Abstract
Claudin18.2 (CLDN18.2) is highly expressed with the development of various malignant tumors, especially gastrointestinal cancers, and is emerging as a new target for cancer treatment. Satricabtagene autoleucel (satri-cel)/CT041 is an autologous chimeric antigen receptor (CAR) T cell targeting CLDN18.2, and the interim results of the CT041-CG4006 trial were reported in June 2022. Here we present the final results of this single-arm, open-label, phase 1 trial, which evaluated the safety and efficacy of satri-cel in patients with CLDN18.2-positive advanced gastrointestinal cancers. This trial included a dose-escalation stage (n = 15) and a dose-expansion stage in four different cohorts (total n = 83): cohort 1, satri-cel monotherapy in 61 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 2, satri-cel plus anti-PD-1 therapy in 15 patients with standard chemotherapy-refractory gastrointestinal cancers; cohort 3, satri-cel as sequential treatment after first-line therapy in five patients with gastrointestinal cancers; and cohort 4, satri-cel monotherapy in two patients with anti-CLDN18.2 monoclonal antibody-refractory gastric cancer. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and immunogenicity. A total of 98 patients received satri-cel infusion, among whom 89 were dosed with 2.5 × 108, six with 3.75 × 108 and three with 5.0 × 108 CAR T cells. Median follow-up was 32.4 months (95% confidence interval (CI): 27.3, 36.5) since apheresis. No dose-limiting toxicities, treatment-related deaths or immune effector cell-associated neurotoxicity syndrome were reported. Cytokine release syndrome occurred in 96.9% of patients, all classified as grade 1–2. Gastric mucosal injuries were identified in eight (8.2%) patients. The overall response rate and disease control rate in all 98 patients were 38.8% and 91.8%, respectively, and the median progression-free survival and overall survival were 4.4 months (95% CI: 3.7, 6.6) and 8.8 months (95% CI: 7.1, 10.2), respectively. Satri-cel demonstrates therapeutic potential with a manageable safety profile in patients with CLDN18.2-positive advanced gastrointestinal cancer. ClinicalTrials.gov identifier: NCT03874897.
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Data availability
The data supporting the findings of this trial are available within the manuscript and its Supplementary Information files. All requests for further data sharing will be reviewed by the leading clinical center, the Department of Gastrointestinal Oncology at Peking University Cancer Hospital & Institute, and the trial collaborator, CARsgen Therapeutics Co., Ltd., to verify whether the request is subject to any intellectual property or confidentiality obligations. Requests for access to individual participant-level data from this trial can be submitted via email to shenlin@bjmu.edu.cn with detailed proposals for approval and will be responded to within 60 days. Each participant’s rights and privacy are key subjects taken into consideration when sharing information. A signed data access agreement with the collaborator is required before accessing shared data.
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Acknowledgements
We thank all the participants in this trial and their families as well as the trial site investigators. This trial was funded, in part, by the National Key Research and Development Program of China (no. 2022YFC2505006 and no. 2023YFC3403700), CARsgen Therapeutics Co., Ltd. and the National Natural Science Foundation of China (no. U22A20327).
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Extended data
Extended Data Fig. 1 Trial flow diagram and procedure schema.
(a) Two-phase trial design: a dose escalation/de-escalation phase and a dose-expansion phase to determine the recommended dose (RD). In dose-expansion stage, satri-cel was evaluated in 4 cohorts. (b) Schema of trial procedure. DLT, dose-limiting toxicity; ECOG, Eastern Cooperative Oncology Group performance status.
Extended Data Fig. 2 Antitumor activity.
Best percentage changes in target lesions in dose escalation stage and each of the 4 cohorts (n = 90). The patients without tumor type labeled were GC/GEJ.
Extended Data Fig. 3 Survival by subgroups in all patients (n = 98).
(a) Progression-free survival. (b) Overall survival. Note: The mPFS and mOS were estimated by Kaplan-Meier method, and the corresponding two-sided 95% CI was calculated using Brookmeyer-Crowley method. Squares and bars represent the mPFS and mOS with 95% CIs for each subgroup.
Extended Data Fig. 4 Association of CAR T cell expansion, cytokines, CRP, and ferritin with different index or outcomes.
(a) CAR copy numbers after first (n = 98), second and third infusions (n = 59) in all patients. (b) CAR copy numbers after first (n = 59), second and third infusions (n = 35) in GC/GEJ patients with monotherapy. (c) CAR copy numbers of satri-cel monotherapy (n = 83) and satri-cel plus PD-1 inhibitor cohort (n = 15) after the first infusion. (d) The association between Cmax after the first infusion and the tumor response. (e) Cmax after the first infusion and CRS grade. (f) Baseline IL-6 and CRS grade. (g) Baseline TGF-β1 and CRS grade. (h) Baseline CRP and CRS grade. (i) Baseline ferritin and CRS grade. Note: Dots and bars show the median and interquartile ranges (IQR) for CAR copies at each visit in plot a-c; The horizontal lines and the boxes show the medians and IQR in plot d-i, whiskers show the minimum observation above the lower fence (1.5 IQR below the 25th percentile) and the maximum observation below upper fence (1.5 IQR above the 75th percentile). The p-values were calculated using the two-sided Wilcoxon rank sum test.
Extended Data Fig. 5 Association between frequencies of T cell subsets and Cmax or AUClast of CAR copies after first infusion in GC/GEJ patients with monotherapy.
The association between Cmax or AUClast of CAR copies after first infusion and the frequencies of, (a) CD3+CD4−CD8+ (cytotoxic T lymphocytes, CTLs) cells, (b) CD3+CD4+CD8− (Th) cells, (c) CD45RA+/CCR7+ (naive T and stem cell-like memory T, TN/SCM) cells, (d) CD45RA−/CCR7+ (central memory T, TCM) cells, (e) CD45RA−/CCR7− (effector memory T, TEM) cells, and (f) CD45RA+/CCR7− (terminally differentiated effector T, TEFF) cells in CT041 product were tested by Spearman Correlation Analysis and p-value was calculated from a Student’s t distribution. Linear regression analyses were performed for the correlation among the frequencies of CD45RA+/CCR7− cells and Cmax (g) or AUClast (h). Shaded bands show the 95% CIs of predicted probability, and lines present the predicted probability of Cmax and AUClast from linear regression analyses. Note: For Fig. 5a–f, Cmax and AUClast were analyzed by quartile of T cell subsets, i.e, Patients were divided into 4 groups based on the quartiles of T cell subset (the 4 groups are the minimum to quartile 1 (Q1), Q1 to median(Q2), median to Q3, and Q3 to maximum). The horizontal lines and the boxes show the medians and IQR, whiskers show the minimum observation above the lower fence (1.5 IQR below the 25th percentile) and the maximum observation below upper fence (1.5 IQR above the 75th percentile). The circular dots represent individual T cell subset level parameters for patients.
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Qi, C., Liu, C., Gong, J. et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results. Nat Med 30, 2224–2234 (2024). https://doi.org/10.1038/s41591-024-03037-z
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DOI: https://doi.org/10.1038/s41591-024-03037-z
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