Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common and life-threatening complication of chimeric antigen receptor (CAR) T-cell therapy, with early detection being critical for timely intervention and improved outcomes. Cytokines such as interleukin-6 (IL-6) are key mediators of the inflammatory cascade underlying ICANS pathogenesis, but prospective clinical evidence establishing whether serial IL-6 elevations precede ICANS onset remains limited. Here we quantify IL-6 levels in a prospective cohort of 40 CAR-T patients (270 serum samples), using a simple in-house microfluidic bead immunoassay. IL-6 levels measured by our assay were significantly associated with next-day ICANS onset. In a generalized estimating equation model adjusted for concurrent cytokine release syndrome grade, each ∼3.4-fold increase in IL-6 levels was linked to a 76% increase in the odds of ICANS onset the following day, independent of other clinical variables. Overall, we show the temporal association of IL-6 with next-day ICANS onset, demonstrate the potential of frequent cytokine measurement to guide CAR-T patient management and develop a simple experimental method to perform such monitoring.

This perspective article describes the Swissmedic Innovation Office, a new regulatory support program from Swissmedic, the Swiss Agency for Therapeutic Products, tailored to Advanced Therapy Medicinal Products (ATMPs) developers. Based on the analysis of more than 100 interactions, it highlights shared scientific and regulatory challenges and proposes some initial considerations to support the early-phase development of ATMPs.

Visible particulate matter is a critical quality attribute in injectable drug products; however, current regulatory standards provide limited guidance for addressing the specific challenges of Cell-Based Advanced Therapies (CT), where conventional inspection and rejection criteria may be incompatible with manufacturing and clinical constraints. Autologous and small-batch therapies often lack manufacturing redundancy, making the rejection of a single unit potentially equivalent to losing an opportunity to provide a life-saving treatment. To address this gap, we present a risk-based framework for evaluating and controlling particulate risk in CT, focusing on how particulate sources, process conditions, and control strategies can be characterized and improved early in development while incorporating benefit-risk considerations unique to these therapeutic modalities. Grounded in principles from international quality and regulatory publications, the proposed Visible Particulate Risk Assessment Matrix guides developers and manufacturers in assessing and managing particulate risk by integrating factors such as particle type and origin, characterization sufficiency, route and administration context, clinical urgency and therapeutic alternatives, system performance and controls, and lot replacement feasibility.

Advanced therapies, including gene therapies, somatic cell therapies, and tissue-engineered products, pose distinctive regulatory challenges because of their scientific complexity, manufacturing variability, clinical uncertainty, and long-term safety considerations. Recent clinical advances have heightened the need for regulatory pathways capable of supporting safe, effective, and sustainable access. Across Latin America, regulatory approaches for these products have evolved unevenly, reflecting differences in legislative development, institutional capacity, and regulatory specialization among National Regulatory Authorities (NRAs). This study aimed to comparatively assess the regulatory development of advanced therapies in selected Latin American countries through the evaluation of key regulatory dimensions, including conceptual definitions, institutional organization, specialized technical oversight mechanisms, authorization pathways, manufacturing requirements, and accumulated regulatory experience. Argentina, Brazil, Chile, Colombia, Cuba, and Mexico were selected based on their regional relevance, recognition of their NRAs by the Pan American Health Organization (PAHO), and the availability of publicly accessible information on biological products and advanced therapies. A narrative comparative regulatory review was conducted using publicly available legal, institutional, and technical information. The analysis was informed by internationally recognized frameworks developed by the World Health Organization (WHO), the International Council for Harmonization (ICH), the European Medicines Agency (EMA), the United States Food and Drug Administration (FDA), and the Pharmaceutical Inspection Co-operation Scheme (PIC/S), with emphasis on risk-based oversight, traceability, Good Manufacturing Practice (GMP), pharmacovigilance, and life-cycle regulation. The analysis identified substantial regional asymmetries in regulatory definitions, institutional specialization, authorization pathways, manufacturing oversight, and implementation capacity. Brazil and Argentina have established the most structured frameworks specifically addressing advanced therapy products, whereas Colombia, Cuba, and Mexico continue to rely primarily on broader provisions applicable to biological products, transplantation activities, or tissue banking. Chile has moved toward a more specialized model through the adoption of Technical Standard No. 257. Differences were also observed in the regulation of stem cell-based products, non-industrial manufacturing models, and specialized oversight mechanisms. Overall, the regulatory landscape for advanced therapies in Latin America remains heterogeneous and continues to evolve. Greater regional convergence, proportionate risk-based approaches, and carefully designed reliance mechanisms may strengthen regulatory preparedness and oversight while supporting the safe and sustainable development of advanced therapies in the region.

