Dataset Information

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19⁺ B cell tumors: a phase 1/2 trial.

ABSTRACT: There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19⁺ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 10⁷ and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .

SUBMITTER: Marin D

PROVIDER: S-EPMC10957466 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19<sup>+</sup> B cell tumors: a phase 1/2 trial.

Marin David D Li Ye Y Basar Rafet R Rafei Hind H Daher May M Dou Jinzhuang J Mohanty Vakul V Dede Merve M Nieto Yago Y Uprety Nadima N Acharya Sunil S Liu Enli E Wilson Jeffrey J Banerjee Pinaki P Macapinlac Homer A HA Ganesh Christina C Thall Peter F PF Bassett Roland R Ammari Mariam M Rao Sheetal S Cao Kai K Shanley Mayra M Kaplan Mecit M Hosing Chitra C Kebriaei Partow P Nastoupil Loretta J LJ Flowers Christopher R CR Moseley Sadie Mae SM Lin Paul P Ang Sonny S Popat Uday R UR Qazilbash Muzaffar H MH Champlin Richard E RE Chen Ken K Shpall Elizabeth J EJ Rezvani Katayoun K

Nature medicine 20240118 3

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19<sup>+</sup> B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progressio ...[more]

PMID: 38238616

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Project description:BackgroundDue to the lack of effective treatment options, the prognosis of patients with relapsed/refractory acute myeloid leukemia (R/R AML) remains poor. Although chimeric antigen receptor (CAR)-T-cell therapy has shown promising effects in acute lymphoblastic leukemia (ALL) and lymphoma, its application in R/R AML is limited by "off-target" effects, which lead to severe bone marrow suppression and limit its clinical application. CAR-natural killer (NK) cells not only exhibit antitumor effects but also demonstrate increased safety and universality. We have developed a new CAR construct that targets CD33 and modified NK cells, specifically eliminating AML cells while reducing severe side effects on stem cells.MethodsThe CD33-targeting domain was selected by CAR-T cells, and this optimized CAR construct was subsequently transduced into umbilical cord-derived NK cells via a retroviral vector. Preclinical efficacy and safety studies were conducted both in vitro and in vivo. Ten eligible patients with R/R AML aged 18-65 years who received one or more infusions of anti-CD33 CAR-NK cells following the preconditioning regimen were enrolled. We assessed the response rates and treatment-related side effects post-infusion, while also documenting the long-term efficacy of the therapy.ResultsThe CD33 sequence was selected on the basis of its antitumor efficacy and safety in CAR-T-cell studies conducted both in vitro and in vivo. CD33 CAR-NK cells demonstrated efficacy comparable to that of CD33 CAR-T cells but showed limited toxicity to hematopoietic stem cells (HSCs). Ten patients, with a median of five prior lines of treatment, completed the efficacy evaluation (range, 3-8). No grade 3-4 adverse events were observed, except bone marrow suppression, which was relieved within one month. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) or graft-versus-host disease (GVHD) were reported following CAR-NK cell infusion. Only one patient experienced grade 2 cytokine release syndrome (CRS) and presented with persistent fever. By day 28, six of ten patients had achieved minimal residual disease (MRD)-negative complete remission.ConclusionsOur preclinical and clinical data demonstrated the primary efficacy and safety of CD33 CAR-NK cells for patients with R/R AML. Expanded samples and longer follow-up periods are needed to provide further efficacy data.Trial registrationNCT05008575 ( https://clinicaltrials.gov/study/NCT05008575 ).

Dataset Information

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19⁺ B cell tumors: a phase 1/2 trial.

Publications

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19<sup>+</sup> B cell tumors: a phase 1/2 trial.

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Dataset Information

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial.

Publications

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19<sup>+</sup> B cell tumors: a phase 1/2 trial.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19⁺ B cell tumors: a phase 1/2 trial.