Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of refractory hematologic malignancies, but its long-term safety has become an increasing concern. Secondary primary malignancies (SPM) following CAR-T-cell therapy have emerged as a growing focus of clinical and translational research. Evidence to date suggests that the incidence of different types of SPMs vary, with a two-year cumulative incidence ranging from approximately 0.08% to 8% and a median time to onset of 9.7 to 26.4 months, predominantly involving myeloid malignancies such as myelodysplastic syndromes and acute myeloid leukemia, while solid tumors and rare T-cell lymphomas have also been reported. CAR transgenes have been detected in only a minority of T-cell lymphoma cases. The mechanisms involved vector-related genomic integration risks, genotoxic stress from prior chemotherapy or hematopoietic stem cell transplantation, immune dysregulation, and clonal hematopoietic expansion. Future research may focus on developing safer gene-editing technologies, moving CAR-T-cell therapy to earlier treatment lines to reduce cumulative toxicity from prior therapies, implementing genetic risk screening before treatment, and establishing long-term systematic monitoring after therapy. By optimizing full-process management, the risk of SPM can be minimized, thereby improving the long-term safety of CAR-T-cell therapy while maintaining its therapeutic efficacy.

Objective: To investigate the bystander effect of endogenous T cells within the tumor microenvironment, as well as their roles and phenotypic changes during remission and relapse in mice with B-cell lymphoma receiving CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy. Methods: At the Institute of Hematology, Xuzhou Medical University, in vitro experiments and mouse models were established using BALB/c mice to evaluate the efficacy of CD19 CAR-T cells in treating CD19(-) and CD19(+)A20 lymphomas. In the in vitro experiments, the mice were categorized into the following groups based on the type of co-cultured cells: activated T cell (n=3) and CD19-targeted CAR-T cell (n=3) groups. In the CD19(-) A20 lymphoma mouse model, the mice were assigned to the activated T-cell (n=5) and CD19 CAR-T cell treatment (n=5) groups based on the type of cells used for treatment. For the CD19(+) A20 lymphoma mouse model, the mice were divided into the activated T cell treatment (n=3-8), CD19 CAR-T cell treatment (n=14), remission (clinical score ≤ 1), and relapse (clinical score >1) groups. Therapeutic efficacy was evaluated, and flow cytometry was used to analyze the subsets, activation status, and cytokine secretion profiles of endogenous T cells at different disease states. Results: In vitro experiments demonstrated that, compared with the activated T-cell group, CD19 CAR-T cells exerted no specific cytotoxic effect on CD19(-) A20 cells [survival rates: (40.83±1.70) %vs (39.07±1.40) %, P=0.238]. However, in immunocompetent mice, compared with the activated T-cell treatment, CD19-targeted CAR-T cell therapy resulted in reduced weight [ (0.14±0.10) vs (0.81±0.24) g, P=0.002] and significantly diminished subcutaneous CD19(-) A20 tumor volume [ (335.40±130.20) vs (542.00±302.40) mm(3), P=0.004], accompanied by increased infiltration of endogenous CD3(+) T cells [ (36.34±6.53) % vs (9.49±9.42) %, P=0.001]. CD8(+) T cells exhibited increased CD69 expression [ (21.38±4.85) % vs (3.15±1.16) %, P=0.001] and a trend toward decreased expression of exhaustion-associated molecules PD-1 and TIGIT (all P value >0.05). In the mouse model of CD19(+) A20 lymphoma remission and relapse, upon disease relapse, the proportion of endogenous CD8(+) T cells in the spleen (SP) and bone marrow (BM) showed a downward trend during disease relapse compared with that during the remission period, the CD69 expression intensity decreased (CD4(+) T cell: BM: 733.20±274.40 vs 1 093.00±131.20, P=0.013; SP: 290.50±142.40 vs 478.70±63.94, P=0.018; CD8(+) T cell: BM: 1 223.00±391.50 vs 1 892.00±540.40, P=0.041; SP: 342.30±258.10 vs 500.00±113.90, P=0.325) and the secretion levels of cytokines IFN-γ, TNF-α, GM-CSF, and granzyme B were all diminished (all P value <0.05). During relapse, the proportion of effector T cell (Teff) cells decreased significantly, whereas the proportions of naive T cell (Tn) cells and memory T cell (Tm) cells increased significantly (all P value <0.05) . Conclusion: The specific cytotoxic activity of CD19-targeted CAR-T cells in vivo can activate endogenous T cells and induce a bystander effect, which non-specifically inhibits lymphoma growth. However, following disease relapse, the cytotoxic function of endogenous T cells gradually diminishes and shifts toward resting and memory phenotypes.

