Engineering and cell therapy

The goal of this research is to provide resources to the cell therapy community to standardize the preparations and facilitate testing of these cellular formulations prior to their introduction into patients.  There are a number of focal points in the development of a cell therapeutic in which engineering tools emerge to create synergy with the biological specimen and to make a cellular formulation more successful.  This can begin with the use of bioprocessing devices to create minimally-manipulated, autologous (using one’s own cells) cellular formulations for personalized medicine. Upon the purification of cellular mixtures, genetic engineering of cells can enable designer drugs that can be controlled in terms of duration and potency for their therapeutic targets. MGH investigators support these efforts as strong and reproducible proof-of-concept methods are developed for scale-up and translation.

Applying principles of biomanufacturing and drug delivery to cell therapy

The enormous potential of cell therapies comes with new challenges in manufacturing, formulating, and administering cells to patients. Importantly, cells use complex mechanisms (for example, differentiation) to impart a therapeutic benefit. The delivery and monitoring of a cell’s mechanism of action when in use is severely limited by conventional approaches. Without sensitive monitoring of cells and delivery considerations of their action mechanism, therapeutics cannot be systematically tested and improved.  MGH investigators have a fundamental interest in understanding the life cycle of a cell therapy from manufacture to administration and beyond. This begins with growing cells under industrial conditions to develop new biochemical process engineering techniques with online simulations.  The investigators specialize in creating engineered cells as model systems to understand the behavior of cells after they are transplanted. This scientific exploration seeks to identify new manufacturing practices and designer therapeutic cell compositions that can overcome rate-limiting aspects of cell therapy delivery and create products that are more durable.

Cell bioreactors for therapeutic delivery and in vivo modeling

MGH investigators have championed the use of mesenchymal stromal cell (MSC) therapy, which uses MSCs as a combined source of metabolic, growth factor, and cytokine therapy, to protect vital organs and reduce further inflammatory reaction.  Sentien Biotechnologies, Inc. has created an engineered MSC bioreactor, which is a device that contains living MSCs at higher doses that could ever be achieved by conventional administration routes, to optimize and deploy the metabolism and secretions of MSCs for their use in patients.  MSCs are inoculated into a blood-contacting bioreactor as a platform to allow MSCs to interact continuously with the bloodstream in a controlled and reproducible fashion with high fidelity.  These hybrid cellular bioreactors have been shown to increase survival rates by 5-fold when compared to the direct implantation of MSC cells in multiple model systems of inflammatory organ failure.  This approach has led to the development of a prototype for human usage that has been shown to support cellular viability and function throughout manufacturing as well as when connected online in model systems.  The bioreactor is well tolerated when tested in ischemic kidney injury model systems and the efficacy results obtained are very promising.  Clinical trials to evaluate the safety of the bioreactor are planned over the next few years.

Systems biology of cell therapy

The application of cell therapeutics involves a complex interaction between donor cells and the host. Apart from the use of genetically modified constructs, donor cells alone can be considerable sources of biologically active molecules like proteins and lipids that can influence the physiology of the host immune response and vital organ function.  MGH investigators continue to develop methods to uncover these secreted factors and the biological response to a cell therapy by taking a systems biology perspective. These studies involve genomic responses of administered cells and targeted genetic manipulations in donor/host response pathways.  It is envisioned that these donor-host interaction studies of cell therapeutics can aid in designing an optimal cell delivery regimen to maximize therapy and minimize risk.

Relevant publications

Fletcher AL, Elman J, Astarita J, Murray R, Saeidi N, D’Rozario J, et al. Lymph node fibroblastic reticular cell transplants show robust therapeutic efficacy in models of high-mortality murine sepsis.  Sci Transl Med. 2014 Aug 13;6(249); PubMed PMID: 25122637

Elman JS, Murray RM, Wang F, Shen K, Gao S, Conway KE, Yarmush ML, Tannous BA, Weissleder R, Parekkadan B. Pharmacokinetics of natural and engineered secreted factors delivered by mesenchymal stromal cells. PLoS One. 2014 Feb 21; 9(2):e89882.  PubMed PMID: 24587097; PubMed Central PMCID: PMC3931832

Milwid JM, Elman JS, Li M, Shen K, Manrai A, Gabow A, Jiao Y, Fletcher AJ, Lee J, Cima MJ, Yarmush ML, Parekkadan B. Enriched protein screening of human bone marrow mesenchymal stromal cell secretions reveals MFAP5 and PENK as novel IL-10 modulators.  Mol Therapy. 2014 May;22(5):999-1007.  PubMed PMID: 24496384; PubMed Central PMCID: PMC4017089

Li M, Tilles AW, Milwid JM, Hammad M, Lee J, Yarmush ML, Parekkadan B. Phenotypic and functional characterization of human bone marrow stromal cells in holl-fibre bioreactors. J Tissue Eng Regen Med. 2012 May; 6(5):369-77.  PubMed PMID: 21710576; PubMed Central PMCID: PMC3183117

Parekkadan B, Milwid JM.  Mesenchymal stem cells as therapeutics.  Ann Rev Biomed Eng.  2010 Aug 15;12:87-117. PubMed PMID: 20415588; PubMed Central PMCID: PMC3759519

Contact

Biju Parekkadan, Ph.D.
Massachusetts General Hospital
Center for Engineering in Medicine
51 Blossom St.
Boston, MA 02114

Visit the Sentien Biotechnologies web site

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