Allogeneic off-the-shelf CAR T-cell therapy for relapsed or refractory B-cell malignancies

Despite clinical benefit with the use of chimeric antigen receptor (CAR) T cells, the need to manufacture patient-specific products limits its clinical utility. To overcome this barrier, we developed an allogeneic "off-the-shelf" CAR T-cell product using Epstein-Barr virus (EBV)-specific T cells (EBV-VSTs) genetically modified with a CD19-specific CAR (19-28z). Patients with relapsed/refractory (R/R) B-cell malignancies were stratified into 3 treatment cohorts: cohort 1 (n = 8; disease recurrence after allogeneic or autologous hematopoietic cell transplantation [HCT]), cohort 2 (n = 6; consolidative therapy after autologous HCT), or cohort 3 (n = 2; consolidative therapy after allogeneic HCT). The primary objective of this trial was to determine the safety of multiple CAR EBV-VST infusions. Most patients (n = 12/16) received multiple doses (overall median, 2.5 [range, 1-3]) with 3 × 106 T cells per kg determined to be the optimal dose enabling multiple treatments per manufactured cell line. Severe cytokine release syndrome or neurotoxicity did not occur after infusion, and no dose-limiting toxicity was observed in the trial. Median follow-up was 48 months (range, 4-135) with 4 deaths due to disease progression. Overall survival of all patients was 81% at 12 months and 75% at 36 months. Postinfusion expansion and persistence were limited, and CAR EBV-VSTs demonstrated a unique T-cell phenotype compared with autologous 19-28z CAR T cells. Our study demonstrates the feasibility and safety of an allogeneic "off-the-shelf" CAR EBV-VST product with favorable outcomes for patients with CD19+ R/R B-cell malignancies. This trial was registered at www.ClinicalTrials.gov as #NCT01430390.

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Publication Details

Journal
Blood Advances
Published
2025-02-05
DOI
https://doi.org/10.1182/bloodadvances.2024015157
Citations
16
Primary Topic
CAR-T cell therapy research
Type
article
Field-Weighted Citation Impact
16.73

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article

Allogeneic off-the-shelf CAR T-cell therapy for relapsed or refractory B-cell malignancies

Jaap Jan Boelens, Kinga Hosszu, Audrey Mauguen, Ann Alice Jakubowski et al.
16 citations
Blood Advances
CAR-T cell therapy research
16.73
article

Allogeneic off-the-shelf CAR T-cell therapy for relapsed or refractory B-cell malignancies

Jaap Jan Boelens, Kinga Hosszu, Audrey Mauguen, Ann Alice Jakubowski, Jennifer Bieler, Craig S. Sauter, Isabelle Rivière, Charlie White, Maria Cancio, Susan E. Prockop, Devin McAvoy, Michel Sadelain, Renier J. Brentjens, Sergio A. Giralt, Nancy A. Kernan, Sanam Shahid, Miguel‐Angel Perales, Andromachi Scaradavou, Xiuyan Wang, Richard J. O’Reilly, Clare Taylor, Kevin J. Curran, G. Flynn, Jagrutiben Chaudhari
article en
16 citations

Abstract

Despite clinical benefit with the use of chimeric antigen receptor (CAR) T cells, the need to manufacture patient-specific products limits its clinical utility. To overcome this barrier, we developed an allogeneic "off-the-shelf" CAR T-cell product using Epstein-Barr virus (EBV)-specific T cells (EBV-VSTs) genetically modified with a CD19-specific CAR (19-28z). Patients with relapsed/refractory (R/R) B-cell malignancies were stratified into 3 treatment cohorts: cohort 1 (n = 8; disease recurrence after allogeneic or autologous hematopoietic cell transplantation [HCT]), cohort 2 (n = 6; consolidative therapy after autologous HCT), or cohort 3 (n = 2; consolidative therapy after allogeneic HCT). The primary objective of this trial was to determine the safety of multiple CAR EBV-VST infusions. Most patients (n = 12/16) received multiple doses (overall median, 2.5 [range, 1-3]) with 3 × 106 T cells per kg determined to be the optimal dose enabling multiple treatments per manufactured cell line. Severe cytokine release syndrome or neurotoxicity did not occur after infusion, and no dose-limiting toxicity was observed in the trial. Median follow-up was 48 months (range, 4-135) with 4 deaths due to disease progression. Overall survival of all patients was 81% at 12 months and 75% at 36 months. Postinfusion expansion and persistence were limited, and CAR EBV-VSTs demonstrated a unique T-cell phenotype compared with autologous 19-28z CAR T cells. Our study demonstrates the feasibility and safety of an allogeneic "off-the-shelf" CAR EBV-VST product with favorable outcomes for patients with CD19+ R/R B-cell malignancies. This trial was registered at www.ClinicalTrials.gov as #NCT01430390.

Blood AdvancesVol. 9(7)
Boston Children's Hospital (US), Roswell Park Comprehensive Cancer Center (US), Cleveland Clinic (US), Memorial Sloan Kettering Cancer Center (US), Columbia University Irving Medical Center (US), Kettering University (US), Boston Children's Museum (US), Dana-Farber/Boston Children's Cancer and Blood Disorders Center (US)
Amgen, Bristol-Myers Squibb, Sanofi, Celgene, Memorial Sloan-Kettering Cancer Center, Regeneron Pharmaceuticals, Les Laboratories Pierre Fabre, Atara Biotherapeutics, Swedish Orphan Biovitrum, Juno Therapeutics
Good health and well-being
Openalex Percentile: Top 1%
CAR-T cell therapy research
16.73
DOIOpen Access PDFOpenAlex
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