Objective: To evaluate the safety, pharmacokinetic profile, and preliminary efficacy of a novel lentiviral-based CD19-targeted in vivo chimeric antigen receptor T (CAR-T) cell therapy in a patient with multiply relapsed/refractory B-acute lymphoblastic leukemia (B-ALL) . Methods: A 28-year-old patient with B-ALL at the 920th Hospital of Joint Logistics Support Force, received a single intravenous infusion of a lentiviral-based CD19-targeted in vivo CAR-T product at a dose of 7×10(8) TU. The safety and pharmacokinetic profiles and disease response data were collected and analyzed. Additionally, the outcomes of the current clinical studies on vivo CAR-T cell therapy were reviewed. Results: The patient with high-risk and heavily pretreated B-ALL achieved minimal residual disease negative complete remission by day 16 post infusion, which was sustained until day 50 and enabled subsequent hematopoietic stem cell transplantation. The adverse events mainly consisted of an acute inflammatory reaction within 24 hours after infusion and cytokine release syndrome during the CAR-T expansion phase. Pharmacokinetic monitoring detected peripheral blood CAR-T cells on day 6, with a peak level of 8 629.38 cells/μl on day 14. Literature review suggested that clinical research on in vivo CAR-T cell therapy remains at an early stage, with limited evidence available, and that no prior clinical outcomes of its application in B-ALL patients were reported. Conclusion: CD19-targeted in vivo CAR-T cell therapy demonstrated manageable safety and robust in vivo expansion in our patient, enabling rapid remission and creating a critical window for transplantation. Our case preliminarily supports the feasibility and potential clinical value of in vivo CAR-T cell therapy in high-risk, heavily pretreated B-ALL patients and provides a valuable practical reference for clinical application.

Adoptive cellular therapies (ACT) have reshaped the treatment landscape of hematologic malignancies and are increasingly being explored in solid tumors. Key approaches include chimeric antigen receptor T-cell (CAR-T) therapy, which targets tumor-associated surface antigens in an HLA-independent manner, and T-cell receptor-engineered T-cell (TCR-T) therapy, which enables recognition of intracellular tumor antigens presented by major histocompatibility complex molecules. However, the application of CAR-T and TCR-T in solid tumors remains limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, manufacturing complexity, and safety concerns related to on-target/off-tumor effects and cytokine-mediated toxicities. The American Society for Clinical Oncology (ASCO) Annual Meeting is a key platform for the presentation of cutting-edge clinical data, and in this brief correspondence, we summarize the principal early-phase clinical trials with CAR-T and TCR-T for solid tumors reported at the 2026 meeting.

Currently, no immunotherapy is approved for T cell acute lymphoblastic leukemia (T‑ALL). High initial response rates to CD7‑directed chimeric antigen receptor (CAR) T cells are limited by profound T cell aplasia and CD7‑negative immune escape, underscoring the need for alternative targets. Here, we show that CD28 is overexpressed on T‑ALL blasts from children and adolescents compared with lymphoid progenitors from healthy donors and is uniformly upregulated in nodal T-follicular helper cell lymphomas (nTFHL-AI, nTFHL-F). Using CRISPR/Cas9-mediated CD28 knockout to prevent fratricide, we generate highly functional anti‑CD28 CAR T cells with selective cytotoxicity against CD28[+] T‑ALL. Anti‑CD28 CAR T cells match anti‑CD7 CAR T cells in vitro and in vivo, but cause markedly less lymphodepletion, largely sparing CD8 T cells and NK cells while preferentially depleting CD4 T cells, particularly TH2 and TH17 subsets. These findings establish CD28 as an actionable target for CAR T cell therapy of T cell malignancies.

