A novel manufacturing process leveraging stirred-tank bioreactors (STBs) may significantly improve the efficacy of CAR-T cell therapies, according to research presented at the 2024 International Society for Cell & Gene Therapy (ISCT) annual meeting in Vancouver, Canada. The study, led by Hélio Tomás, PhD, from the Instituto de Biologia Experimental e Tecnológica in Lisboa, Portugal, highlights the impact of controlled cell culture conditions on CAR-T cell phenotype and function within tumor microenvironments.
Enhanced CD8 T Cell Production
The research team manufactured CAR-T cells in STBs and assessed their performance in a simulated tumor microenvironment characterized by high concentrations of reactive oxygen species. Results indicated that STBs generated a higher proportion of CD8 T cells compared to static cultures after 10 days of bioreactor inoculation. CD8 T cells are critical for directly killing tumor cells, suggesting a potential mechanism for improved therapeutic efficacy.
Optimized CD4/CD8 Ratio
Furthermore, the study revealed a lower CD4/CD8 ratio in CAR-T cells produced in STBs. This is clinically significant because lower CD4/CD8 ratios have been associated with improved patient responses to CAR-T cell treatment. According to the researchers, carefully selected cell culture conditions can also enhance the transduction of CAR genes carried by lentiviral vectors, further optimizing the CAR-T cell product.
Targeting HER2-Positive Breast Cancer
To validate the process, the researchers produced CAR-T cells targeting HER2-positive breast cancer cells using the STB method. The results demonstrated that the optimized bioprocessing approach could enhance a range of CAR-T cell-based therapies. "Overall, these results highlight the potential of scalable and tightly controlled manufacturing processes toward the generation of CAR-T cells with improved potency," Tomás' team concluded.
The findings suggest that STB-based manufacturing offers a promising avenue for producing more effective CAR-T cell therapies by optimizing critical process parameters and enhancing CAR-T cell phenotype.
