“Are They Ready Yet?”: release criteria for autologous CAR T cells
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CRISPR knock-in of a chimeric antigen receptor into GAPDH 3’UTR locus generates potent B7H3-specific NK-92MI cells
CAR-NK therapy is becoming a promising approach to treat solid tumors. However, the random insertion of the CAR gene and inflexible CAR expression caused by common preparation methods significantly impact its efficacy and safety. Here we successfully established a novel type of CAR-NK cells by integrating CAR sequences into the GAPDH 3’UTR locus of NK-92MI cells (CRISPR-CAR-NK), achieving site-specific integration of the CAR gene and allowing endogenous regulatory components to govern CAR expression. CRISPR-CAR-NK cells had comparable growth capacity but displayed superior anti-tumor activity compared with their lentiviral counterparts. They activated and degranulated more effectively when co-cultured with tumor cells, due to increased expression of activating receptors and decreased expression of inhibitory molecules. They also enhanced the production of Granzyme B and IFN-γ, and more effectively triggered the IFN-γ pathway. Moreover, CRISPR-CAR-NK cells demonstrated distinct properties from conventional CAR-NK concerning metabolic features and signal dependence. Notably, CRISPR-CAR-NK cells exhibited lower metabolic levels without compromising antitumor activity, and their function was less reliant on the PI3K-AKT pathway, implying that the CRISPR-CAR-NK cells have significant potential for enhanced synergy with AKT inhibitors and adaptation to nutrient stress within the tumor microenvironment. These findings provide a novel potential strategy for cancer immunotherapy and an experimental foundation and paradigm for optimizing CAR-NK cells utilizing CRISPR technology, highlighting the potential of CRISPR to advance immunotherapies.
International myeloma working group immunotherapy committee recommendation on sequencing immunotherapy for treatment of multiple myeloma
T-cell redirecting therapy (TCRT), specifically chimeric antigen receptor T-cell therapy (CAR T-cells) and bispecific T-cell engagers (TCEs) represent a remarkable advance in the treatment of multiple myeloma (MM). There are several products available around the world and several more in development targeting primarily B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GRPC5D). The relatively rapid availability of multiple immunotherapies brings the necessity to understand how a certain agent may affect the safety and efficacy of a subsequent immunotherapy so MM physicians and patients can aim at optimal sequential use of these therapies. The International Myeloma Working Group conveyed panel of experts to review patient and disease-related factors affecting efficacy and safety of immunotherapy, summarize existing information on sequencing therapy and provide a series of core recommendations.
The 2023 EBMT report on hematopoietic cell transplantation and cellular therapies. Increased use of allogeneic HCT for myeloid malignancies and of CAR-T at the expense of autologous HCT
In 2023, 47,731 HCT (20,485 (42.9%) allogeneic and 27,246 (57.1%) autologous) in 43,902 patients were reported by 696 European centers. 6042 patients received advanced cellular therapies, 4888 of which were CAR-T. Compared to the previous year there was an increase in CAR-T (+52.5%), in allogeneic HCT (+7.8%) but none in autologous HCT (+0.4%). Main indications for allogeneic HCT were myeloid (11,748; 60.7%), lymphoid malignancies (4,850; 25.0%), and non-malignant disorders (2558; 13.2%). Use of allogeneic HCT increased for AML (+12.1%) and for NHL (+11.0%), particularly in T-NHL (+25.6%). Main indications for autologous HCT were lymphomas (7890; 32.2%), PCD (14,271; 58.2%), and solid tumors (1608; 6.6%) with recovering numbers for autoimmune diseases. In patients with allogeneic HCT, the use of sibling donors increased by +1.0%, haploidentical donors by +11.7%, and unrelated donors by +11.1%. Cord blood HCT decreased again by −5.4%. Pediatric HCT activity increased slightly (5455; +0.1%) with differences between allogeneic (4111; −0.5%) and autologous HCT (1344: +1.7%). Use of CAR-T increased to a cumulative total of 13,927 patients including patients treated for autoimmune diseases. Overall, numbers show a complete recovery from the pandemic dip with increased cellular therapy at the expense of autologous HCT. Allogeneic HCT activity focuses on myeloid malignancies.
A combination of measures limits demand for critical materials in Sweden’s electric car transition
Electrification of passenger cars will result in an increased demand for critical raw materials. Here we estimate the quantities of nickel, manganese, cobalt, lithium, and graphite that could be required for a transition to electric cars in Sweden and how different measures can limit material demand. We find notable reduction potentials for shorter battery range—enabled by improved charging infrastructure, increased vehicle energy efficiency, and reduced travel demand compared to a reference scenario. The reduction potentials for downsizing and more lightweight cars, and car sharing are more modest. The combined impact of these measures would be 50–75% reduction in cumulative demand and 72–87% reduction in in-use stock in 2050, depending on the material and battery chemistry pathway. Generally, the reduction potentials are larger than the potential contributions from recycling, suggesting that these complementary measures may be more effective in reducing material demand.
γδ T-cell autoresponses to ectopic membrane proteins: a new type of pattern recognition
T-cell receptor (TCR) γδ-expressing cells are conserved lymphocytes of innate immunity involved in first-line defense and immune surveillance. TCRγδ recognizes protein/nonprotein ligands without the help of the major histocompatibility complex (MHC), especially via direct binding to protein ligands, which is dependent primarily on the δ chain complementary determining region 3 (CDR3δ). However, the mechanism of protein‒antigen recognition by human γδ TCRs remains poorly defined. We hypothesize that γδ TCRs recognize self-proteins expressed ectopically on the cell membrane that are derived from intracellular components under stress. Here, we mapped 16 intercellular self-proteins among 21,000 proteins with a huProteinChip as putative ligands for Vδ1/Vδ2 TCRs, 13 for Vδ1 TCRs and 3 for Vδ2 TCRs. Functional tests confirmed that ectopic nucleolin (NCL) is a ligand for the Vδ1 TCR, whereas protein-glutamine γ-glutamyltransferase K (TGM1) is a ligand for the Vδ2 TCR. In the context of radiation exposure, the ectopic expression of intracellular proteins on the tumor cell surface is related to the increased antitumor cytotoxicity of γδ T cells both in vitro and in vivo. In conclusion, the recognition of intracellular proteins that are ectopically expressed on somatic cells by human γδ TCRs is a basic interaction mechanism that enables new types of immune pattern recognition and a novel γδ TCR-ligand-based strategy for tumor immunotherapy.
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