Abstract
Large-scale, reproducible manufacturing of therapeutic cells with consistently high quality is vital for translation to clinically effective and widely accessible cell therapies. However, the biological and logistical complexity of manufacturing a living product, including challenges associated with their inherent variability and uncertainties of process parameters, currently make it difficult to achieve predictable cell-product quality. Using a degradable microscaffold-based T cell process as an example, we developed an Artificial Intelligence (AI)-driven experimental-computational platform to identify a set of critical process parameters (CPP) and critical quality attributes (CQA) from heterogeneous, high dimensional, time-dependent multi-omics data, measurable during early stages of manufacturing and predictive of end-of-manufacturing product quality. Sequential, Design-of-Experiment (DOE)-based studies, coupled with an agnostic machine-learning framework, were used to extract feature combinations from media assessment that were highly predictive of total live CD4+ and CD8+ naïve and central memory (CD63L+CCR7+) T cells and their ratio in the end-product. This computational workflow could be broadly applied to any cell therapy and provide a roadmap for discovering CQAs and CPPs in cell manufacturing.
Competing Interest Statement
B.L.L. declares financial interest intellectual property and patents in the field of cell and gene therapy (University of Pennsylvania Alliance with Novartis, licensing, and royalty fees). B.L.L. is a consultant for Novartis, Terumo, and Lilly Asia Ventures and he is part of the Scientific Advisory Board for Avectas, Brammer Bio/TF Viral Vector Services, Immuneel, Incysus, Ori Biotech, and Vycellix. Moreover, B.L.L. is the co-founder and equity holder Tmunity Therapeutics and all of his conflict of interest is managed in accordance with University of Pennsylvania policy and oversight. T.K. is the Chief Executive Officer of Evolved Analytics, LLC. The remaining authors declare no competing interests. K.R declares consulting, intellectual property, and patents in cell and gene therapy. K.R. is a consultant to Terumo, Merck. LEK consulting, Mubadala Ventures, Anzu Partners, Decibio, and Clearview Healthcare Partners. K.R. serves on the advisory board of the MIT-Singapore Cell therapy Partnership.
Footnotes
Ethics declarations
Competing Interests B.L.L. declares financial interest intellectual property and patents in the field of cell and gene therapy (University of Pennsylvania Alliance with Novartis, licensing, and royalty fees). B.L.L. is a consultant for Novartis, Terumo, and Lilly Asia Ventures and he is part of the Scientific Advisory Board for Avectas, Brammer Bio/TF Viral Vector Services, Immuneel, Incysus, Ori Biotech, and Vycellix. Moreover, B.L.L. is the co-founder and equity holder Tmunity Therapeutics and all of his conflict of interest is managed in accordance with University of Pennsylvania policy and oversight. T.K. is the Chief Executive Officer of Evolved Analytics, LLC. The remaining authors declare no competing interests. K.R declares consulting, intellectual property, and patents in cell and gene therapy. K.R. is a consultant to Terumo, Merck. LEK consulting, Mubadala Ventures, Anzu Partners, Decibio, and Clearview Healthcare Partners. K.R. serves on the advisory board of the MIT-Singapore Cell therapy Partnership.