Novel strategies to manage CAR-T cell toxicity
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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.
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.
Risk factors for CAR T-cell manufacturing failure and patient outcomes in large B-cell lymphoma: a report from the UK National CAR T Panel
CAR T-cell manufacturing failure (MF) is a situation where the manufacturing process fails to yield a product or results in one which is out-of-specification (OOS). We conducted a multicentre retrospective review of factors contributing to MF and patient outcomes. Of 981 large B-cell lymphoma (LBCL) patients approved for CAR T-cell therapy, 38 (3.87%) had MF. Eleven patients received delayed infusion with a product in-specification (delayed-infused) following 21 remanufacturing attempts. OOS product was infused in 13 (OOS-infused), and 14 were not infused. For comparison, we included 38 LBCL controls without MF; 29 received infusion (controls-infused). Prior bendamustine was the only baseline variable associated with MF risk, largely due to therapy within 6 months; 23.7% MF vs 0% controls (P = 0.0029). Overall survival (OS) and progression-free survival (PFS) were not significantly different for infused patients, with 1-year OS (PFS) of 52.8% (46.2%), 46.8% (24.2%) and 68.4% (41.4%) for OOS-infused, delayed-infused and controls-infused respectively (PFS HR OOS-infused vs controls-infused 1.41, P = 0.40; delayed-infused vs controls-infused 1.64, P = 0.25; and OOS-infused vs delayed-infused 0.86, P = 0.76). CRS, ICANS and cytopenias were not significantly different between cohorts. Outcomes for OOS-infused LBCL patients following MF are encouraging. Remanufacturing led to infusion of a product in-specification in around 50% and may be an option for patients where a suitable OOS product is not available.
Clinical characteristics and outcomes of BCMA-targeted CAR-T cell recipients with COVID-19 during the Omicron wave: a retrospective study
Patients with relapsed or refractory multiple myeloma (R/R-MM) are more susceptible to develop severe coronavirus disease 2019 (COVID-19) for their immunocompromised states. Despite good responses to B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cell therapy, deficiencies in humoral immunity following CAR-T cell infusions can still cause life-threatening complications in these patients. We conducted a comparative study to delineate the clinical characteristics and outcomes between recipients of BCMA-targeted CAR-T cell therapy who contracted COVID-19 vs. unaffected counterparts. Advanced age (odds ratio [OR] = 1.367, 95% confidence interval [CI] = 1.017–1.838, P = 0.038) was a risk factor for developing severe COVID-19, while complete remission (CR) achieved by CAR-T cell therapy (OR = 0.012, 95% CI = 0.000–0.674, P = 0.032) was protective. Male sex (hazard ratio [HR] = 5.274, 95% CI = 1.584–17.562, P = 0.007) and CR achieved by CAR-T cell therapy (HR = 3.107, 95% CI = 1.025–9.418, P = 0.045) were protective factors associated with COVID-19 duration. CR achieved by CAR-T cell therapy (HR = 0.064, 95% CI = 0.007–0.589, P = 0.015) was also a protective factor for OS, while progression disease at the time of COVID-19 diagnosis (HR = 14.206, 95% CI = 1.555–129.819, P = 0.019) was regarded as a risk factor. Thus, older patients with R/R-MM and those who do not achieve CR after CAR-T cell therapy should be most protected from COVID-19 infection by the Omicron variant.
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