Gene-engineered autologous cell (GEAC) therapies for hematologic cancers and inherited disorders are earninggrowing numbers of FDA approvals, but manufacturing inefficiencies (90+% scrap rates) contribute to longworkflows and high costs. Current automation efforts do not offer a solution, because the cell processingtechniques they automate - like Ficoll-based cell enrichment, magnetic cell sorting (MACS), expansion and cellwashing - are themselves inefficient (in terms of cell recoveries). This Phase 1 SBIR will validate the suitabilityof significantly more efficient cell handling processes (enabled by applicant's functionally closed X-Series cellprocessing 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 of90-100% (for T cells and hematopoietic stem cells), and to wash or volume-reduce cells with equal recoveryefficiency. Similarly, X-BACS reagents used in X-Series cartridges prove 50% more efficient than conventionalMACS at target cell isolation at very high purity. Combined, these innovations can offer at least a 6-foldimprovement in cell yield relative to conventional techniques. Target blood cells thus prepared have been shownto 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-Seriescartridge with additional features required to support the subsequent Aim; and (2) to validate and optimize theperformance of all the steps of GEAC manufacturing (from blood to transduced, expanded and washed cellscomprising a typical therapeutic dose) in a single such cartridge ("one-pot' workflow), the milestone for applicationfor 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 maysubstantially improve patient experiences and outcomes by enabling the industry to (1) make these therapiesmore 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 tothe point of care (hospitals).
Public Health Relevance Statement: 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.
Project Terms: Antibodies ; Automation ; Biological Sciences ; Biologic Sciences ; Bioscience ; Life Sciences ; Blood ; Blood Reticuloendothelial System ; Blood Cells ; Peripheral Blood Cell ; Capital ; Cell physiology ; Cell Function ; Cell Process ; Cellular Function ; Cellular Physiology ; Cellular Process ; Subcellular Process ; Cell Separation ; Cell Isolation ; Cell Segregation ; Cell Separation Technology ; cell sorting ; Cells ; Cell Body ; Centrifugation ; Centrifugation Fractionation ; Data Collection ; Decentralization ; Disease ; Disorder ; Engineering ; Equipment ; Erythrocytes ; Blood erythrocyte ; Erythrocytic ; Marrow erythrocyte ; Red Blood Cells ; Red Cell ; blood corpuscles ; Ficoll ; alpha-D-Glucopyranoside, beta-D-fructofuranosyl, homopolymer ; Gases ; Goals ; Hematopoietic stem cells ; Blood Precursor Cell ; Hematopoietic Progenitor Cells ; blood stem cell ; hematopoietic progenitor ; hematopoietic stem progenitor cell ; hemopoietic progenitor ; hemopoietic stem cell ; Hereditary Disease ; Inborn Genetic Diseases ; Inherited disorder ; hereditary disorder ; heritable disorder ; inborn error ; inherited diseases ; inherited genetic disease ; inherited genetic disorder ; Hospitals ; Industry ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Leukapheresis ; Leukocytapheresis ; Therapeutic Leukopheresis ; Methods ; Microprocessor ; Legal patent ; Patents ; Patients ; Production ; Quality Control ; Reagent ; Savings ; T-Lymphocyte ; T-Cells ; thymus derived lymphocyte ; Technology ; Thalassemia ; Time ; Translating ; polycarbonate ; Price ; pricing ; Cost Savings ; CD3 Antigens ; CD3 ; CD3 Complex ; CD3 molecule ; OKT3 antigen ; T3 Antigens ; T3 Complex ; T3 molecule ; base ; improved ; Clinical ; Phase ; Series ; peripheral blood ; Failure ; Individual ; Recovery ; Transgenes ; cell mediated therapies ; cell-based therapeutic ; cell-based therapy ; cellular therapy ; Cell Therapy ; Therapeutic ; instrument ; Filamentous Fungi ; Molds ; Hematologic Cancer ; Hematologic Malignancies ; Hematological Malignancies ; Hematological Neoplasms ; Hematological Tumor ; Hematopoietic Cancer ; Malignant Hematologic Neoplasm ; Hematologic Neoplasms ; Autologous ; Source ; Techniques ; System ; meetings ; magnetic ; Magnetism ; experience ; Performance ; success ; magnetic cell separation system ; magnetic cell separation ; sterile ; Sterility ; expectation ; mate ; Partner in relationship ; novel technologies ; new technology ; Devices ; Position ; Positioning Attribute ; Sampling ; cell engineering ; cellular engineering ; Microbubbles ; CD34 ; HPCA1 ; CD34 gene ; Address ; Dose ; Harvest ; Mononuclear ; Engineered Gene ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Validation ; Characteristics ; Molecular ; Process ; point of care ; cost ; feeding ; design ; designing ; Outcome ; manufacturing process ; Lentivirus Vector ; Lentiviral Vector ; innovation ; innovate ; innovative ; cellular transduction ; cell transduction ; transduced cells ; prototype ; operation ; Formulation ; Injections ; chimeric antigen receptor T cells ; CAR T cells ; T cells for CAR ; chimeric antigen receptor (CAR) T cells ;
