Efficient automated processing for gene-engineered autologous cell therapies

ABSTRACT Gene-engineered autologous cell (GEAC) therapies for hematologic cancers and inherited disorders are earning growing numbers of FDA approvals, but manufacturing inefficiencies (90+% scrap rates) contribute to long workflows and high costs. Current automation efforts do not offer a solution, because the cell processing techniques they automate – like Ficoll-based cell enrichment, magnetic cell sorting (MACS), expansion and cell washing – are themselves inefficient (in terms of cell recoveries). This Phase 1 SBIR will validate the suitability of significantly more efficient cell handling processes (enabled by applicant’s functionally closed X-Series cell processing cartridge and X-BACS buoyancy-based cell isolation reagents, distributed by Corning Life Sciences) for integration into a ‘one-pot’ GEAC manufacturing workflow lending itself to full automation in the simple, compact, moderately priced Quintessence instrument (the subject of a follow-on Phase 2 SBIR proposal). X-Series cartridges are proven to enrich mononuclear cells from blood with target cell recovery efficiencies of 90-100% (for T cells and hematopoietic stem cells), and to wash or volume-reduce cells with equal recovery efficiency. Similarly, X-BACS reagents used in X-Series cartridges prove 50% more efficient than conventional MACS at target cell isolation at very high purity. Combined, these innovations can offer at least a 6-fold improvement in cell yield relative to conventional techniques. Target blood cells thus prepared have been shown to be transduced with lentiviral vectors as readily as are conventionally produced target cells. This proposal’s Specific Aims are: (1) to prototype and manufacture in small quantities an enhanced X-Series cartridge with additional features required to support the subsequent Aim; and (2) to validate and optimize the performance of all the steps of GEAC manufacturing (from blood to transduced, expanded and washed cells comprising a typical therapeutic dose) in a single such cartridge (‘one-pot’ workflow), the milestone for application for a Phase 2 SBIR to design and validate the Quintessence instrument that will fully automate that workflow. Success in delivering low-cost, high-efficiency, fully automated GEAC manufacturing technology may substantially improve patient experiences and outcomes by enabling the industry to (1) make these therapies more affordable; (2) reduce GEAC’s high manufacturing failure rate (failure to produce a full clinical dose); (3) reduce lead times from Rx to treatment; (4) produce more robust cells by minimizing ex vivo cell expansion; (5) switch from leukapheresis to peripheral blood as the manufacturing input; and (6) decentralize manufacturing to the point of care (hospitals).NARRATIVE The clinical reach of gene-engineered, autologous cell (GEAC) therapies for diseases like hematologic cancers and inherited disorders such as thalassemias is today limited by their high prices, owing in part to high manufacturing costs due to inordinate scrap rates (90+% of starting target cells). To address this issue, this application proposes validation of the potential for new cell-processing methods, made possible by applicant’s high-efficiency X-Series cartridges and X-BACS buoyancy-activated cell sorting (BACS) reagents, to be integrated into a ‘one pot’ GEAC manufacturing process from blood to therapeutic dose, combining target cell enrichment, isolation, transduction, expansion and washing in a single container, with unprecedented cell recovery efficiency at every step, into an uninterrupted workflow suitable for full automation. Success will not only reduce GEAC therapeutics’ manufacturing costs, but may also translate into improved patient experiences and outcomes by enabling therapeutic manufacturing at the point of care (hospitals), saving more lives.