Human cell-processed therapeutic products (hCTPs) pose potential tumorigenesis risk due to transformed cell impurities. Sensitive and validated assays for detecting these impurities should be employed to minimize this risk. The digital soft agar colony formation (D-SAC) assay, a highly sensitive and robust test for detecting tumorigenic cells as impurities in hCTPs, requires high proficiency. The recently developed digital low-molecular-weight agar colony formation (D-LAC) assay uses a three-dimensional (3D) culture technique in which the addition of low-molecular-weight agar LA717 to the culture medium controls cell migration and ensures uniform cell dispersion, thereby enabling 3D culture in liquid medium and eliminating the need to layer agarose media of different concentrations, which improves assay operativity. To understand the assay performance validity, we compared the colony-forming efficiency (CFE) of tumorigenic reference cells between several laboratories and investigated the specificity and sensitivity of the D-LAC assay in several laboratories. Cultured human mesenchymal stromal cells were used as model drug products, and positive control samples were prepared by spiking them with HeLa cells. First, we estimated CFEs, assessed their variation and found low intra/inter-laboratory variations, indicating a highly robust test performance. Under the assay conditions, we confirmed the detectability of ultra-low concentrations of HeLa cells and could detect 1 ppm and 0.1 ppm of HeLa cells in hMSCs (10 HeLa cells per 1 × 10[7] and 1 × 10[8] hMSCs, respectively) at multiple laboratories. Simply counting the wells in which colonies were present without counting the actual number of colonies resulted in a similar test performance. Furthermore, the formation and shape of colonies of cancer cells varied with each cell line (MIA PaCa-2, PANC-1 and HepG2) in the D-LAC assay. Overall, the D-LAC assay is a highly sensitive and robust test for detecting several types of tumorigenic cells as hCTP impurities. This assay can replace the traditional soft agar colony assay and is potentially more versatile than D-SAC because of its high operativity.

Macrophages are of interest as candidates for adoptive cell therapy for solid tumors because they can infiltrate tumor tissue, engage target cells and influence the tumor microenvironment. However, macrophage products derived from primary monocytes remain difficult to standardize, expand and genetically modify. Pluripotent stem cell-derived myeloid cell lines (PSC-MLs) provide a renewable and engineerable myeloid platform, but their use as direct tumor-targeting effectors has remained incompletely defined. In this study, we generated macrophage-like cells from PSC-MLs carrying a doxycycline (DOX)-inducible anti-HER2 chimeric antigen receptor (CAR) and evaluated three separable features of the platform: in vitro tumor-cell control, contact-associated and CAR-modified transcriptional responses and postadministration persistence in vivo. Cells established from 2 human PSC backgrounds retained macrophage-associated phenotypes after differentiation. In coculture with HER2-expressing tumor cells, the cells showed measurable antitumor activity relative to untreated controls. The DOX-treated condition was compatible with a CAR-associated contribution in some comparisons, but uniform CAR-dependent enhancement was not established across tumor models. Live imaging documented phagocytic events but did not quantify their frequency. Transcriptomic profiling associated tumor-cell contact with inflammatory, trafficking and uptake-related programs, and the CAR-induced coculture condition with a relative emphasis on vesicular, lysosomal and proteostasis-related modules. In a subcutaneous coimplantation assay, in which tumor and effector cells were introduced together, treated groups showed short-term tumor-control signals relative to untreated controls at later observation points. However, an incremental benefit of the CAR-induced (DOX) condition was not clearly resolved. Luciferase-based tracking of ML-MPs showed marked loss by day 3 and no detectable signal by day 7. Repeated dosing was feasible, but its incremental benefit over single dosing could not be established in the small exploratory experiment.