A Breakthrough for Cellular Therapy Manufacturing: Clinical-Scale High-Yield Nonviral Gene Delivery

CAMBRIDGE, MA—Draper scientists have created a new technology that will help increase patient access to life-saving state-of-the-art cellular therapies.

Currently available autologous (personalized) cellular therapies, including CAR T-cell therapies, have demonstrated successful results in treating certain types of hematological cancers. Some autologous cellular therapies have also demonstrated better efficacy than conventional forms of cancer therapy. These successes have raised expectations for the next generation of cellular therapies that could potentially address indications ranging from solid tumors to autoimmune diseases.

However, manufacturing challenges continue to limit widespread adoption of cellular therapies, even as the safety and efficacy of the therapies continues to improve. As a result, these therapies can cost hundreds of thousands of dollars and require weeks to manufacture, limiting patient access.

One of the biggest challenges in cell therapy manufacturing is delivering genes into immune cells, a process that reprograms them to fight a specific disease. The most common gene delivery method in manufacturing employs viruses, but viruses are expensive, and the process is time-consuming and difficult to scale to the growing needs of next-generation therapies.

Cellular therapy researchers are working to produce allogeneic, off-the-shelf cellular therapies so that they can be delivered on demand. Allogeneic processes will likely increase the demands on number of cells processed by a factor of 10 or more, from billions of cells to trillions of cells. Traditional gene delivery technologies cannot keep up with these increasing demands.

To address the emerging large-scale manufacturing needs driven by the expansion and development of novel autologous and allogeneic cellular therapies, Draper researchers have designed a new scalable and tunable gene delivery system that can process up to 9.6 billion cells in one hour using electroporation. This gene delivery system was tested in conjunction with Draper’s partners in pharma. The new research was published in the journal Advanced Materials Technologies.

In the paper, Draper demonstrates the ability to transfect human T cells with Cas9-guide ribonucleic acid (RNA) ribonucleoprotein complexes (RNP) and messenger RNA (mRNA) with up to 99–100% efficiency and minimal impact on viability, at throughputs of up to 9.6 billion/hr. In addition, the device transfected 3.5 kilobase pair plasmid deoxyribonucleic acid with up to 86% efficiency.

“Our primary goal with this research is to increase patient access to life-saving cellular therapies, and this technology has the potential to make manufacturing cell and gene therapies faster, better and less expensive,” says Vishal Tandon, PhD,  leader of the Multiphysics Microfluidics Design group at Draper. Tandon, the corresponding author of the study, is leading development of Draper’s electroporation system.

“Our continuous-flow electroporation device uses high-precision microfluidics to tightly control cells’ exposure to electrical fields, increases throughput and reduces manual touch labor,” said Michaela Welch, lead author of the paper and one of the technical staff at Draper. “Our new research demonstrates the scalability of electroporation as a preferred transfection method over viral transduction for next-generation therapies.”

Draper designed the technology to accommodate the full range of applications, from research studies to large scale manufacturing, and to support the rapid translation from R&D to clinical process, cutting therapy development costs.

In addition to electroporation, Draper has invested in technologies and engineering capabilities to address the complete cell therapy manufacturing process. Capabilities in development include scalable cell separation by acoustophoresis, a shear-controlled cell oxygenation platform, a membrane viral transduction system and various in-line sensor technologies. In collaboration with industry, Draper is actively working to bring these solutions to market as part of customer-specific cell therapy workflows, as standalone modules or as an end-to-end to solution to automate cell therapy production.