Allogeneic iPSC-derived iNKT cells in recurrent head and neck cancer: a phase 1 trial
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE290757 | GEO | 2025/09/28
REPOSITORIES: GEO
Similar Datasets
Project description:Phase I Safety, Pharmacokinetic and Pharmacogenomic Trial of ES-285, a Novel Marine Cytotoxic Agent Administered as an Infusion over 24 h Every 21 Days in Patients with Solid Tumors Purpose: A dose-escalation, phase I study evaluated the safety, pharmacokinetics, pharmacogenomics and efficacy of ES-285, a novel agent isolated from a marine mollusc, in adult cancer patients. Experimental design: Patients received a 24-hour i.v. infusion of ES-285 once every 3 weeks until disease progression or unacceptable toxicity. The starting dose was 4mg/m2. Dose escalation proceeded according to the worst toxicity observed in the previous cohort. Results: 28 patients were treated with 72 courses of ES-285 across 8 dose levels. No doselimiting toxicities (DLTs) were seen between 4mg/m2 and 128mg/m2. Two out of 4 patients treated at 256mg/m2 had dose-limiting reversible grade 3 transaminitis; one patient at 256mg/m2 also had transient grade 3 central neurotoxicity. One of 3 patients subsequently treated at 200mg/m2 died following drug-related central neurotoxicity. Pharmacokinetic studies indicated dose-proportionality with high volume of distribution (median Vss at 256mg/m2 was 2389L, range 1615-4051L) and long elimination half life (median t1/2 at 256mg/m2 was 29h, range 21-32h). The 3 patients with DLT had the highest drug exposure. Pharmacogenomic studies of paired surrogate tissue samples identified changes in gene expression following treatment that correlated with increasing dose. Pre-treatment 59- and 49-gene sets were identified in blood and skin respectively, that may predict DLT. Disease stabilisation for 6 to 18 weeks was recorded in 9 patients. Conclusion: Using this schedule, 128 mg/m2 was considered safe and feasible. At this dose, pharmacologically relevant concentrations of drug were safely achieved with pharmacogenomic studies indicating changes in the expression of genes of potential biological relevance. Keywords: dose response
2009-04-01 | GSE12062 | GEO
Project description:KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptorpositive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level.
2018-08-26 | GSE82161 | GEO
Project description:We report here a phase I trial (NCT02208362) evaluating locoregional delivery of IL13Rα2-targeted CAR T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were to evaluate safety and feasibility, and secondary objectives were to assess therapy-related cytokine dynamics, CAR T cell persistence and clinical outcomes. Feasibility and safety were established for three routes of locoregional CAR T cell administration [intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV], with IL13Rα2-CAR T cells being well-tolerated with clinically manageable adverse events at all dose levels. Stable disease or better was achieved in 50% of patients, with two partial responses, one complete response (CR), and a second CR after additional CAR T cycles off protocol therapy. Patients with rGBM treated on Arm 5, utilizing dual ICT/ICV delivery and an optimized manufacturing process exhibited the best overall survival of 10.2 months. . Central nervous system (CNS) increases in inflammatory cytokines, including IFNγ, CXCL9, and CXCL10, were associated with CAR T cell administration and bioactivity. Further, pre-treatment intratumoral CD3 T cell levels were positively associated with survival, suggesting an interplay between host immunity and CAR T cells as a determinant of outcomes. These findings advance our understanding of CAR T cell immunotherapy for malignant brain tumors. ClinicalTrials.gov Identifier: NCT02208362
2024-02-20 | GSE255850 | GEO
Project description:T cells in cutaneous T-cell lymphoma (CTCL) are functionally exhausted, expressing immune inhibitory molecules such as PD1 and PD-L1. Durvalumab selectively targets PD-L1 on exhausted T cells and distinct cells within the CTCL tumor microenvironment (TME) and may restore an anti-tumor immune response. The oral immunomodulator lenalidomide, which has shown activity in CTCL, may enhance immune checkpoint blockade by durvalumab. We initiated a phase 1/2 clinical trial of lenalidomide and durvalumab in patients with refractory/advanced CTCL (NCT03011814). Primary objectives were to assess safety and tolerability and identify the maximum tolerated dose/recommended phase 2 dose. Secondary and tertiary objectives were to investigate efficacy and the effects on the TME. Thirteen patients enrolled in sequential cohorts received fixed dose durvalumab and dose escalation of lenalidomide. Thirteen patients were evaluable for toxicities and 12 for response in phase 1. No serious adverse events (AEs) or dose-limiting toxicities (DLTs) were observed during cycles 1-3 (DLT evaluation period). The most frequent AEs were tumor flare, fatigue, neutropenia and leukopenia. Three patients developed grade 1/2 autoimmune thyroiditis that resolved with treatment. Median cycles of treatment were 11 (range, 3-42+). Median duration of response was 25.5 (range 8-36.5) months. Anti-PD-L1/lenalidomide showed clinical activity; there were 7 partial responses, 4 stable disease and 1 progressive disease. Adaptive and innate immune signatures potentially predictive of response seen in gene expression profiling of serial skin samples were downregulation of TNF-alpha signaling via NFκB, IFN-gamma, and PI3-AKT-mTOR signaling pathways in responders vs up-regulation of MYC targets and pro-inflammatory pathways in non-responders. Profiling of immune cell compositions revealed changes in individual immune cell clusters based on treatment status and response.
