A Phase Ib/II Exploratory Clinical Trial of Memory-Enhanced 7×19-THEMIS CAR-T Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma

Determination of the Recommended Phase II Dose (RP2D)

Based on the incidence of DLTs, CAR-T cell kinetics, preliminary efficacy, and safety data from the Phase Ib dose-escalation phase, the Safety Review Committee (SRC) determined the RP2D following a comprehensive evaluation.

Objective Response Rate (ORR)

At 3 months (±7 days) after infusion, the proportion of patients achieving complete remission (CR) or partial remission (PR) was assessed according to the Lugano 2014 criteria, and a descriptive comparison was made with the historical control cohort.

Complete Remission Rate (CR Rate)

At 3 months (±7 days) after infusion, the proportion of patients who achieved complete remission (CR) was assessed according to the Lugano 2014 criteria, and a descriptive comparison was made with the historical control cohort.

Incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) graded according to ASTCT 2019 criteria

The incidence and severity of CRS and ICANS will be assessed according to the American Society for Transplantation and Cellular Therapy (ASTCT) 2019 consensus grading criteria. The incidence of each grade (Grades 1-4) will be summarized, with particular attention to the incidence of Grade ≥3 CRS and Grade ≥3 ICANS.

Incidence and duration of Grade ≥3 hematologic toxicities assessed according to CTCAE version 5.0

The incidence and duration of Grade ≥3 neutropenia, anemia, and thrombocytopenia will be assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

Incidence of clinically significant infections requiring anti-infective treatment or hospitalization

The incidence of bacterial, fungal, and viral infections requiring anti-infective treatment or hospitalization will be recorded and summarized.

Progression-Free Survival (PFS)

Progression-free survival is defined as the time from CAR-T cell infusion to the first documented disease progression (PD) or death from any cause, whichever occurs first. Median PFS and PFS rates at 12 and 24 months will be estimated using the Kaplan-Meier method.

Single-Cell Functional Characterization of CAR-T Products

Detection of various cytokines secreted by CAR-T infusion products at the single-cell level upon stimulation with the CD19 antigen.

Spearman correlation between memory T-cell subset proportions in the CAR-T infusion product and 3-month complete response

The proportions of stem cell memory T cells (TSCM), central memory T cells (TCM), effector memory T cells (TEM), and terminal effector T cells (TTE) in the CAR-T infusion product will be measured by multicolor flow cytometry. T-cell subsets will be defined as TSCM (CD45RA+CCR7+CD95+), TCM (CD45RA-CCR7+), TEM (CD45RA-CCR7-), and TTE (CD45RA+CCR7-). The proportion of each subset will be expressed as the percentage of CAR-T cells. The correlation between memory T-cell subset proportions and complete response at 3 months will be assessed using Spearman rank correlation and exploratory group comparisons using the Mann-Whitney U test.

Trends in Anti-CAR Antibodies (ADA)

Determination of the Prevalence and Titer of Anti-FMC63 Antibodies (ADA) in Serum

Area under the receiver operating characteristic curve (AUC) of peak serum cytokine and chemokine levels within 28 days after CAR-T infusion for discrimination of objective response

Peak serum concentrations of IL-7, CCL19, MIP-1α, MIP-1β, and SDF-1α during the first 28 days after CAR-T cell infusion will be measured using the protocol-specified serum cytokine/chemokine assay. Receiver operating characteristic (ROC) curve analysis will be performed to evaluate the ability of each biomarker to discriminate objective response, defined as complete response or partial response according to protocol-defined disease response criteria. The AUC and the optimal biomarker cutoff value will be determined for each biomarker.