IV (WHO-validated public registry; http://www.who.int/ictrp/network/rpcec/en, trial number PCEC00000205) was launched in 178 policlinics (at least one investigation site per state municipality) and 25 hospitals. Patients will be recruited by the oncologists in the specialized oncology services, but will be treated in their neighborhood, at the primary health care facilities. The aim is to grant vaccine access and to improve treatment compliance. In this trial, EGF concentration will be measured but not as an inclusion criterion. Instead, EGF at baseline will be retrospectively correlated with the clinical efficacy. An EGF quantification system was developed in the country by the National Center for Immunoassay, to accompany the vaccine prescription (37). Both studies will permit the consolidation of the scientific evidence of the EGF as a biomarker. Other translational studies are planned to gather more information on the relevance of the lymphocyte subpopulation as well as the individual tumor biology (mainly associated with EGFR mutations) for the CIMAvax-EGF efficacy.

Author Contributions

DS was involved in the evaluation of immunogenicity and predictive biomarkers of CIMAvax-EGF efficacy (EGF concentration and immunophenotyping). TC was involved in trials’ design and implementation. Both authors participated in the analysis, writing, and revision of the manuscript.

Conflict of Interest Statement

Both authors, DS and TC, are employees of the Center of Molecular Immunology, the institution that owns the patent and manufactures CIMAvax-EGF. Neither author receive additional compensation associated with CIMAvax-EGF registration or marketing.

Acknowledgments

Both authors are very grateful to the research teams from the hospitals or the primary health care institutions participating in the study. Their contribution to the project has been invaluable, for 20 years. The authors are also extremely thankful to our patients and their relatives that supported unconditionally the clinical research.

Funding

This research was funded by the Center of Molecular Immunology and the National Ministry of Health.

References

1. Fuge O, Vasdev N, Allchorne P, Green JS. Immunotherapy for bladder cancer. Res Rep Urol (2015) 7:65–79. doi:10.2147/RRU.S63447

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Snyder A, Zamarin D, Wolchok JD. Immunotherapy of melanoma. Prog Tumor Res (2015) 42:22–9. doi:10.1159/000436998

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Chee J, Robinson BW, Holt RA, Creaney J. Immunotherapy of lung malignancies – from gene sequencing to novel therapies. Chest (2016). doi:10.1016/j.chest.2016.10.007

CrossRef Full Text | Google Scholar

4. Hughes PE, Caenepeel S, Wu LC. Targeted therapy and checkpoint immunotherapy combinations for the treatment of cancer. Trends Immunol (2016) 37(7):462–76. doi:10.1016/j.it.2016.04.010

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Tsiatas M, Mountzios G, Curigliano G. Future perspectives in cancer immunotherapy. Ann Transl Med (2016) 4(14):273. doi:10.21037/atm.2016.07.14

PubMed Abstract | CrossRef Full Text | Google Scholar

6. Nicodemus CF. Antibody-based immunotherapy of solid cancers: progress and possibilities. Immunotherapy (2015) 7(8):923–39. doi:10.2217/imt.15.57

PubMed Abstract | CrossRef Full Text | Google Scholar

7. Jiang T, Zhou C. The past, present and future of immunotherapy against tumor. Transl Lung Cancer Res (2015) 4(3):253–64. doi:10.3978/j.issn.2218-6751.2015.01.06

PubMed Abstract | CrossRef Full Text | Google Scholar

8. Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med (2015) 373(17):1627–39. doi:10.1056/NEJMoa1507643

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Brahmer J, Reckamp KL, Baas P, Crinò L, Eberhardt WE, Poddubskaya E, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med (2015) 373(2):123–35. doi:10.1056/NEJMoa1504627

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet (2016) 387(10027):1540–50. doi:10.1016/S0140-6736(15)01281-7

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med (2016) 375(19):1823–33. doi:10.1056/NEJMoa1606774

CrossRef Full Text | Google Scholar

12. Romero D. Immunotherapy: atezolizumab becomes POPLAR. Nat Rev Clin Oncol (2016) 13(5):266. doi:10.1038/nrclinonc.2016.52

CrossRef Full Text | Google Scholar

13. Fehrenbacher L, Spira A, Ballinger M, Kowanetz M, Vansteenkiste J, Mazieres J, et al. POPLAR Study Group. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, Phase 2 randomised controlled trial. Lancet (2016) 387(10030):1837–46. doi:10.1016/S0140-6736(16)00587-0