T cell proliferative capacity and persistence determine the therapeutic efficacy of chimeric antigen receptor (CAR) T cells. However, strategies to externally enhance CAR-T cell expansion without genetic rewiring are lacking. Here, we engineer CAREp, programmable DNA-scaffolded PLGA microparticles displaying CAR-targeting antigens and CD28-costimulatory antibodies, to repeatedly stimulate human CD8[+] CAR-T cells ex vivo. CAREp sustains a-EGFR CAR-T cell expansion for over 100 days across both 4-1BBζ and CD28ζ constructs, achieving up to 10[18]-fold cumulative expansion and surpassing tumor-cell or CD3/CD28-Dynabeads stimulation. Expanded cells retain effector function and mitochondrial fitness while exhibiting clonal enrichment, initially preserved memory-associated progenitor states, delayed exhaustion, and transiently activated telomerase delaying telomere attrition. Early transcriptomic responses show coordinated activation of DNA repair, chromatin remodeling, telomere maintenance, and mitochondrial function while restricting differentiation-associated signaling programs, mirroring long-term functional outcomes. These findings demonstrate that nanoscale ligand organization synchronizes acute CAR-T signaling with durable proliferative and metabolic states.

Immunization is a cornerstone of global public health, preventing substantial morbidity and mortality worldwide. However, the long-term success of immunization programs depends not only on vaccine effectiveness but also on robust systems for monitoring and managing vaccine safety. Adverse Events Following Immunization (AEFIs), defined by the World Health Organization (WHO) as any untoward medical occurrence that follows immunization and does not necessarily have a causal relationship with vaccine use, remain an important challenge for vaccine safety surveillance and public confidence. This narrative review synthesizes evidence on the classification, biological and immunological mechanisms, clinical manifestations, surveillance, causality assessment, and public health management of AEFIs. Literature was identified through searches of PubMed/MEDLINE and Scopus, complemented by relevant grey literature from authoritative organizations, including WHO and the United States Centers for Disease Control and Prevention (CDC). The review considers evidence from both COVID-19 and non-COVID-19 vaccination programs, with emphasis on vaccine safety surveillance, pharmacovigilance, clinical assessment, and public health response. AEFIs were examined according to the WHO classification framework, comprising vaccine product-related, vaccine quality defect-related, immunization error-related, immunization anxiety-related, and coincidental events. Biological and immunological mechanisms range from expected innate inflammatory responses to rare immune-mediated and hypersensitivity reactions. Although most AEFIs are mild and self-limiting, rare serious events require timely recognition, investigation, and appropriate clinical management. Global vaccine safety monitoring capacity remains uneven, with substantial differences in reporting, surveillance infrastructure, diagnostic capacity, and health-system resources across settings. Strengthening pharmacovigilance, active and passive surveillance, healthcare worker training, causality assessment, and transparent risk communication is essential to ensure vaccine safety, sustain public confidence, and support the continued success of immunization programs worldwide.

