Genetically modified T cells expressing chimeric antigen receptors (CARs) manufactured ex vivo have demonstrated high efficacy in patients with lymphoid hematologic malignancies, but their logistic complexity limits pati...Genetically modified T cells expressing chimeric antigen receptors (CARs) manufactured ex vivo have demonstrated high efficacy in patients with lymphoid hematologic malignancies, but their logistic complexity limits patient access. In vivo approaches generate the CAR-expressing T cells within the body but may have their own challenges. Recent clinical reports provide proof-of-concept for the feasibility and therapeutic potential of in vivo CAR gene delivery. We summarize clinical evidence and discusses the critical technical, biological, and safety considerations of this approach.
The BCL-2 inhibitor venetoclax has shown promise in acute lymphoblastic leukemia (ALL), but its role in first-line therapy for newly diagnosed (ND) Philadelphia chromosome-negative (Ph⁻) ALL is undefined. In this prospec...The BCL-2 inhibitor venetoclax has shown promise in acute lymphoblastic leukemia (ALL), but its role in first-line therapy for newly diagnosed (ND) Philadelphia chromosome-negative (Ph⁻) ALL is undefined. In this prospective phase 2 study, 167 adolescents and adults (aged 14-60 years) with ND Ph⁻ ALL received venetoclax combined with pediatric-inspired chemotherapy. The primary endpoint was the rate of measurable residual disease (MRD) negativity by multiparameter flow cytometry (MFC) after induction. The complete remission rate was 91.0%, and 73.0% of responders achieved MFC-MRD negativity, meeting the primary endpoint. After a median follow-up of 19.3 months, median overall and disease-free survival were not reached; estimated 2-year survival rates were 78.5% and 76.7%, respectively. Propensity score-matched analysis confirmed superior survival compared with historical chemotherapy-only controls. Grade ≥ 3 adverse events were primarily hematologic toxicities and infections, with an incidence comparable to that of the historical cohort. These results demonstrate that adding venetoclax to pediatric-inspired chemotherapy significantly improves MRD response and survival outcomes in ND Ph⁻ ALL, with a manageable safety profile. This trial was registered with ClinicalTrials.gov under the identifier NCT05660473.
Peripheral T-cell lymphoma (PTCL) represents a highly heterogeneous and aggressive lymphoid neoplasm, lacking pathogenic biomarkers of RNA modification with therapeutic potential. IGF2BP2 is recognized as an N6-methylade...Peripheral T-cell lymphoma (PTCL) represents a highly heterogeneous and aggressive lymphoid neoplasm, lacking pathogenic biomarkers of RNA modification with therapeutic potential. IGF2BP2 is recognized as an N6-methyladenosine (m6A) reader, critically involved in oncogenesis. In this study, we observed consistently high expression of IGF2BP2 across common nodal PTCL subtypes in three independent external cohorts, which was further confirmed in our RNA sequencing (RNA-seq) dataset of 196 patients with newly diagnosed PTCL. Both in vitro and in vivo, IGF2BP2 promoted tumor cell growth and inhibited CD8+ T cell infiltration within the tumor microenvironment. Mechanistically, IGF2BP2 bound to endosome-related genes (RAB4, VPS35, RAB9, and STAM) to maintain their stability, resulting in enhanced endocytic activity and increased internalization of membrane proteins, and ultimately induced tumor cell proliferation and inhibition of CD8+ T cell-mediated tumor cytotoxicity. The relationship between IGF2BP2 and endocytosis-associated genes was confirmed by RNA-seq data of PTCL patients. IGF2BP2 as an upstream regulator of both tumor growth and immune suppression was further demonstrated by patient-derived xenograft models and co-culture system established by tumor samples of PTCL patients and peripheral blood mononuclear cells. Of note, therapeutic targeting of IGF2BP2 with CWI1-2 suppressed endocytosis and impeded tumor growth in both cell lines and patient-derived xenograft models. Collectively, our findings highlight IGF2BP2 as a clinically relevant oncogenic driver in PTCL that integrates tumor-intrinsic growth signals with immune evasion through endocytosis-centered regulation, providing a novel therapeutic rationale for RNA modification-based strategies that concurrently target tumor cells and tumor microenvironment.
