17 maart 2021: Aanvullend op onderstaande informatie is deze studie naar de werking van het CIMAvax vaccin bij longkankerpatiënten interessant. Het gaat om deze studie: (clinical trial registration number: RPCEC00000161, http://registroclinico.sld.cu/).

Het Cimavax-EGF vaccin blijkt bij de longkankerpatiënten uit een fase III studie veel antistofffen te genereren tegen de EGFR mutatie, vooral bij degenen waar het vaccin goed aansloeg waren er veel antistoffen en van goede kwaliteit gemeten. Kanker met een EGFR mutatie is in het algemeen moeilijker te behandelen dan vormen van kanker zonder EGFR mutatie of met andere mutaties.

Officiele conclusie uit de studie: het CIMAvax-EGF-vaccin induceert een EGF-specifieke beschermende humorale respons bij een hoog percentage van de gevaccineerde patiënten met niet-kleincellige longkanker, waarvan de hoeveelheid en kwaliteit geassocieerd waren met klinisch voordeel. 

Zie het hele studierapport via onderstaande link. Het abstract staat onderaan dit artikel

Anti-EGF antibodies as surrogate biomarkers of clinical efficacy in stage IIIB/IV non-small-cell lung cancer patients treated with an optimized CIMAvax-EGF vaccination schedule


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.

the CIMAvax-EGF vaccine induces an EGF-specific protective humoral response in a high percent of NSCLC vaccinated patients, the quantity and quality of which were associated with clinical benefit

Anti-EGF antibodies as surrogate biomarkers of clinical efficacy in stage IIIB/IV non-small-cell lung cancer patients treated with an optimized CIMAvax-EGF vaccination schedule

Article: 1762465 | Received 24 Jan 2020, Accepted 29 Mar 2020, Published online: 25 May 2020

We previously reported that CIMAvax-EGF vaccine is safe, immunogenic and efficacious to treat advanced non-small-cell lung cancer (NSCLC) patients. A phase III trial was designed using an optimized immunization schedule. It included higher antigen dose and injections at multiple sites. Immune response and circulating biomarkers were studied in a subset of patients. EGF-specific antibody titers, IgG subclasses, peptide immunodominance and circulating biomarkers were assessed by ELISA. In vitro EGF-neutralization capacity of immune sera and EGF-IgG binding kinetics was evaluated by Western Blot and Surface Plasmon Resonance (SPR) technology, respectively. We show that CIMAvax-EGF elicited mainly IgG3/IgG4 antibodies at titers exceeding 1:4000 in 80% of vaccinated patients after 3 months of treatment. The EGF-specific humoral response was directed against the central region of the EGF molecule. For the first time, the kinetic constants of EGF-specific antibodies were measured evidencing affinity maturation of antibody repertoire up to month 12 of vaccination. Notably, the capacity of post-immune sera to inhibit EGFR phosphorylation significantly increased during the course of the immunization scheme and was related to clinical outcome (P = .013, log-rank test). Basal concentrations of EGF and TGFα in the serum were affected by EGF-based immunization. In conclusion, the CIMAvax-EGF vaccine induces an EGF-specific protective humoral response in a high percent of NSCLC vaccinated patients, the quantity and quality of which were associated with clinical benefit (clinical trial registration number: RPCEC00000161, http://registroclinico.sld.cu/).

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