CrossRef Full Text | Google Scholar

14. Tsuchida N, Murugan AK, Grieco M. Kirsten Ras* oncogene: significance of its discovery in human cancer research. Oncotarget (2016) 7(29):46717–33. doi:10.18632/oncotarget.8773

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Mitsudomi T. Molecular epidemiology of lung cancer and geographic variations with special reference to EGFR mutations. Transl Lung Cancer Res (2014) 3(4):205–11. doi:10.3978/j.issn.2218-6751.2014.08.04

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Nurwidya F, Takahashi F, Takahashi K. Gefitinib in the treatment of nonsmall cell lung cancer with activating epidermal growth factor receptor mutation. J Nat Sci Biol Med (2016) 7(2):119–23. doi:10.4103/0976-9668.184695

CrossRef Full Text | Google Scholar

17. Socinski MA, Villaruz LC, Ross J. Understanding mechanisms of resistance in the epithelial growth factor receptor in non-small cell lung cancer and the role of biopsy at progression. Oncologist (2017) 22(1):3–11. doi:10.1634/theoncologist.2016-0285

CrossRef Full Text | Google Scholar

18. Barron F, de la Torre-Vallejo M, Luna-Palencia RL, Cardona AF, Arrieta O. The safety of afatinib for the treatment of non-small cell lung cancer. Expert Opin Drug Saf (2016) 15(11):1563–72. doi:10.1080/14740338.2016.1236910

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Park K, Tan EH, O’Byrne K, Zhang L, Boyer M, Mok T, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a Phase 2B, open-label, randomised controlled trial. Lancet Oncol (2016) 17(5):577–89. doi:10.1016/S1470-2045(16)30033-X

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Singh B, Carpenter G, Coffey RJ. EGF receptor ligands: recent advances. F1000Res (2016) 5. doi:10.12688/f1000research.9025.1

CrossRef Full Text | Google Scholar

21. Salazar R, Capellà G, Tabernero J. Paracrine network: another step in the complexity of resistance to EGFR blockade? Clin Cancer Res (2014) 20(24):6227–9. doi:10.1158/1078-0432.CCR-14-1615

PubMed Abstract | CrossRef Full Text | Google Scholar

22. Crombet Ramos T, Rodríguez PC, Neninger Vinageras E, Garcia Verdecia B, Lage Davila A. CIMAvax EGF (EGF-P64K) vaccine for the treatment of non-small-cell lung cancer. Expert Rev Vaccines (2015) 14(10):1303–11. doi:10.1586/14760584.2015.1079488

PubMed Abstract | CrossRef Full Text | Google Scholar

23. Rodríguez PC, Rodríguez G, González G, Lage A. Clinical development and perspectives of CIMAvax EGF, Cuban vaccine for non-small-cell lung cancer therapy. MEDICC Rev (2010) 12(1):17–23.

PubMed Abstract | Google Scholar

24. García B, Neninger E, de la Torre A, Leonard I, Martínez R, Viada C, et al. 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. doi:10.1158/1078-0432.CCR-07-1050

PubMed Abstract | CrossRef Full Text | Google Scholar

25. Neninger E, de la Torre A, Osorio M, Catala M, Bravo I, Mendoza M, et al. Phase II randomized controlled trial of an epidermal growth factor vaccine in advanced non-small-cell lung cancer. J Clin Oncol (2008) 26(9):1452–9. doi:10.1200/JCO.2007.11.5980

CrossRef Full Text | Google Scholar

26. Rodriguez PC, Popa X, Martínez O, Mendoza S, Santiesteban E, Crespo T, 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) 22(15):3782–90. doi:10.1158/1078-0432.CCR-15-0855

PubMed Abstract | CrossRef Full Text | Google Scholar

27. Hasegawa T. Group sequential monitoring based on the weighted log-rank test statistic with the Fleming-Harrington class of weights in cancer vaccine studies. Pharm Stat (2016) 15(5):412–9. doi:10.1002/pst.1760

PubMed Abstract | CrossRef Full Text | Google Scholar

28. Cunningham AL, Garçon N, Leo O, Friedland LR, Strugnell R, Laupèze B. Vaccine development: from concept to early clinical testing. Vaccine (2016) 34(52):6655–64. doi:10.1016/j.vaccine.2016.10.016

CrossRef Full Text | Google Scholar

29. Saavedra D. Immune response in long-term NSCLC survivors treated with CIMAvax-EGF vaccine. V International Workshop on CIMAvax-EGF. Abstract retrieved from Proceedings of the V International CIMAvax-EGF Workshop (Accession No. 4). Havana (2015).