Chimeric antigen receptor T-cell (CAR-T) therapy has transformed the treatment of hematologic malignancies, yet durable responses remain inconsistent and clinically significant toxicities persist. Emerging evidence identifies the gut microbiota as an extratumoral determinant of CAR-T efficacy, persistence, and toxicity. However, taxonomic signatures associated with clinical outcomes show limited reproducibility and are influenced by antibiotics, geography, diet, and methodological heterogeneity. Building on prior reviews addressing microbiome-CAR-T associations and CAR-T-cell immunometabolism separately, here we synthesize clinical, translational, and preclinical evidence into an integrated, metabolome-centered framework spanning the full CAR-T treatment and manufacturing trajectory. Broad-spectrum antibiotic exposure disrupts microbial metabolic output, depleting short-chain fatty acids, indole derivatives, and other bioactive metabolites, and has been associated with inferior clinical outcomes in several cohorts, although these associations are heterogeneous and may be confounded by baseline disease severity, systemic inflammation, and infection-related factors. Experimental studies further indicate that butyrate, valerate, inosine, indoles, and succinate modulate mitochondrial fitness, memory differentiation, epigenetic programming, cytotoxicity, and exhaustion through interconnected metabolic and receptor-mediated pathways. We propose that the gut microbiota acts as a distributed metabolic organ whose collective output shapes CAR-T-cell fitness and therapeutic response. This framework supports the development of metabolite-based biomarkers and therapeutic strategies, including microbiota-conscious antibiotic stewardship, ecosystem restoration, dietary or metabolite-based interventions, and ex vivo metabolic conditioning during CAR-T manufacturing. Shifting from descriptive microbiome profiling to functional metabolomics may improve both prediction and optimization of CAR-T therapy.

The metabolic interface between tumor and immune cells is an emerging determinant of immunotherapy resistance, yet its therapeutic exploitation in hepatocellular carcinoma (HCC) remains limited. Adoptive cellular immunotherapies, including NK cell infusion, tumor-infiltrating lymphocytes (TILs), and chimeric antigen receptor T (CAR-T) cells, have transformed hematologic oncology but repeatedly fail to achieve durable responses in HCC. We argue that an underappreciated driver of this resistance is the acidic tumor microenvironment (TME): hypoxia-driven glycolytic reprogramming acidifies the HCC niche through lactate and proton accumulation, lowering extracellular pH (pHe) to approximately 6.5-6.8 (measured 6.66 ± 0.19 in human HCC by CEST MRI), rewiring macrophages, neutrophils, dendritic cells, NK cells, myeloid-derived suppressor cells, and T lymphocytes toward immunosuppressive or exhausted states. Although lactate and tumor acidity have each been reviewed extensively, the specific implications of acidosis for the design and delivery of cell-based therapies remain scattered and unsynthesized, a gap of growing urgency as the first pH-targeting and acidity-armored cellular products enter clinical testing, as summarized in this review. This mini review delineates how the acidic TME is established in HCC, summarizes cell-type-specific mechanisms of acidosis-driven immune dysfunction, and critically evaluates unresolved issues: the incomplete dissociation of acidity- versus lactate-mediated effects, the metabolic double-edged sword of systemic glycolytic blockade, and the gap between preclinical pH modulation and clinical translation. We conclude that ex vivo metabolic preconditioning and acidity-responsive cell engineering, rather than systemic metabolic intervention, offer the most tractable path toward durable cellular immunotherapy in HCC.

In patients with cytokine release syndrome receiving chimeric antigen receptor (CAR) T-cell therapy, fever often leads to unnecessary use of IV antibiotics. Early antibiotic de-escalation may reduce antibiotic exposure withou.

Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infection (ALRI) in infants, with low- and middle-income countries (LMICs) bearing a disproportionately high burden. While novel RSV prophylactic products including long-acting monoclonal antibodies and a maternal vaccine are being rolled out for protecting the general infant population in high-income countries, implementation in LMICs is only expected by 2028, potentially exacerbating health inequities. We aimed to assess regional inequality in infant RSV disease burden with and without the implementation of these interventions.

