Research Appraisals
Evidence-based critical appraisals of the latest medical research, systematically evaluated using Oxford CEBM methodology.
Showing 4 appraisals
Journal for immunotherapy of cancer
Clinical outcomes and spatial transcriptomic profiles of CD19/20 CAR-T therapy in relapsed or refractory B-cell non-Hodgkin's lymphoma
BACKGROUND: Relapsed or refractory (R/R) B-cell non-Hodgkin's lymphoma (B-NHL) remains a major therapeutic challenge despite CD19-directed chimeric antigen receptor (CAR) T-cell therapies, with treatment failure often driven by antigen escape and limited CAR-T persistence. Dual targeting of CD19 and CD20 may mitigate antigen loss. We conducted an expanded phase I/II study of bispecific CD19/20 CAR-T cells and incorporated spatially resolved single-cell transcriptomics to evaluate tumor-intrinsic and microenvironmental factors of clinical response. METHODS: Patients with R/R B-NHL received CD19/20 CAR-T cells following lymphodepletion. Efficacy, safety, CAR-T expansion/persistence, and B-cell reconstitution were assessed. Pretreatment tumor biopsies from five patients with divergent outcomes underwent spatial single-cell transcriptomic profiling. RESULTS: 32 patients were treated, including 24 with diffuse large B-cell lymphoma. Among 31 evaluable patients, the best overall response rate was 74%, including 58% achieving complete remission. Median progression-free and overall survival were 6.8 and 22.1 months, respectively. Response rates were higher in patients with normal lactate dehydrogenase. CAR-T expansion peaked on days 7-17, and persistence exceeded 500 days in long-term responders. Cytokine release syndrome occurred in 53% (12% grade ≥3) and immune effector cell-associated neurotoxicity syndrome in 9% (all grade 3), with no lasting deficits. Spatial profiling identified two dominant tumor architectures: (1) a B-cell-dominant phenotype, in which durable remission was associated with heightened apoptotic competence in malignant B cells, and (2) a fibroblast-enriched and monocyte/macrophage-enriched phenotype, in which response correlated with a chemokine-rich, T-cell-permissive microenvironment. CONCLUSIONS: Bispecific CD19/20 CAR-T therapy produced durable clinical activity with manageable toxicity. Spatial single-cell analysis reveals distinct tumor-intrinsic and microenvironmental features associated with CAR-T responsiveness, providing a spatially informed framework for understanding heterogeneous therapeutic outcomes. TRIAL REGISTRATION NUMBER: NCT04723914.
18 May 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
First-in-Human Study of IL15-Activated Cytokine-Induced Killer Cells After Allogeneic HCT Shows Durable Remission and Serotherapy-Associated Immune Reconstitution in Leukemia
PURPOSE: Patients with high-risk (HR) leukemia remain at substantial risk of early relapse, treatment-related toxicity, and poor survival, underscoring the need for effective relapse prevention therapies. To our knowledge, this first-in-human, disease burden-guided study evaluated the feasibility, safety, and efficacy of donor-derived allogeneic interleukin-15-activated cytokine-induced killer cells (IL15-CIK) combining T-cell and natural killer cell properties for post-transplant disease control. METHODS: In a prospective, multicenter phase I/II trial (EudraCT 2013-005446-11) and an identically designed pilot study, 53 adult and pediatric patients with HR leukemia received 56 courses of IL15-CIK monotherapy after human leukocyte antigen (HLA)-matched or HLA-mismatched transplantation. Treatment intent was categorized as consolidation (13%), preemptive (61%), or salvage (27%) with 169 infusions administered as a single dose (29%) or according to adaptable dose-escalation regimens (71%). RESULTS: Acute graft-versus-host disease (GVHD) grades 1-2 and grade 3 occurred in 27% and 4% of cases, respectively; no extensive chronic GVHD or treatment-related mortality was observed. IL15-CIK-associated adverse events were predominantly mild. Disease clearance, assessed by the cumulative incidence of complete molecular remission, peaked at day 700, reaching 74% in the preemptive and 13% in the salvage setting. The five-year progression-free survival was 50% overall and highest (69%) in pediatric acute myeloid leukemia. The five-year overall survival (OS) was 71% in the consolidation, 61% in the preemptive, and 20% in the salvage setting. Multivariable analysis demonstrated significantly lower relapse rates with Campath compared with ATG, superior OS in myeloid malignancies, and reduced IL15-CIK efficacy in advanced disease. The median follow-up was 7.3 years. CONCLUSION: IL15-CIK monotherapy is feasible and safe and demonstrates promising relapse-preventive activity after hematopoietic stem-cell transplantation. Clinical outcomes are strongly influenced by disease burden at treatment initiation and previous serotherapy, supporting optimized patient selection and timing in future post-transplant immunotherapeutic strategies.