FLT3 internal tandem duplications (FLT3-ITD) are major genetic events in acute myeloid leukemia (AML). Although the clinical impact of FLT3-ITD "macroclones" (allelic ratio [AR] ≥0.05) is well established, the significan...FLT3 internal tandem duplications (FLT3-ITD) are major genetic events in acute myeloid leukemia (AML). Although the clinical impact of FLT3-ITD "macroclones" (allelic ratio [AR] ≥0.05) is well established, the significance of low-level FLT3-ITD subclones ("microclones") remains uncertain. We conducted a post-hoc analysis of 1 733 patients with newly diagnosed AML enrolled in the BIG-1 trial (NCT02416388). Using next-generation sequencing (NGS), we detected FLT3-ITD microclones (AR between 0.0004 and 0.05) in 17.4% of patients without FLT3-ITD macroclones. Microclones and macroclones (low and high AR) were independently associated with increased relapse risk (sHR 1.50 [95% CI 1.18-1.91], 1.98 [1.50-2.62], and 2.33 [1.69-3.22], respectively) after adjustment for age, white blood cell count, other gene mutations, midostaurin treatment, and allogeneic hematopoietic stem cell transplantation. At 2 years, cumulative incidence of relapse reached 42.5% (95% CI 37.0-47.9) in patients with macroclones, 45.1% (38.3-51.6) in patients with microclones, and 29.4% (26.6-32.3) in patients without FLT3-ITD. In NPM1-mutated AML, both microclones and macroclones were associated with higher levels of measurable residual disease (MRD) and increased relapse risk, without independent impact on overall survival after adjustment for MRD. Analysis of paired samples further revealed that 41.8% of relapses in patients with FLT3-ITD microclones at diagnosis were associated with a macroclone at relapse. These findings challenge current risk stratification models and support the integration of NGS-based FLT3-ITD detection into the diagnostic and prognostic workflow for AML. Prospective trials addressing the management of patients with FLT3-ITD microclones are warranted, as is their consideration in future ELN guidelines.
We identified biallelic loss-of-function BPNT1 mutations in three patients with recurrent vitamin B12-dependent megaloblastic anemia. Mechanistically, BPNT1 deficiency caused accumulation of 3'-phosphoadenosine 5'-phosph...We identified biallelic loss-of-function BPNT1 mutations in three patients with recurrent vitamin B12-dependent megaloblastic anemia. Mechanistically, BPNT1 deficiency caused accumulation of 3'-phosphoadenosine 5'-phosphate (PAP), impaired ribosome biogenesis, and reduced ileal expression of the cubam receptor complex in Bpnt1-null mice.
Creamer JP, Ray S, Stewart S
… +16 more, Gulsuner S, Saliba AN, Wu J, Huang FY, Leppä AM, Wang B, Abbas HA, Abkowitz JL, Appelbaum JS, Kaufmann SH, Becker PS, Trumpp A, Jobanputra V, Fang M, Swisher EM, Doulatov S
Clonal acquisition of multiple chromosomal abnormalities in hematopoietic stem and progenitor cells (HSPCs) is a hallmark of high-risk acute myeloid leukemias with complex karyotype (AML-CK). AML-CK is associated with TP...Clonal acquisition of multiple chromosomal abnormalities in hematopoietic stem and progenitor cells (HSPCs) is a hallmark of high-risk acute myeloid leukemias with complex karyotype (AML-CK). AML-CK is associated with TP53 mutations and chromosome 5q deletions (del5q); however, the drivers and clonal trajectories of aneuploid evolution in HSPCs remain unknown. We have developed a patient-derived induced pluripotent stem cell (iPSC) model in which preleukemic HSPCs clonally evolve to distinct, highly aneuploid states following transient mitotic inhibition. By tracking chromosome evolution at single cell resolution, we show that TP53-mutant HSPCs with del5q, but not TP53- mutation alone, evolved complex chromosomal changes. Clonal evolution was marked by stepwise acquisition of numerical and structural chromosome changes seen in AML-CK patients, with individual abnormalities conferring fitness advantage. iPSC-derived aneuploid HSPCs and primary AML-CK patient samples exhibited a conserved gene expression signature marked by upregulation of PTEN, cohesins, and anti-apoptotic factor BCL2, indicative of a shared aneuploid cell state in HSPCs. Clinical BCL2 inhibitor venetoclax eradicated BCL2-dependent aneuploid clones, with resistant clones undergoing a lineage switch to upregulate alternative BCL2 factors. In summary, we demonstrate that mutant TP53 and del5q drive chromosome evolution marked by stepwise acquisition of individual abnormalities. Moreover, aneuploid HSPCs exhibit a shared gene expression state which confers unique targetable therapeutic vulnerabilities in AML-CK.
