Effective Treatment Of Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma With Autologous T Cells Genetically-Engineered To Express An Anti-CD19 Chimeric Antigen Receptor
Notice bibliographique
Résumé
Abstract We have treated 20 patients and administered 23 total T-cell infusions on a clinical trial of autologous T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19. This is the largest reported clinical trial of anti-CD19-CAR T cells. The first 9 CAR-T-cell treatments have been reported (Kochenderfer et al. Blood 2010 and Blood 2012). This abstract communicates unreported results from 14 patients who received anti-CD19-CAR T cells produced with a new 10-day culture process. These patients did not receive exogenous interleukin-2. Of these 14 patients, 5 obtained complete remissions (CR), and 6 obtained partial remissions (PR), (see table).TablePatientAge/GenderMalignancyNumberof priortherapiesTotal cyclo-phosphamidedose(mg/kg)Number ofCAR+ T cellsinfused(X106/kg)Response(timeafter cellinfusion inmonths)156/MSMZL41205PR (20+)243/FPMBCL4605CR (19+)361/MCLL2604CR (16+)430/FPMBCL31202.5NE563/MCLL41202.5CR (10+)648/MCLL1602.5CR (7+)742/MDLBCL5602.5CR (4+)844/FPMBCL10602.5PR (6+)938/MPMBCL31202.5SD (1)1057/FLow-grade NHL4601PR (4+)1158/FDLBCL from CLL13601PR (2)1260/FDLBCL3601SD (1+)1368/MCLL4601PR (2+)1443/MDLBCL2601PR (1+) The CAR used in this work is encoded by a gammaretrovirus and incorporates the variable regions of an anti-CD19 antibody, part of CD28, and part of CD3-zeta. A mean of 70.5% of the infused T cells expressed the CAR, and the infused cells produced cytokines and degranulated in a CD19-specific manner. Because prior chemotherapy has been shown to enhance the activity of adoptively-transferred T cells, patients received cyclophosphamide (total doses shown in table) plus fludarabine (25 mg/m2 daily for 5 days) before a single infusion of anti-CD19-CAR-transduced T cells. This is the first report of successful treatment of chemotherapy-refractory primary mediastinal B-cell lymphoma (PMBCL) and diffuse large B-cell lymphoma not otherwise specified (DLBCL) with anti-CD19-CAR T cells. All of the 8 treated patients with either PMBCL or DLBCL were chemotherapy-refractory, and 5 of these 8 patients obtained either a CR or PR on this trial. We defined chemotherapy-refractory as progression or no response 1 month after the end of the most recent chemotherapy. For example, Patient 2 had PMBCL that was refractory to 3 different chemotherapy regimens and that relapsed after radiation therapy. Patient 2 obtained a CR after infusion of anti-CD19 CAR T cells and remains in CR 19 months post-infusion. Blood B-cell depletion lasting more than 3 months occurred in 3 of 3 evaluable patients. Most patients were not evaluable for B-cell depletion due to B-cell depletion by prior treatments. One patient died suddenly of unknown etiology 16 days after infusion of CAR T cells. Acute toxicities including fever, hypotension, and delirium occurred after infusion of anti-CD19-CAR T cells. The toxicities resolved in less than 3 weeks after the cell infusion and were temporally associated with elevated serum interleukin-6 and interferon gamma levels in most patients. Peak blood levels of cells containing the CAR gene ranged from 2.3% to 66.5% of blood mononuclear cells. These results demonstrate the feasibility of treating patients with chemotherapy-refractory B-cell malignancies by using autologous anti-CD19 CAR T cells. The numerous remissions obtained should encourage further development of this approach. SMZL, splenic marginal zone lymphoma; PMBCL, primary mediastinal B-cell lymphoma; CLL, chronic lymphocytic leukemia; DLBCL, diffuse large B-cell lymphoma not otherwise specified. CR, complete remission; NE, not evaluable; PR, partial remission; SD, stable disease. (+) indicates an ongoing response. Disclosures: Rosenberg: Kite Pharma: Research Funding.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 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 | 0,001 |
| 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 source (Gemma direct ou Codex distillé), 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 ».