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Abstract Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using ‘off-the-shelf’ products, such as allogeneic CAR natural killer T (^AlloCAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem and progenitor cells into^AlloCAR-NKT cells, but the use of three-dimensional culture and xenogeneic feeders precluded its clinical application. Here we describe a clinically guided method to differentiate and expand IL-15-enhanced^AlloCAR-NKT cells with high yield and purity. We generated^AlloCAR-NKT cells targeting seven cancers and, in a multiple myeloma model, demonstrated their antitumor efficacy, expansion and persistence. The cells also selectively depleted immunosuppressive cells in the tumor microenviroment and antagonized tumor immune evasion via triple targeting of CAR, TCR and NK receptors. They exhibited a stable hypoimmunogenic phenotype associated with epigenetic and signaling regulation and did not induce detectable graft versus host disease or cytokine release syndrome. These properties of^AlloCAR-NKT cells support their potential for clinical translation. 

Changes driven by both unanticipated human activities and management actions are creating wicked management landscapes in freshwater and marine ecosystems that require new approaches to support decision-making. By linking a predictive model of nutrient- and temperature-driven bottom hypoxia with observed commercial fishery harvest data from Lake Erie (United States–Canada) over the past century (1928–2022) and climate projections (2030–2099), we show how simple, yet robust models and routine monitoring data can be used to identify tradeoffs associated with nutrient management and guide decision-making in even the largest of aquatic ecosystems now and in the future. Our approach enabled us to assess planned nutrient load reduction targets designed to mitigate nutrient-driven hypoxia and show why they appear overly restrictive based on current fishery needs, indicating tradeoffs between water quality and fisheries management goals. At the same time, our temperature results show that projected climate change impacts on hypoxic extent will require more stringent nutrient regulations in the future. Beyond providing a rare example of bottom hypoxia driving changes in fishery harvests at an ecosystem scale, our study illustrates the need for adaptive ecosystem–based management, which can be informed by simple predictive models that can be readily applied over long time periods, account for tradeoffs across multiple management sectors (e.g., water quality, fisheries), and address ecosystem nonstationarity (e.g., climate change impacts on management targets). Such approaches will be critical for maintaining valued ecosystem services in the many aquatic systems worldwide that are vulnerable to multiple drivers of environmental change.