2024-07-11 | GSE271668 | GEO
Project description:Combining venetoclax, a selective BCL-2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL-2 inhibitor, may potentiate therapeutic BCL-2 and BCL XL inhibition without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase 1 dose escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase 2 dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen (28%) patients proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population.
2021-02-17 | GSE162894 | GEO
Project description:Invariant natural killer T (iNKT) cells are a distinct subset of T lymphocytes that possess unique properties making them highly suitable for addressing the challenges of solid tumor immunotherapy. Unlike conventional T cells, which are restricted by polymorphic major histocompatibility complex (MHC) molecules and recognize peptide antigens, iNKT cells are restricted by the non-polymorphic CD1d molecule and respond to lipid antigens. Chimeric antigen receptor (CAR)-redirected iNKT (CAR-iNKT) cells represent a significant advancement in cancer immunotherapy. However, optimizing sustained activation and long-term persistence of CAR-iNKT cells remains a critical need for effective solid tumor treatment. To address these limitations, we develop the iNKT cell-targeted microparticle recruitment and activation system (iMRAS), a biomimetic platform designed to enhance iNKT cell functionality through localized immunostimulation in vivo. This biomimetic platform is designed to function as an in vivo “charging station” containing chemotactic and activation signals for the recruitment, activation, and expansion of CAR-iNKT cells, leading to more effective tumor killing and longer persistence of CAR-iNKT cells, as demonstrated in the therapy of lymphoma and melanoma. Through its biomimetic design and localized immunostimulatory effects, iMRAS helps overcome the limitations of current therapies for solid tumors, establishing a robust platform for enhancing systemic CAR-iNKT cell-mediated immunotherapy.
2025-05-07 | GSE291443 | GEO
Project description:Elderly, non-fit AML/MDS patients relapsed/refractory (R/R) after HMA-based treatment represent a highly unmet clinical need, necessitating the development of age-appropriate therapies with an acceptable safety profile, e.g. with all-trans retinoic acid (ATRA). As histone demethylase LSD1 (KDM1A) is a rational therapeutic target in AML, we conducted a phase I trial with the LSD1 inhibitor tranylcypromine (TCP, dose levels [DL] 20, 40, 60, 80mg p.o. d1-28) combined with fixed-dose ATRA (45mg/m2 p.o. d10-28) and low-dose cytarabine (LDAC, 40mg s.c. d1-10). The primary endpoint was dose limiting toxicity (DLT) in the first 28 days of treatment. The aim was the determination of the maximum tolerated dose (MTD). Enrollment into DLs was performed using the rolling six design. Twenty-three patients with R/R AML and 2 with relapsed MDS were accrued, with a median age 75 years (range 62-84), after a median of two prior treatment lines (range, 1-5). Three, 6, 6 and 10 patients were allocated to DL 20, 40, 60, and 80 mg TCP, respectively, with 3, 12, 6 , 4 patients achieving the respective dose of 20, 40, 60, and 80 mg, and 3 patients on each DL being fully evaluable for MTD. TCP was administered for a median of 39.5 days (range 11-228), for >60 days in 30% of patients. No dose-limiting toxicities (DLTs) were observed at any DL, MTD could not be established. Most common adverse events > grade 3 occurring in >10% of patients were: pneumonia (16%) and febrile neutropenia (12%). No differentiation syndrome occurred. Two patients attained a partial remission; stable disease was achieved in 10 of 22 evaluable patients. Median overall survival was 62 days (range 14-325). Accompanying studies included pharmacokinetics, serial determinations of fetal hemoglobin and genes known to be regulated by LSD1 or ATRA, such as CD86, CD38 and GFI1B. Patients’ quality of life, anxiety and depression were determined before and after treatment. In conclusion, the combination of TCP with ATRA and LDAC was well feasible, even at the highest DL. Almost half of the patients attained stable disease, indicating limited cross-resistance with prior HMA treatment. Hence, studies with more potent LSD1 inhibitors appear warranted.
2025-05-01 | GSE277031 | GEO
Project description:Chimeric antigen receptor anti-CD19 (CAR19)-T cell immunotherapy-induced clinical remissions in CD19+ B cell lymphomas are often short-lived. We tested whether CAR19-engineering of the CD1d-restricted invariant NKT (iNKT) cells would result in enhanced anti-lymphoma activity. CAR19-iNKT cells co-operatively activated by CD1d- and CAR19-CD19-dependent interactions are more effective than CAR19-T cells against CD1d-expressing lymphomas in vitro and in vivo. The swifter in vivo anti-lymphoma activity of CAR19-iNKT cells and their enhanced ability to eradicate brain lymphomas underpinned an improved tumor-free and overall survival. CD1d transcriptional de-repression by all-trans retinoic acid results in further enhanced cytotoxicity of CAR19-iNKT cells against CD19+ chronic lymphocytic leukemia cells. Thus, iNKT cells are a highly efficient platform for CAR-based immunotherapy of lymphomas and possibly other CD1d-expressing cancers.
| EGAS00001003176 | EGA
Project description:A phase I trial of a SRC kinase Inhibitor, dasatinib, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer. Background: We conducted a phase I study of dasatinib, an oral SRC tyrosine kinase inhibitor, in combination with paclitaxel and carboplatin in advanced and recurrent epithelial ovarian cancer (EOC). Methods: The primary objective was to determine the maximum tolerated dose (MTD). Secondary objectives included toxicity, response rate (RR), pharmacokinetics and pharmacodynamics. Based on the 3+3 design, cohorts of 3-6 pts received paclitaxel 175 mg/m2 and carboplatin AUC 6 every three weeks with escalating doses of dasatinib (100, 120, 150 mg daily), followed by an 8 patient expansion cohort. Results: Twenty patients were enrolled between 06/07 and 12/09. The median age was 61 yrs (42-82) with a median of 2 prior regimens (0-6), and 71% had platinum-sensitive disease. There were 3-6 pts in each cohort, and 8 in the expansion cohort. Pharmacokinetics were observed over the first 2 cycles of therapy. One DLT was observed in the 100 mg dasatinib cohort (grade 3 myalgia. Other toxicities in all cycles included neutropenia (95% grade 3-4), thrombocytopenia (35% grade 3-4), and fatigue (10% grade 3). The RR was 45% (complete responses, 3/18(17%); partial responses, 5/18(28%)) and 56% (10/18) had stable disease. The PFS6-month actuarial estimate was 86%. The median PFS and OS were 7.8 and 16.2 months, respectively. Conclusions: Due to the high incidence of myelosuppression with subsequent cycles the recommended phase II dose is 150 mg daily of dasatinib in combination with paclitaxel and carboplatin. The combination was safe with evidence of clinical activity in advanced EOC. Global profiles of expression were characterized using unsupervised clustering methods and gene- and pathway-analyses of differential expression.
2012-04-11 | E-GEOD-37180 | biostudies-arrayexpress
Project description:Clinical trials of MSCs in the treatment of OA have been carried out and good results have been obtained. However, these data on the dose of transplanted cells, the number of transplants, the therapeutic effect especially cartilage regeneration and safety are incomplete. Therefore, we constructed a cynomolgus macaque model consistent with the pathogenesis of OA. We have also established clinical-grade human umbilical cord-derived mesenchymal stem cell line. We selected two cell doses (2.5*10e7 cells per knee and 5*10e6 cells per knee, respectively) to assess differences in treatment effects and to assess the systemic safety of MSC therapy. High-dose hUC-MSCs can regenerate cartilage, increase joint space, and improve bone condition by ultrasound and MRI scans. But low-dose hUC-MSCs simply prevented further deterioration of the joint
2024-05-01 | GSE250569 | GEO