Francisco Conesa Buendía: Next-Gen CAR-T – TranspoCART19
Francisco Conesa Buendía, Assistant in Cell and Gene Therapies Manufacturing at Memorial Sloan Kettering Cancer Center, shared an article by Begoña Diez, et al. on LinkedIn:
“Next-Gen CAR-T: Non-Viral Sleeping Beauty Transposons for Affordable and Scalable Cell Therapy
CAR-T therapies have transformed cancer treatment, but high costs, complex viral vector manufacturing, and safety concerns remain major obstacles. A new study introduces TranspoCART19, a Sleeping Beauty (SB) transposon-based CAR-T cell therapy that is cost-effective, scalable, and clinically viable, offering an alternative to conventional viral approaches.
What Makes TranspoCART19 a Game-Changer?
Non-Viral Gene Delivery
- Instead of costly lentiviral or gamma-retroviral vectors, TranspoCART19 uses the SB transposon system, which integrates CAR constructs into T cells via electroporation, significantly reducing production costs (~10% of lentiviral costs) while maintaining efficacy.
Optimized GMP Manufacturing for Scale-Up
- Electroporation with MaxCyte ExPERT GTx ensures high transfection efficiency.
- Expansion in G-Rex bioreactors allows reproducible large-scale CAR-T production.
- Validated in multiple GMP facilities, ensuring robust and reproducible clinical manufacturing.
Comparable Anti-Tumor Efficacy
- In vitro & in vivo studies confirm that TranspoCART19 matches lentiviral CAR-T therapies in tumor-killing potency.
- Demonstrates strong cytotoxic activity against CD19+ malignancies, including B-ALL and DLBCL.
- High expansion & persistence observed in preclinical xenograft models.
Enhanced Safety Profile
- Lower vector copy number (VCN) per cell (5.16 copies/cell) reduces genotoxicity risk.
- SB transposon integration is near-random, avoiding hotspots linked to oncogenesis.
- No detectable transposase or residual transposon DNA in final CAR-T products.
Built-in Safety Switch: hEGFRt for Controlled Elimination
- TranspoCART19 incorporates a truncated human EGFR (hEGFRt), allowing rapid depletion of CAR-T cells via cetuximab infusion—a critical safety feature for mitigating toxicity.
Clinical Translation Milestone: Phase I/IIa Trial Approved
The Spanish Agency of Medicines and Medical Products (AEMPS) has approved a Phase I/IIa trial (NCT06378190) to evaluate TranspoCART19 in relapsed/refractory B-cell lymphomas (DLBCL, PCNSL, MCL, FL, and MZL).
- Dose-escalation study (3+3 design) with three dose levels: 1, 3, and 5×10⁶ CAR-T cells/kg.
- Manufacturing validated for both fresh & cryopreserved leukapheresis samples.
Why Does This Matter?
Current CAR-T therapies are transformative but financially unsustainable for widespread use. By eliminating viral vectors and streamlining manufacturing, SB transposon-based CAR-T products could make personalized immunotherapy significantly more accessible.
Could non-viral gene transfer help expand the use of CAR-T therapy?”
Generation and GMP scale-up of human CAR-T cells using non-viral Sleeping Beauty transposons for B cell malignances.
Authors: Begoña Diez, et al.
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