Yellow fever virus (YFV) is a re- emerging mosquito- borne flavivirus that causes severe hemorrhagic fever with high case- fatality rates. Due to vaccine contraindications, incomplete immunization coverage, and the absence of approved specific antivirals, host- directed drug discovery targeting cellular machinery exploited by YFV is a critical therapeutic priority. Here, 1-[4-(2- difluoromethoxyphenyl)- 5- methylthiazol- 2- yl]- 3-(naphthalen- 1- yl)urea (DFMNTU) was synthesized, characterized by NMR, MS, and HPLC, and evaluated for antiviral efficacy against YFV strain 17 D in Vero cells. DFMNTU potently inhibited virus- induced cytopathic effects, with EC 50 values of 4.3 µg/mL (neutral red uptake) and 2. 4 µg/mL (visual CPE assessment), and corresponding cytotoxicity (CC 50) values of 22 and 13 µg/mL, yielding selectivity indices (SI) of 5. 5.2 and 5. 5.5, respectively. Machine- learning target prediction via SuperPred identified 23 putative human protein kinase targets, with casein kinase 2 (CK 2) showing the highest probability (95. 82%). Biochemical kinase profiling confirmed concentration- dependent inhibition of recombinant human CK 2 α (IC 50 = 22 ± 8 µM), whereas non- receptor tyrosine kinase ABL 1 was only weakly inhibited (20% at 20 µM). Computational molecular docking into the ATP- binding cleft of human CK 2 α (PDB ID: 4 UBA) revealed key hydrogen- bonding interactions with Lys 68 and Asp 175, along with optimal steric accommodation of the 2- difluoromethoxyphenyl ring in the adenine pocket. In silico ADMET profiling revealed high lipophilicity (MolLogP = 5. 431), low predicted aqueous solubility (MolLogS =- 7. 225), and low passive gastrointestinal absorption (SwissADME BOILED- Egg model). Extensive Structure-Activity Relationship (SAR) analysis identified the urea linker and difluoromethoxy substituent as key pharmacophores for target binding, while highlighting the hydrophobic 1- naphthyl moiety as the main driver of biopharmaceutical liabilities. DFMNTU serves as a viable host- directed antiviral hit compound, providing a clear computational and structural foundation for hit- to- lead optimization.

The COVID-19 pandemic severely disrupted routine immunization globally and across Cameroon, causing a surge in 'zero-dose' (ZD) children and exacerbating 'missed opportunities for vaccination' (MOV). This necessitated accelerated recovery initiatives like the Big Catch-Up (BCU). This study explores BCU's operationalization, implementation and sustainability in Cameroon, assessing how vertical funding interacted with national health systems to reach ZD and under immunized (UI) children. Focusing on four districts (urban, conflict-affected, isolated island, and remote rural), we triangulated data from 34 document reviews (e.g., national policies, operational plans, budget frameworks, and EPI reports), 37 key informant interviews across all health system levels, and 11 Focus Group Discussions (FGD) with 86 community stakeholders, including caregivers. Thematic analysis reveals that while BCU remained a campaign-style intervention with parallel reporting structures, its funding acted as a critical accelerator to operationalize Cameroon's pre-existing but under-implemented 2021 National Policy and Guidelines on Catch-up Immunization. However, centralized financial control created top-down pressures that were mitigated through bottom-up co-creation during local micro-planning. Operationally, reducing MOV required a shift from passive screening to active 'Catch and Vaccinate' models, necessitating context-specific delivery adaptations in conflict zones and island populations. Despite these operational successes, stakeholders expressed deep concern regarding the long-term institutionalization due to an impending fiscal cliff. The system's heavy reliance on external donor financing threatens the sustainability of Community Health Workers' (CHW) incentives essential for demand generation. Furthermore, while the parallel IASO digital platform enabled real-time geolocation of missed children, it created double-reporting burdens, highlighting the structural challenge of synchronizing campaign tools with the national routine health information system. Ultimately, while recovery funding can successfully catalyze national policies and drive immediate equity gains, sustained resilience requires an urgent transition to domestic financing, the embedding of adaptive service delivery models into routine primary care, and the harmonization of digital tracking systems.