Dataset Information

CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia.

ABSTRACT: Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent antitumor effects in B-cell malignancies including acute lymphoblastic leukemia (ALL), but antigen loss remains the major cause of treatment failure. To mitigate antigen escape and potentially improve the durability of remission, we developed a dual-targeting approach using an optimized, bispecific CAR construct that targets both CD19 and BAFF-R. CD19/BAFF-R dual CAR T cells exhibited antigen-specific cytokine release, degranulation, and cytotoxicity against both CD19-/- and BAFF-R-/- variant human ALL cells in vitro. Immunodeficient mice engrafted with mixed CD19-/- and BAFF-R-/- variant ALL cells and treated with a single dose of CD19/BAFF-R dual CAR T cells experienced complete eradication of both CD19-/- and BAFF-R-/- ALL variants, whereas mice treated with monospecific CD19 or BAFF-R CAR T cells succumbed to outgrowths of CD19-/BAFF-R+ or CD19+/BAFF-R- tumors, respectively. Further, CD19/BAFF-R dual CAR T cells showed prolonged in vivo persistence, raising the possibility that these cells may have the potential to promote durable remissions. Together, our data support clinical translation of BAFF-R/CD19 dual CAR T cells to treat ALL.

SUBMITTER: Wang X

PROVIDER: S-EPMC8983465 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia.

Wang Xiuli X Dong Zhenyuan Z Awuah Dennis D Chang Wen-Chung WC Cheng Wesley A WA Vyas Vibhuti V Cha Soung-Chul SC Anderson Aaron J AJ Zhang Tiantian T Wang Zhe Z Szymura Szymon J SJ Kuang Benjamin Z BZ Clark Mary C MC Aldoss Ibrahim I Forman Stephen J SJ Kwak Larry W LW Qin Hong H

Leukemia 20220118 4

Chimeric antigen receptor (CAR) T cells targeting CD19 mediate potent antitumor effects in B-cell malignancies including acute lymphoblastic leukemia (ALL), but antigen loss remains the major cause of treatment failure. To mitigate antigen escape and potentially improve the durability of remission, we developed a dual-targeting approach using an optimized, bispecific CAR construct that targets both CD19 and BAFF-R. CD19/BAFF-R dual CAR T cells exhibited antigen-specific cytokine release, degranu ...[more]

PMID: 35039637

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Project description:BackgroundChimeric antigen receptor natural killer (CAR-NK) cells represent a promising advancement in CAR cell therapy, addressing limitations observed in CAR-T cell therapy. However, our prior study revealed challenges in CAR-NK cells targeting CD19 antigens, as they failed to eliminate CD19+ Raji cells in NSG tumor-bearing mice, noting down-regulation or loss of CD19 antigen expression in some Raji cells. In response, this study aims to enhance CD19 CAR-NK cell efficacy and mitigate the risk of tumor recurrence due to target antigen escape by developing CD19 and CD20 (CD19/CD20) dual-targeted CAR-NK cells.MethodsInitially, mRNA encoding anti-CD19 CARs (FMC63 scFv-CD8α-4-1BB-CD3ζ) and anti-CD20 CARs (LEU16 scFv-CD8α-4-1BB-CD3ζ) was constructed via in vitro transcription. Subsequently, CD19/CD20 dual-targeted CAR-NK cells were generated through simultaneous electrotransfection of CD19/CD20 CAR mRNA into umbilical cord blood-derived NK cells (UCB-NK).ResultsFollowing co-electroporation, the percentage of dual-CAR expression on NK cells was 86.4% ± 1.83%, as determined by flow cytometry. CAR expression was detectable at 8 h post-electric transfer, peaked at 24 h, and remained detectable at 96 h. CD19/CD20 dual-targeted CAR-NK cells exhibited increased specific cytotoxicity against acute lymphoblastic leukemia (ALL) cell lines (BALL-1: CD19+CD20+, REH: CD19+CD20-, Jurkat: CD19-CD20-) compared to UCB-NK, CD19 CAR-NK, and CD20 CAR-NK cells. Moreover, CD19/CD20 dual-targeted CAR-NK cells released elevated levels of perforin, IFN-γ, and IL-15. Multiple activation markers such as CD69 and cytotoxic substances were highly expressed.ConclusionsThe creation of CD19/CD20 dual-targeted CAR-NK cells addressed the risk of tumor escape due to antigen heterogeneity in ALL, offering efficient and safe 'off-the-shelf' cell products. These cells demonstrate efficacy in targeting CD20 and/or CD19 antigens in ALL, laying an experimental foundation for their application in ALL treatment.

Project description:BackgroundRecent evidence suggests that resistance to CD19 chimeric antigen receptor (CAR)-modified T cell therapy may be due to the presence of CD19 isoforms that lose binding to the single-chain variable fragment (scFv) in current use. As such, further investigation of CARs recognize different epitopes of CD19 antigen may be necessary.MethodsWe generated a new CD19 CAR T (HI19α-4-1BB-ζ CAR T, or CNCT19) that includes an scFv that interacts with an epitope of the human CD19 antigen that can be distinguished from that recognized by the current FMC63 clone. A pilot study was undertaken to assess the safety and feasibility of CNCT19-based therapy in both pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia (R/R B-ALL).ResultsData from our study suggested that 90% of the 20 patients treated with infusions of CNCT19 cells reached complete remission or complete remission with incomplete count recovery (CR/CRi) within 28 days. The CR/CRi rate was 82% when we took into account the fully enrolled 22 patients in an intention-to-treat analysis. Of note, extramedullary leukemia disease of two relapsed patients disappeared completely after CNCT19 cell infusion. After a median follow-up of 10.09 months (range, 0.49-24.02 months), the median overall survival and relapse-free survival for the 20 patients treated with CNCT19 cells was 12.91 months (95% confidence interval [CI], 7.74-18.08 months) and 6.93 months (95% CI, 3.13-10.73 months), respectively. Differences with respect to immune profiles associated with a long-term response following CAR T cell therapy were also addressed. Our results revealed that a relatively low percentage of CD8+ naïve T cells was an independent factor associated with a shorter period of relapse-free survival (p = 0.012, 95% CI, 0.017-0.601).ConclusionsThe results presented in this study indicate that CNCT19 cells have potent anti-leukemic activities in patients with R/R B-ALL. Furthermore, our findings suggest that the percentage of CD8+ naïve T cells may be a useful biomarker to predict the long-term prognosis for patients undergoing CAR T cell therapy.Trial registrationClinicalTrials.gov : NCT02975687; registered 29 November, 2016. https://clinicaltrials.gov/ct2/keydates/NCT02975687.

Project description:BackgroundCD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients.MethodsWe conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics.ResultsA total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden.ConclusionsIn the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).

Dataset Information

CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia.

Publications

CD19/BAFF-R dual-targeted CAR T cells for the treatment of mixed antigen-negative variants of acute lymphoblastic leukemia.

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