Google Scholar

30. Raaberg L, Nexø E, Jørgensen PE, Poulsen SS, Jakab M. Fetal effects of epidermal growth factor deficiency induced in rats by autoantibodies against epidermal growth factor. Pediatr Res (1995) 37:175. doi:10.1203/00006450-199502000-00009

PubMed Abstract | CrossRef Full Text | Google Scholar

31. Kelloff GJ, Sigman CC, Scher HI. Biomarker development in the context of urologic cancers. Urol Oncol (2015) 33(6):295–301. doi:10.1016/j.urolonc.2015.01.007

PubMed Abstract | CrossRef Full Text | Google Scholar

32. Chang S, Kohrt H, Maecker HT. Monitoring the immune competence of cancer patients to predict outcome. Cancer Immunol Immunother (2014) 63(7):713–9. doi:10.1007/s00262-014-1521-3

PubMed Abstract | CrossRef Full Text | Google Scholar

33. Saavedra D, García B, Lorenzo-Luaces P, González A, Popa X, Fuentes KP, et al. Biomarkers related to immunosenescence: relationships with therapy and survival in lung cancer patients. Cancer Immunol Immunother (2016) 65(1):37–45. doi:10.1007/s00262-015-1773-6

PubMed Abstract | CrossRef Full Text | Google Scholar

34. Neninger E, Verdecia BG, Crombet T, Viada C, Pereda S, Leonard I, et al. Combining an EGF-based cancer vaccine with chemotherapy in advanced nonsmall cell lung cancer. J Immunother (2009) 32(1):92–9. doi:10.1097/CJI.0b013e31818fe167

PubMed Abstract | CrossRef Full Text | Google Scholar

35. Fridlender ZG, Sun J, Singhal S, Kapoor V, Cheng G, Suzuki E, et al. Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms. Mol Ther (2010) 18(11):1947–59. doi:10.1038/mt.2010.159

PubMed Abstract | CrossRef Full Text | Google Scholar

36. Di Blasio S, Wortel IM, van Bladel DA, de Vries LE, Duiveman-de Boer T, Worah K, et al. Human CD1c(+) DCs are critical cellular mediators of immune responses induced by immunogenic cell death. Oncoimmunology (2016) 5(8):e1192739. doi:10.1080/2162402X.2016.1192739

PubMed Abstract | CrossRef Full Text | Google Scholar

37. Castells Martínez EM, Del Valle R, González EC, Melchor A, Pérez PL, González I, et al. An enzyme immunoassay for determining epidermal growth factor (EGF) in human serum samples using an ultramicroanalytical system. J Immunoassay Immunochem (2016) 16:1–12. doi:10.1080/15321819.2016.1236729

CrossRef Full Text | Google Scholar

Keywords: non-small cell lung cancer, cancer vaccine, clinical trial, CIMAvax-EGF, immunotherapy

Citation: Saavedra D and Crombet T (2017) CIMAvax-EGF: A New Therapeutic Vaccine for Advanced Non-Small Cell Lung Cancer Patients. Front. Immunol. 8:269. doi: 10.3389/fimmu.2017.00269

Received: 29 November 2016; Accepted: 24 February 2017;
Published: 13 March 2017

Edited by:

Alexis Labrada, Centro Nacional de Biopreparados, Cuba

Reviewed by:

María Marcela Barrio, Fundación Cáncer FUCA, Argentina
Graham Robert Leggatt, The University of Queensland, Australia

Copyright: © 2017 Saavedra and Crombet. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Tania Crombet, taniac@cim.sld.cu


Plaats een reactie ...

Reageer op "CIMAvax-EGF vaccin geeft uitstekende resultaten op overall overleving en ziektevrije tijd bij longkanker en andere vormen van kanker met EGFR mutatie"


Gerelateerde artikelen
 

Gerelateerde artikelen

Tisotumab vedotin plus chemo >> Dendritische celtherapie heeft >> sTILs - tumor infiltrating >> CAR-T cel therapie is een >> Verkoudheidsvirus Delta-24-RGD >> Immuuntherapie met het gemoduleerde >> lenvatinib samen met pembrolizumab >> Vrouw met uitgezaaide hormoongevoelige >> Utopie of uitdaging: immuuntherapie >> Immuuntherapie met een gemoduleerd >>