Clonal Evolution
6 results on this topic.
Research Papers
Targeted CD22/CD19 CAR-T Therapy for Consolidation in Standard-Risk B-ALL
This is a single-center, open-label, single-arm prospective study designed to evaluate the safety, tolerability, and efficacy of dual-target CD22/CD19 chimeric antigen receptor (CAR)-T cell therapy as consolidation treatment in patients with standard-risk B-cell acute lymphoblastic leukemia (B-ALL) in remission. Eligible patients will undergo leukapheresis for CAR-T cell manufacturing, followed by lymphodepleting chemotherapy and CAR-T cell infusion. Patients will be closely monitored for safety, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), hematologic toxicity, and infections. Efficacy endpoints include event-free survival (EFS), overall survival (OS), progression-free survival (PFS), relapse rate, and mortality. Exploratory analyses will assess CAR-T cell expansion kinetics and clonal evolution. The total follow-up duration is planned to be 2 years. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: B-cell Acute Lymphoblastic Leukemia Interventions: CD22/CD19 Dual-Target CAR-T Cells
Exploratory Study of CD22/CD19 Dual-Target CAR-T Cell Therapy as Consolidation Treatment After First Remission in High-Risk B-Cell Acute Lymphoblastic Leukemia
This single-center, open-label, single-arm, prospective study will evaluate the safety, tolerability, and efficacy of CD22/CD19 dual-target CAR-T cell therapy as consolidation treatment in patients with high-risk B-cell acute lymphoblastic leukemia (B-ALL) who have achieved first remission after standard induction therapy and consolidation chemotherapy. Approximately 30 patients will be enrolled. Participants will undergo screening, cell collection for CAR-T manufacturing, lymphodepleting chemotherapy, and subsequent CAR-T cell infusion, followed by scheduled safety and efficacy follow-up. Safety assessments will include monitoring for cytokine release syndrome, neurotoxicity, hematologic toxicity, organ toxicity, infections, and other adverse events. Efficacy assessments will include event-free survival, overall survival, progression-free survival, duration of response, relapse, and mortality. Exploratory analyses will assess CAR-T cell kinetic characteristics and clonal evolution after treatment. Phase: PHASE1, PHASE2 Status: RECRUITING Conditions: B-cell Acute Lymphoblastic Leukemia Interventions: CD22/CD19 Dual-Target CAR-T Cells
Bone Marrow Stem Cell Connexins: Misconceptions and New Insights.
Hematopoietic regeneration requires coordinated activation of hematopoietic stem and progenitor cells (HSPCs) and adaptive remodeling of the bone marrow (BM) microenvironment to meet extreme metabolic and oxidative demands imposed by cytotoxic injury, transplantation, and inflammation. While soluble factors and cytokine signaling are central to this process, emerging evidence identifies direct intercellular communication as a critical regulatory layer in stress hematopoiesis. Connexins, particularly Connexin-43 (Cx43), form an evolutionarily conserved communication network that integrates metabolic coupling, redox buffering, and organelle dynamics across hematopoietic and stromal compartments. Beyond canonical gap junction channel activity, connexins exert non-junctional, compartment-specific functions through cytoplasmic, nuclear, and mitochondrial pools that regulate signaling scaffolds, transcriptional programs, cytoskeletal organization, mitochondrial dynamics, calcium homeostasis, and bioenergetics. In HSPCs, mitochondrial Cx43 functions as a metabolic checkpoint that preserves regenerative capacity by supporting oxidative phosphorylation, limiting chronic AMPK activation, maintaining fusion-fission balance, and preventing mitochondrial Ca²⁺ overload. In parallel, Cx43 enables mitochondrial transfer from donor HSPCs to stromal niche cells, restoring stromal metabolic competence and promoting effective niche repair and engraftment. Dysregulation of connexin networks contributes to marrow failure, clonal evolution, leukemic niche remodeling, and chemoresistance, highlighting their context-dependent roles in health and disease. This review synthesizes advances in connexin biology in hematopoiesis, reframes connexins as integrators of metabolic and regenerative signaling rather than passive conduits, and defines emerging translational opportunities. Isoform- and compartment-specific targeting of connexin pathways offers a therapeutic strategy to enhance hematopoietic recovery, preserve long-term stem cell function, and disrupt pathological niche support in hematologic malignancies.
Evolution of tumor subclones and T-cell dynamics underlie variable ibrutinib responses in Waldenström macroglobulinemia
To elucidate the molecular basis underlying differential response and resistance to ibrutinib in Waldenström's macroglobulinemia (WM), we conducted a prospective phase II trial (ClinicalTrials.gov; NCT02604511) of ibrutinib monotherapy in treatment-naïve patients. Seventy-four sequential bone marrow (BM) aspirates from 17 patients, collected from baseline through 48 treatment cycles, were profiled using single-cell multi-omics. BM cells segregated primarily into B/plasma cell and T-cell compartments. Longitudinal clonal tracking of malignant B/plasma cells identified three distinct evolutionary patterns: "evolution" (early clone contraction with late clone expansion and increasing genomic complexity), "devolution" (early clone expansion with late clone contraction and genomic simplification), and "no-evolution" (stable clonal architecture). The "evolution" pattern was strongly associated with disease progression, whereas "devolution" correlated with durable clinical response. Transcriptomic profiling of resistant clones enabled development and validation of the Waldenström's Ibrutinib Prediction (WIP) score, which predicted treatment response at baseline. Within the WIP signature, LYN emerged as a key regulator; LYN knockdown or inhibition significantly increased WM cell sensitivity to ibrutinib, suggesting a rational combinatorial strategy. In parallel, GZMB⁺ CD8⁺ effector-memory (TEM) cells expanded post-treatment in progressing patients and co-existed with tumor "evolution". These cells exhibited persistently impaired cytotoxic programs (e.g., GNLY), a de-differentiated memory-like state, elevated PDCD1 expression, and reduced TCR diversity. Together, this study provides the first single-cell framework of tumor clonal evolution and T-cell dysfunction under ibrutinib in WM; introduces the WIP score as a predictive biomarker for treatment response; and identifies actionable tumor-intrinsic and immune mechanisms driving resistance.
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.