13 May 2026
Read appraisal →Cancer immunology, immunotherapy : CII
A phase I, single-arm, open-label, dose-escalation, multicenter study of SAR445419, an off-the-shelf, ex vivo expanded allogeneic natural killer cell product, in participants with relapsed or refractory acute myeloid leukemia
BACKGROUND: SAR445419 is an investigational, off-the-shelf, allogeneic NK cell therapy derived from donor peripheral blood mononuclear cells and expanded ex vivo using PM21 particles. METHODS: This multicenter, Phase 1, dose-escalation study (NCT05712278) evaluated optimal dose(s), safety, and tolerability of SAR445419 in adults (aged ≥ 18 years) with relapsed/refractory acute myeloid leukemia (R/R AML). Following lymphodepleting chemotherapy (fludarabine 30 mg/m2/day and cytarabine 2 g/m2/day for 5 days), participants received six intravenous SAR445419 (1 × 109 and 3 × 109 NK cells/dose) doses, starting with the lower dose. The primary endpoint was the incidence of dose-limiting toxicities (DLTs), and key secondary endpoints included adverse events (AEs), hematological recovery, hematopoietic stem cell transplantation, and response rate. RESULTS: Of the 12 planned participants, 7 patients were enrolled, of whom 6 received SAR445419 before sponsor decided early study termination for reasons unrelated to safety or efficacy. No DLTs were observed. All participants experienced treatment-emergent adverse events (TEAEs); six had grade ≥ 3 TEAEs; and four had serious adverse events (SAEs). Two SAR445419-related SAEs (infusion-related reactions: both grade 2) were managed with supportive care. All participants experienced grade 3 anemia and grade 4 thrombocytopenia and neutropenia. Five deaths were reported, all due to disease progression, none related to SAR445419. No clinical responses were observed. CONCLUSIONS: This study demonstrated the overall safety of off-the-shelf ex vivo expanded allogeneic NK cells in patients with R/R AML. The successful manufacturing and distribution support the feasibility of donor-derived off-the-shelf NK cells in a clinical setting. Further investigations are required to improve the clinical efficiency of NK cells.
12 Apr 2026
Read appraisal →Journal of clinical oncology : official journal of the American Society of Clinical Oncology
Phase II Study of BCMA Chimeric Antigen Receptor T-Cell Therapy in Patients With Newly Diagnosed Multiple Myeloma Ineligible for or Not Proceeding to Autologous Stem-Cell Transplantation (CAREMM-001)
PURPOSE: Patients with newly diagnosed multiple myeloma (NDMM) who are ineligible for or not proceeding to autologous stem-cell transplantation (ASCT)-often because of age or frailty-have limited opportunities to receive multiple effective lines of therapy, underscoring the need for novel frontline strategies. METHODS: In this phase II, open-label, single-arm trial (ClinicalTrials.gov identifier: NCT05860036), patients received 3-4 cycles of protocol-allowed induction, followed by B-cell maturation antigen (BCMA) CAR-T infusion, and subsequent consolidation and lenalidomide maintenance. The primary end point was the rate of minimal residual disease (MRD) negativity (10-5) at Month three postinfusion. RESULTS: Between April 4, 2023, and December 26, 2024, 43 patients were screened, 40 were enrolled, and 36 received infusion (median age, 68 years [46-75]). In the infused cohort, the MRD negativity rate at Month three postinfusion was 100% (36 of 36; 95% CI, 90.3 to 100.0). With a median follow-up of 15.8 months postinfusion (range, 4.3-26.0), no MRD recurrence was observed. The complete response rate (CRR) increased from 33.3% (12 of 36; 95% CI, 18.6 to 51.0) preinfusion to 69.4% (25 of 36; 95% CI, 51.9 to 83.7) at Month 3% and 94.4% (34 of 36; 95% CI, 81.3 to 99.3) at last follow-up. The most common grade 3 to 4 adverse events were transient cytopenia, including lymphopenia (100%), neutropenia (88.9%), leukopenia (80.6%), thrombocytopenia (19.4%), and anemia (8.3%). Cytokine release syndrome occurred in 52.8% of patients (all grade 1 to 2), immune effector cell-associated neurotoxicity in 5.6% (all grade 1), and infections in 30.6% (grade ≥3 in 19.4%). No deaths or disease progressions occurred by cutoff. CONCLUSION: Frontline BCMA CAR-T therapy induces deep, rapid, and durable remissions with a manageable safety profile in the NDMM population ineligible for or not proceeding to ASCT. These findings support its investigation as a potentially practice-changing strategy for this population.
11 Apr 2026
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