Preliminary Safety and Efficacy of PBCAR0191, an Allogeneic 'Off-the-Shelf' CD19-Directed CAR-T for Patients with Relapsed/Refractory (R/R) CD19+ B-ALL
Notice bibliographique
Résumé
Abstract Introduction: CD19-directed autologous CAR-T products induce high response rates in adults with R/R B-ALL, yet many patients relapse within the first year. Additionally, cell manufacturing timelines, and poor t-cell fitness may imperil efficacy, especially among those with proliferative disease. This makes access to a donor-derived, readily available CAR-T product of great interest in this patient population, particularly when consolidation with allogeneic stem cell transplant (allo-SCT) is possible. We report preliminary safety, efficacy, and correlative data for the R/R B-ALL patients dosed with at least 3 x 10 6 CAR-T cells/kg of PBCAR0191, an allogeneic 'off-the-shelf' CD19-directed CAR-T. Methods: Subjects were 18 years or older with CD19+ R/R B-ALL after at least 2 prior lines of therapy. Patients were required to have adequate organ function and no active GvHD, CNS disease, active infections, or other active medical issues. Prior allo-SCT and/or autologous CAR-T therapy were allowed. Subjects received either standard (sLD; 30mg/m2/day and 500mg/m2/day x 3 days fludarabine and cyclophosphamide, respectively) or enhanced (eLD; 30mg/m2/day x 4 days flu and 1000mg/m2/day x 3 days cy) lymphodepletion preceding PBCAR0191 infusion. Correlative laboratory samples were taken for CAR-T expansion, persistence, molecular response to treatment and safety assessments. Results: As of August 2, 2021, 15 subjects with R/R CD19+ B-ALL have been dosed with dose Dose level 3/4a (3 X 10 6 CAR-T cells/kg or equivalent, n=11) or a Dose level 4b (flat dose of 5 X 10 8 CAR-T cells, n=4). Demographics, baseline disease, and prior treatment data are presented in the table. Most of the Adverse events (AE) reported to date were mild, with no cases of GvHD, no Grade ≥3 CRS and 1 case of Grade 3 ICANS which resolved within 48 hours. 67% of subjects treated (10/15) experienced PBCAR0191 related AEs, with 60% (9/15) of subjects experiencing serious AEs (one related to PBCAR0191, ICANS Grade 3). The complete response (CR) or CRi (incomplete marrow recovery) rate at Day ≥28 is 33% (2/6) in DL3/4a and sLD, 80% (4/5) in DL3/4a with eLD and 75% (3/4) in DL4b with sLD. Importantly, 4/15 (27%) responding subjects underwent allo-SCT, with one additional subject not able to receive transplant due to eligibility yet maintaining an MRD- CR for >250 days, and one refusing to proceed with transplant. Product accessibility was evident compared to autologous CAR-T products, with median time from screening completion to PBCAR0191 infusion of 7 days (median of 1 day until start of LD) and all eligible subjects receiving PBCAR0191 infusion. Conclusion: PBCAR0191 has demonstrated a manageable safety profile and high complete response rate at day 28 or later, providing an adequate window for potential bridge to allo-SCT. Figure 1 Figure 1. Disclosures Jain: Adaptive Biotechnologies: Honoraria, Research Funding; Precision Biosciences: Honoraria, Research Funding; Cellectis: Honoraria, Research Funding; Pfizer: Research Funding; Janssen: Honoraria; Genentech: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Beigene: Honoraria; TG Therapeutics: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Incyte: Research Funding; AbbVie: Honoraria, Research Funding; Fate Therapeutics: Research Funding; Servier: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Pharmacyclics: Research Funding. Kantarjian: KAHR Medical Ltd: Honoraria; Ascentage: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Aptitude Health: Honoraria; Ipsen Pharmaceuticals: Honoraria; Precision Biosciences: Honoraria; Novartis: Honoraria, Research Funding; Astra Zeneca: Honoraria; AbbVie: Honoraria, Research Funding; NOVA Research: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Sauter: Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Heery: Precision BioSciences: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Arcellx: Current Employment, Current holder of stock options in a privately-held company. List: Halia Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; CTI Biosciences: Consultancy; Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Aileron Therapeutics: Consultancy. Johnson: Precision BioSciences, Inc: Current Employment, Current equity holder in publicly-traded company. Lou: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company. Vainorius: Precision BioSciences: Current Employment, Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; United Therapeautics: Current equity holder in publicly-traded company. Olszewski: Genentech, Inc.: Research Funding; TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genmab: Research Funding. Stein: Amgen: Consultancy, Speakers Bureau; Celgene: Speakers Bureau; Stemline: Speakers Bureau. Shah: Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Pfizer: Consultancy, Other: Expenses; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; BeiGene: Consultancy, Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding; Servier Genetics: Other. OffLabel Disclosure: PBCAR0191 is not FDA approved
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 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) | 0,002 | 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 ».