PHASE I/II CLINICAL TRIAL OF AN ACTIVATED WHOLE TUMOR CELL VACCINE FOLLOWED BY TRANSFER OF IMMUNE T CELLS IN PATIENTS WITH MANTLE CELL LYMPHOMA
Notice bibliographique
Résumé
Introduction: We report interim results of a CpG-activated whole tumor cell vaccine for patients with newly diagnosed Mantle Cell Lymphoma (MCL). This phase I/II trial (NCT00490529) had the primary end points of safety and freedom from minimal residual disease (MRD) at 1 year post autologous stem-cell transplant (ASCT). Secondary end points include time to treatment failure (TTF) from initial chemotherapy, overall survival (OS), and T cell immune response. Methods: Prior to treatment, patient-specific vaccines were made by activating freshly collected tumor cells with PF-3512676 (CpG) followed by radiation (200 Gy). Patients with a partial or complete response after standard immunochemotherapy received three subcutaneous injections with the vaccine product together with additional CpG (18 mg). T-cells were collected by leukapheresis after the last vaccine and cryopreserved. The day after an ASCT, the T-cell product was infused and a 4th vaccination was given. A 5th booster vaccination was given ~3 months post ASCT. Blood samples were collected at various time points for measurement of anti-tumor immune responses and for detection of MRD by VDJ high throughput sequencing of blood mononuclear cells (ClonoSeq™). Results: Between April 2008 and August 2016, 65 patients were enrolled and 43 patients have completed ASCT and are included in the safety analysis. The CpG MCL vaccine was well tolerated. The most common toxicity was grade I/II erythematous rash at the injection site (98%), and no unexpected toxicities were seen before or after ASCT. 34 patients are at least 1 year post ASCT and included in the primary analysis. 31 (91%) patients were MRD negative at the previously validated threshold (1 MCL clone per 10,000 input genome equivalents of DNA). MRD negativity at 1-year post ASCT predicted longer subsequent remission duration (p < 0.0001) and survival (p = 0.0021). Lower levels of MRD down to 1 per million were occasionally detected but were not associated with relapse or survival. Median TTF and OS have not been reached (NR) with an average follow-up of 4.91 years. By comparison a contemporaneous cohort of similar patients with MCL who received the same ASCT at our institution, but with no vaccine, have a median TTF of 4.03 years (p = 0.164). Analysis of the vaccine characteristics revealed that patients whose tumor cells demonstrated CpG-induced elevation of PD-L1 had significantly worse TTF (2.4 years vs NR, p = 0.0037) and OS (3.2 years vs NR, p = 0.0042). We also detected tumor-specific CD4+ and CD8+ T cell immune responses following vaccination. Conclusion: The addition of a CpG-activated, autologous tumor cell vaccination and adoptive immune T-cell product to standard therapy for MCL is feasible and safe. At this interim analysis, vaccinated patients had freedom from MRD at 1 year post transplant that surpasses previously reported rates. Keywords: B-cell lymphoma; mantle cell lymphoma (MCL); minimal residual disease (MRD)
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,002 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».