Treatment of adult ALL patients with third-generation CD19-directed CAR T cells: results of a pivotal trial.
Acute lymphoblastic leukemia (ALL)
CART-associated toxicities
CD39
Cytokine release syndrome (CRS)
Cytopenia
Immune effector cell-associated neurotoxicity syndrome (ICANS)
Investigator-initiated trial (IIT)
Third-generation chimeric antigen receptor (CAR) T cells
Journal
Journal of hematology & oncology
ISSN: 1756-8722
Titre abrégé: J Hematol Oncol
Pays: England
ID NLM: 101468937
Informations de publication
Date de publication:
22 07 2023
22 07 2023
Historique:
received:
28
02
2023
accepted:
20
06
2023
medline:
24
7
2023
pubmed:
23
7
2023
entrez:
22
7
2023
Statut:
epublish
Résumé
Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL). Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 10 For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response. In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www. gov as NCT03676504.
Sections du résumé
BACKGROUND
Third-generation chimeric antigen receptor (CAR)-engineered T cells (CARTs) might improve clinical outcome of patients with B cell malignancies. This is the first report on a third-generation CART dose-escalating, phase-1/2 investigator-initiated trial treating adult patients with refractory and/or relapsed (r/r) acute lymphoblastic leukemia (ALL).
METHODS
Thirteen patients were treated with escalating doses of CD19-directed CARTs between 1 × 10
RESULTS
For all patients, CART manufacturing was feasible. None of the patients developed any grade of Immune effector cell-associated neurotoxicity syndrome (ICANS) or a higher-grade (≥ grade III) catokine release syndrome (CRS). CART expansion and long-term CART persistence were evident in the peripheral blood (PB) of evaluable patients. At end of study on day 90 after CARTs, ten patients were evaluable for response: Eight patients (80%) achieved a complete remission (CR), including five patients (50%) with minimal residual disease (MRD)-negative CR. Response and outcome were associated with the administered CART dose. At 1-year follow-up, median overall survival was not reached and progression-free survival (PFS) was 38%. Median PFS was reached on day 120. Lack of CD39-expression on memory-like T cells was more frequent in CART products of responders when compared to CART products of non-responders. After CART administration, higher CD8 + and γδ-T cell frequencies, a physiological pattern of immune cells and lower monocyte counts in the PB were associated with response.
CONCLUSION
In conclusion, third-generation CARTs were associated with promising clinical efficacy and remarkably low procedure-specific toxicity, thereby opening new therapeutic perspectives for patients with r/r ALL. Trial registration This trial was registered at www.
CLINICALTRIALS
gov as NCT03676504.
Identifiants
pubmed: 37481608
doi: 10.1186/s13045-023-01470-0
pii: 10.1186/s13045-023-01470-0
pmc: PMC10363324
doi:
Substances chimiques
cell-associated neurotoxicity
0
Adaptor Proteins, Signal Transducing
0
Antigens, CD19
0
Banques de données
ClinicalTrials.gov
['NCT03676504']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
79Informations de copyright
© 2023. The Author(s).
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