04/06/2021
GFME actualité 724
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Vaccination telomerase sur le glioblastome essai UCPVAX

 

 

N° Centre

Hôpital

Hôpital

Dr Clotilde VERLUT

Medical oncologie

CHU de Besançon
boulevard Fleming
25030 Besançon cedex

Pr Antoine CARPENTIER

Medical oncologie

Neuro oncology       
Hôpital
Saint Louis
1 avenue Claude Vellefaux
75010
PARIS

Pr GHIRINGHE
LLI François

Medical oncologie

et

immunologie

Centre
Georges François
Leclerc
1 rue du Professeur Marion
BP 77980
21079 Dijon Cedex

 

 

 

Intérêt du vaccin Telomerase sur le glioblastome 

Il y a un fort rationnel de développer un vaccin telomerase dans le glioblastome. La telomerase (TERT) est un oncogene majeur, en particulier dans le cerveau . Les modifications dans TERT sont très fréquentes dans les tumeurs du système nerveux et surtout les gliome. Les mutations dans TERT sont trouvées dans approximativement 80% des glioblastomes. De plus, TERT et les mutations ATRX sont mutuellement exclusives dans les gliomes, suggérant l'une ou l'autre des mutations peuvent être suffisantes pour conduire à la formation de gliomes. Plusieurs méta-analyses récentes de mutations TERT dans les gliomes montrent un pronostic uniformément réduit. Plusieurs études récentes ont esquissé la classification des gliomes basée sur les mutations TERT. TERT répare les fins de telomere de chromosomes pendant la division cellulaire où l'upregulation aberrante de TERT qui est un des mécanismes d'immortalité cellulaire vue dans les cancers pendant la division, y compris les gliomes. En outre, un rapport antérieur de vaccination avec des cellules dentritiques battues avec un mini ARN de telomerase a montré une énumération de la réponse immunitaire dans le glioblastome. Les telles données suggèrent que la telomerase est un bon antigène pour viser le glioblastome.
Nous avons observé récemment des réponses anti-TERT spontanés Th1 dans le sang de malades avec glioblastome. En se basant sur le rôle critique des cellules T-CD4 dans l'immunité l'antitumorale et la plus haute infiltration dans les glioblastomes des cellules T-CD4 par contraste avec le cellules T-CD8, nous supposons l'efficacité du vaccin rehaussée grandement en stimulant les cellules T-CD4 Ces conclusions supportent fortement de développer le vaccin qui vise la telomerase dans le glioblastome.

Représentez-en 1: Anti-TERT spontané réponse Th1 dans sang des malades avec glioblastome et sa corrélation avec la survie globale.

 

Titre de l'étude

Anticancer therapeutic vaccination using telomerase-derived UNIVERSAL CANCER peptide: an exploratory cohort in glioblastoma

Acronyme

UCPVax – expansion cohort in glioblastoma

Nature de la recherche

Exploratory cohort of UCPVax study

Nombre de centres

3 centers (University Hospital of Besançon, St Louis Hospital, Paris and CGFL Dijon).

Nombre de patients prévus

28 patients

Médicament UCPVax

UCPVax is a therapeutic cancer vaccine composed of two separate peptides called UCP2 and UCP4 derived from telomerase combined with Montanide ISA 51 VG as adjuvant.

Traitement

The UCPVax vaccination protocol will start one month after glioblastoma patients have completed their initial phase of treatment with concomitant radiochemotherapy. In this protocol, subjects with unmethylated MGMT will not do the 6 additional cures of temozolomide and will receive the vaccination protocol only
The two peptides included (UCP2 and UCP4) in UCPVax will be injected subcutaneously in separate sites (one site per peptide, see in part VI-1), on days 1, 8, 15, 29, 36 and 43 and every two months until tumor progression, for a maximum of one year (Figure 3). In patients with a clinical benefit, treatment beyond progression will be allowed.

 

Objectifs

Primary objective: to evaluate the immunogenicity of UCPVax in patients with glioblastoma

Secondary objectives:

  • To evaluate the safety of the administration of UCPVax in patients with glioblastoma.
  • To evaluate progression free survival after administration of UCPVax in patients with glioblastoma

Critères

Inclusion criteria:
Patients must satisfy all of the following criteria to entry into the protocol:
1- Male or female patients, age ≥ 18 and ≤ 75 years old
2- Written informed consent
3- Histologically confirmed glioblastoma
4- Patient with unmethylated MGMT status
5- Patients previously pre-treated with standard radiochemotherapy (without the 6 additional cures of temozolomide.)
6- Karnofsky Performance status ≥ 70%

Ineligibility criteria:
Patients will not be eligible for the study for any of the following reasons:
1– Presence of known extracranial metastatic or leptomeningeal disease
2- Glioblastoma with mutated IDH1 (assessed by Immunohistochemistry)
3- Current or recent treatment with another investigational drug
4- Carmustine implant during surgery
5- History of autoimmune diseases (lupus, rheumatoid arthritis, inflammatory bowel disease…)
6- Prohibited medications:

  • Chronic treatment with immunosuppressive drugs
  • Ongoing requirement for supraphysiologic steroid defined as >10 mg prednisone daily (or equivalent)

 

 

Critères

Primary endpoint:
Anti-TERT specific CD4 T cell responses measured in peripheral blood using IFN-gamma ELISPOT before and during UCPVax treatment. Immune response will be considered positive if ≥ 10 TERT-specific CD4 T cells are detected.

Secondary endpoints:
Evaluation of safety: Severity of adverse events will be graded according to CTCAE v 4.03. Adverse events meeting the following definition occurring which are not related to progressive or intercurrent disease will be classified as Dose Limiting Toxicity (DLT).

Méthodes

The following hypotheses will be considered:
H0 (null): an immune response rate of 30% at 3 months  (uninteresting to pursue any further investigation)
H1 (alternative): an immune response rate of 60% at 3 months (warrants further investigation).

 

According to A’Hern design with a one-sided 5% type I error and power of 90%, 25 evaluable patients will need to be included in order to test the previous hypotheses.

With an expected 10% rate of patients not evaluable or lost to follow-up at 3 months, it will be necessary to include 28 patients

Durée de l'essai

Expected duration of recruitment for this cohort: 18 months (phase II)
Estimated patients participation: 14 months: 2 months for priming phase and boost phase for a maximum of 1 more year.
Follow-up period: 6 months after the last vaccination.

Etude

Assessment of theranostic biomarkers:
Previous clinical studies have shown that various parameters such as tumor associated immune suppression, inflammation status; lipid metabolism, tumor angiogenesis and gut microbiota can modulate host immune response and then limit the efficacy of cancer vaccine.
Thus, we will evaluate all these parameters in order to identify biomarkers, which could be used as patient’s selection criteria and for therapeutic combination in future clinical trials.

 

 

 

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