Dataset Information

Decitabine-Primed CAR T-Cell Therapy for Relapsed/Refractory Non-Hodgkin's Lymphoma: A Phase 1/2 Clinical Study Demonstrating Enhanced Efficacy and Prolonged Survival

ABSTRACT: Relapsed/refractory Non-Hodgkin's lymphoma (R/R NHL) remains a therapeutic challenge despite advances in immune checkpoint inhibitors (ICIs). While chimeric antigen receptor (CAR) T-cell therapy has shown promise in hematologic malignancies, its efficacy in NHL is limited by T-cell exhaustion and tumor microenvironment (TME) immunosuppression. Preclinical studies suggest that low-dose decitabine, a DNA hypomethylating agent, can epigenetically reprogram T cells to enhance cytotoxicity and persistence. This open-label phase 1/2 trial (NCT04697940) enrolled 33 R/R NHL patients (aged 16–73 years) to evaluate the safety and efficacy of decitabine-primed CAR T cells targeting CD19/CD20 (CART19/20). Patients received lymphodepletion followed by escalating doses (0.5–5×10^6 cells/kg) of decitabine-activated CAR T cells. Primary endpoints included dose-limiting toxicities (DLTs) and objective response rate (ORR); secondary endpoints encompassed progression-free survival (PFS) and mechanistic analyses of T-cell dynamics.In the phase 1 cohort (n=18), no severe cytokine release syndrome (CRS) or neurotoxicity was observed, establishing 5×10^6 cells/kg as the recommended phase 2 dose (RP2D). Among 15 evaluable patients in phase 2, the ORR reached 86.7% (13/15), with a complete remission (CR) rate of 60% (9/15). Median PFS was 22.1 months, significantly surpassing historical controls of PD-1 monotherapy (median PFS: 12–15 months). Mechanistic studies revealed that decitabine pretreatment upregulated AP-1 transcription factor JunD in CAR T cells, promoting clonal expansion of progenitor-exhausted CD8+ T cells and enhancing tumor infiltration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295634 | GEO | 2026/03/05

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Background. Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Patients and Methods. We profiled expession of 24526 genes by means of whole genome 24K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab+chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results. Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1+TFF2+MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p=0.007), but not in the Control set (ORR 36.4%, p=0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1+TFF2+MCM5) profile versus any other ALDH6A1+TFF2+MCM5 profile was 15 (p=0.018) in the Bevacizumab qPCR set but only 0.72 (p=0.63) in the Control set. The tumor expression profile of (KLF12-high+TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high + TFF2-low) tumors had superior PFS (median 14 months, 95% CI 2-21) compared to patients with any other (KLF12+TFF2) expression profile (median PFS 7 months, 95% CI 5-10, p=0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12+TFF2 expression profile was 2.92 (p=0.03) in the Validation and 1.29 (p=0.39) in the Control set. Conclusions. Our <three-stage> hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer. 18 tumor tissue samples were analysed, no replicates

Project description:Importance: Autophagy has been identified as a resistance mechanism to BRAF and MEK inhibition in BRAF mutant melanoma. In the BAMM trial, hydroxychloroquine (HCQ) was used to inhibit autophagy in combination with dabrafenib and trametenib in BRAF mutant melanoma patients. Objective: To a) determine safety and maximal tolerated dose (MTD) of hydroxychloroquine when combined with dabrafenib and trametinib and b) determine antitumor activity of the combination. Design: Open label non-randomized phase I/II clinical trial Setting: Prospective therapeutic clinical trial conducted in 4 centers Participants: Unresectable Stage III or Stage IV BRAF mutant melanoma patients Intrevention: HCQ twice daily, dabrafenib 150 mg twice daily and trametinib 2 mg daily (D+T) Main Outcome: Primary outcomes were safety and 1-year progression-free survival (PFS) rate Results: Between December 2014 and January 2020, 50 patients were screened, 38 patients were enrolled and evaluable for toxicity and 34 patients were evaluable for 1-year PFS rate. Patient demographics were: 29% were ECOG PS 1, 47% had elevated LDH, 52% were Stage IV M1c or M1d and 53% had previously received therapy for advanced melanoma. In the phase I trial there was no dose limiting toxicity of HCQ at either 400 (n=3) or 600 (MTD) mg po bid combined with D+T. For the entire study population, the 1-year PFS rate was 41% (95% CI = ), median PFS was 11.9 months (95% CI = ), overall response rate (ORR) was 85% (95% exact CI=64-95%)and complete response rate of 41% (95% exact CI=25-59%). In a prespecificed subgroup analysis in 18 patients with elevated LDH, the ORR was 88% and median PFS was 8 months Conlusion and Relevance: The combination of HCQ, dabrafenib and trametinib was well tolerated and produced a high response rate but did not meet the prespecified criteria for success with respect to the 1-year PFS rate. In patients with elevated LDH , the response rate and PFS were encouraging. A randomized placebo controlled trial of dabrafenib and trametinib with/without HCQ in advanced BRAF mutant melanoma patients with elevated LDH and previously treated with immunotherapy is being conducted through the National Clinical Trial Network.

Dataset Information

Decitabine-Primed CAR T-Cell Therapy for Relapsed/Refractory Non-Hodgkin's Lymphoma: A Phase 1/2 Clinical Study Demonstrating Enhanced Efficacy and Prolonged Survival

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets