Ctcl
3 results on this topic.
Research Papers
A Phase I Trial Anti-CC Chemokine Receptor 4 Chimeric Antigen Receptor T Cells (CCR4 CAR T Cells) for CCR4 Expressing T-cell Malignancies Including Peripheral T-cell Non-Hodgkin Lymphoma (PTCL) and Cutaneous T-cell Non-Hodgkin Lymphoma (CTCL)
Background: Chemokine receptor 4 (CCR4) is a protein that is found on the surface of certain T-cell lymphoma cells and is common in mature T-cell cancers. White blood cells can be changed with molecules called anti-CCR4 to express a chimeric antigen receptors (CAR), which is a molecule that directs a white blood cell to attack other cells. The CAR in this study attacks the CCR4 protein found on your T-cell lymphoma. This type if therapy is called gene therapy. Gene therapy involves a person s own white blood cells modified to target cancer cells. More research is needed to find out if gene therapy can treat T-cell cancers and do it safely. Objective: To test safety of giving people with certain mature T-cell lymphomas their own white blood cells modified with anti-CCR-4 CAR. Eligibility: People aged 18 and older with certain mature T-cell lymphomas that have not responded to or have come back after treatment. They must have a T-cell lymphoma that has CCR4 on the surface of the cancer cells. Design: Participants will be screened. They will have a medical history and physical exam. Tests of blood, urine, and heart and lung function will be done. Participants will have tests: Computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging scans: They will lie on a table that slides into a donut-shaped machine or a tube. Pictures of the inside of the body will be taken. Before the PET scan, they will get an injection of radioactive fluid in a vein in the arm. Before the MRI, they may get a contrast dye injected through a vein (IV) in the arm. A biopsy of the tumor may be taken. A bone marrow sample may be taken from the hip: The area will be numbed and a large needle inserted through the skin. Leukapheresis will be done to obtain T-cells that will be genetically modified to express anti-CCR4 CARs on T-cells: Blood is drawn through an IV in one arm, circulated through a machine, and then returned through an IV in the other arm. Chemotherapy drugs will be given in an IV to prepare the body to accept the modified CAR T cells. The modified cells will be given in an IV. Participants will be followed for 15 years: This will require blood tests over the first 1-2 years followed by yearly visits and possibly telehealth updates. Phase: PHASE1 Status: RECRUITING Conditions: Relapsed and/or Refractory Mature T Cell Malignancy; Peripheral T-Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Hepatosplenic T-cell Lymphoma; Monomorphic Epithelialtropic Intestinal Lymphoma; Enteropathy Associated T-cell Lymphoma; Cutaneous T-Cell Lymphoma; Mycosis Fungoides; Subacute Panniculitis-like T-cell Lymphoma Interventions: Cyclophosphamide; Fludarabine; Autologous CCR4 CAR T cells
Multi-omic Study of Cutaneous T-Cell Lymphoma Reveals Single Cell Clonal Evolution in Progression and Therapy Resistance
Cutaneous T-cell lymphoma (CTCL) remains a challenging disease due to its significant heterogeneity, therapy resistance, and relentless progression. Multi-omics technologies offer the potential to provide uniquely precise views of disease progression and response to therapy. We present here a comprehensive multi-omics view of CTCL clonal evolution, incorporating exome, whole genome, epigenome, bulk, single cell (sc) TCR, and scRNA sequencing of 99 clinically annotated serial skin, peripheral blood, and lymph node samples from 34 CTCL patients. We leveraged this extensive dataset to define the molecular underpinnings of CTCL progression in individual patients at single cell resolution with the goal of identifying clinically useful biomarkers and therapeutic targets. Our studies identified recurrent progression-associated clonal genomic alterations; we highlight mutation of CCR4, PI3K signaling, and PD-1 checkpoint pathways as evasion tactics deployed by malignant T-cells. We identified a gain of function mutation in STAT3 (D661Y) and demonstrated by CUT&RUN- and RNA-seq that it enhances binding to and transcription of genes in Rho GTPase pathways. With our previous work implicating this pathway in HDACi-resistant CTCL, these data provide further support for a previously unrecognized role for Rho GTPase pathway dysregulation in CTCL progression. Recurrent progression-associated mutations were common in the epigenetic modifier EZH2, suggesting that EZH2 inhibition may benefit patients with CTCL. Our findings support an approach in which genomic analysis is widely utilized for improved disease monitoring, biomarker-informed clinical trial design, and genome-guided therapeutic decision making. Moreover, these molecular changes present new opportunities for therapeutic targeting in this challenging and incurable cancer.