Uncertainty remains about whether sickle cell trait (SCT) shortens life or predispose to disease. Therefore, we examined whether SCT-carriers had increased risk of death or diseases linked to SCT. We studied 467,779 gene...Uncertainty remains about whether sickle cell trait (SCT) shortens life or predispose to disease. Therefore, we examined whether SCT-carriers had increased risk of death or diseases linked to SCT. We studied 467,779 general population individuals from the UK Biobank. All had whole-exome sequencing performed and were followed prospectively for a median of 15 years. Individuals with SCT (n=1,253) were not at increased risk of all-cause death (hazard ratio[HR]:1.04;95%CI:0.84-1.29), cardiovascular death (1.34;0.90-2.00), or for having myocardial infarction (0.72;0.42-1.24), ischemic stroke (1.30;0.88-1.94), pulmonary embolism (1.29;0.84-1.99), or heart failure (0.79;0.55-1.14) compared to non-carriers. However, SCT-carriers had increased risk of diabetes (HR:1.30;95%CI:1.12-1.50), chronic kidney disease (HR:1.46;95%CI:1.18-1.80), and hypertension (odds ratio:1.24;95%CI:1.08-1.42). Surprisingly, risk of cardiovascular death was increased in SCT-carriers with diabetes when compared to non-carriers with diabetes (HR:2.17;95%CI:1.14-4.12). To examine whether selection bias may explain why previous studies based on hospital-diagnosed SCT found increased risk of cardiovascular disease, we repeated our analyses using hospital diagnoses of SCT from national registries, instead of defining SCT from genotyping. Individuals registered as SCT-carriers in hospital registries had markedly increased risk of all-cause death (HR:2.24;95%CI:1.42-3.52) and ischemic stroke (2.92;1.30-6.60), likely due to selection bias. In conclusion, SCT-carriers were not at increased risk of all-cause death or cardiovascular disease.
Zhou D, Qi Y, Ma S
… +21 more, Sun Q, Gu W, Xia J, Zhang X, Chen W, Cheng H, Qi K, Zhu F, Xia F, Zhu L, Li H, Zhang H, Yan D, Qiu T, Zhang Y, Peng S, Sang W, Li D, Chang AH, Pan B, Yan Z
Relapsed or refractory multiple myeloma (RRMM) patients with extraosseous extramedullary disease (EMD) have inferior outcomes and lack effective therapies. We developed anti-BCMA/GPRC5D bispecific chimeric antigen recept...Relapsed or refractory multiple myeloma (RRMM) patients with extraosseous extramedullary disease (EMD) have inferior outcomes and lack effective therapies. We developed anti-BCMA/GPRC5D bispecific chimeric antigen receptors (CARs) to investigate the activity and safety of the CAR T cells in patients with extraosseous EMD. In this single-arm, open-label, phase 2 trial, we enrolled 37 RRMM patients with extraosseous EMD, and anti-BCMA/GPRC5D bispecific CAR T cells were administered at 2·0×10⁶ CAR T cells per kilogram. At a median follow-up of 10·1 months (IQR 6·4-19·1), 36 (97%) of 37 patients obtained an overall response and measurable residual disease (MRD) negativity, including 16 (43%) with stringent complete response (sCR). The median progression-free survival (PFS) was 5·8 months (95% confidence interval [CI]: 2·2-9·4), and the median overall survival (OS) was not reached. The most common grade 3 or worse adverse events were hematologic toxicities (except lymphopenia) (37/37). 27 (73%) patients experienced cytokine release syndrome (CRS), of which all cases were grade 1 or 2. Two (5%) patients had grade 1 or 3 immune effector cell-associated neurotoxicity syndrome (ICANS). These findings support that anti-BCMA/GPRC5D bispecific CAR T cells induced a high response rate in RRMM patients with extraosseous EMD, and the safety profile was manageable. This trial was registered with ClinicalTrials.gov (NCT05509530) and is ongoing.