Disease recurrence is the main cause of treatment failure after CD19-directed CAR T cells, often due to CD19 antigen loss, stability and/or coverage. To overcome single-antigen escape, we evaluated a trispecific CAR targeting CD19, CD20, and CD22 with OX40 co-stimulatory domain. Preclinical studies demonstrated potent, antigen-specific cytotoxicity in in vitro and in vivo lymphoma models. We then conducted a first-in-human phase I trial in patients with relapsed/refractory B-cell malignancies. Sixteen patients received infusions at a median vein-to-vein time of 7 days, at doses of 0.5-2×10⁶ cells/kg. No severe cytokine release syndrome nor neurotoxicity occurred. Overall response rate was 50%, including complete responses in 83% of lymphoma patients. One-year overall survival rate was 61%, with durable remissions observed in lymphoma. CAR T expansion did not correlate with dose or response. T-cell exhaustion in apheresis cells correlated with progressive disease. Trispecific CAR T cells are safe and potentially active in lymphoma.
S. Vasu, N. Denlinger, No-Joon Song et al.· Blood Cancer Discovery· 0 citations
Objective: To review the existing genetic engineering strategies commonly used for generating chimeric antigen receptor (CAR)-T cell therapy. Methods: This article provides a comprehensive literature review and compares different approaches on viral, non-viral and precision genome editing technologies, aiming to provide an overview and guidelines for methods selection during clinical CAR-T cell manufacturing. Results: CAR-T cell therapy has revolutionized cancer treatment for hematological malignancies. The manufacturing of CAR-T cell therapy relies on the genetic modification of T cells to achieve ectopic CAR gene expression. Depending on the evolving CAR designs, viral, non-viral, and genome editing platforms are used for optimal CAR expression, which could determine the clinical efficacy and safety profiles of these products. Efforts have been ongoing to empower CAR-T cell efficacy while minimizing toxicity over the past decades. Conclusion: Successful CAR-T cell therapy depends on rational platform selection and optimization of gene delivery methods based on clinical needs and context.
Wing Keung Chan, M. Lima· JOURNAL OF BONE MARROW TRANS...· 0 citations