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Mar 15, 2013 (Vol. 33, No. 6)

Medicine: Getting Personal

  • “Start thinking about automation even before you know the clinical efficacy of your product if you expect it to be ready by the time you get to Phase III,” said Miesowicz. With automation, he is confident that cell therapies will be able to achieve costs that are in the range of existing cancer drugs.

    Argos uses mRNA technology to target the dendritic cell-based vaccine. The vaccine is stored in liquid nitrogen and can be maintained for five years. Vaccine is prepared individually for each patient, initially through a fully manual process that involves extracting DNA from the renal tumor, preparing the mRNA through reverse transcription and PCR, and preparing the dendritic cells from a leukophoresis sample from the patient.

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    ISTO’s cell-based orthobiologic platform uses juvenile cartilage cells to create products designed to repair and restore function to damaged cartilage tissue.

    On a large scale, however, vaccine preparation will not be feasible as a manual process and will require automation. “This is a scale-out, not a scale-up scenario,” said Miesowicz. Automation with a closed disposable process stream will be essential for consistency, to decrease the size of the facility and the number of personnel required, and to eliminate the possibility of cross-contamination and provide segregation between processes and products.

    The automated system encompasses three units: one for cell preparation; one for producing amplified tumor RNA, with a robotic arm and sterile connector, and only the equipment interacts with the patient material; and one for performing electroporation and finish/fill steps.

    ISTO Technologies, an orthobiologics company, has two cell-based allogeneic products in development. Its De Novo® ET product for cartilage regeneration is in a Phase III trial for knee injuries in sports medicine. ISTO is working with juvenile chondrocytes, which are up to 100-fold more efficient than adult cells in producing new cartilage tissue, according to Mitchell Seyedin, Ph.D., president and CEO of ISTO. The company’s cell expansion platform involves creation of a cell bank by growing chrondrocytes in a bioreactor of its own design using a scaffold-free method.

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    Miltenyi Biotech’s CliniMACS® Prodigy reportedly offers advanced integrated solutions to streamline cell-processing workflows: from cell fractionation through cell culture to formulation of the final product.

    Illustrating how automation can streamline cell procetssing for clinical adoptive immunotherapy applications, Kai Pinkernell, M.D., global head of clinical business at Miltenyi Biotec presented a semi-automated scenario involving a five-step process that begins with antigen stimulation of cells and culminates with interferon-gamma enrichment reagent labeling and magnetic selection and elution. For a GMP lab, he estimated that this semi-automated approach would require two to three days of work, with a throughput of two runs/week per full-time employee (FTE). Using a fully automated system such as Miltenyi’s CliniMACS® Prodigy single-use disposable platform, cell processing in a GMP environment would entail one day of work, with a throughput of five runs/week/FTE and reduce cleanroom requirements and hands-on time.

  • Managing Risk

    In a workshop led by Thermo Fisher Scientific, Joseph Granchelli, Ph.D., manager of applications and technical support, introduced the company’s new department, “Customer Applications and Compliance Support,” which encompasses the company’s materials and regulatory compliance groups.

    Dr. Granchelli noted that as cell therapy production moves into automated, single-use disposable process streams, one over-arching concern relates to the potential for polymeric materials used to make the single-use bags, connectors, and tubing, for example, to be resorptive, reactive, or additive and to adulterate the final product. Further confounding this issue at present is a lack of clarity and standardization on how and when to test for these effects, what to look for, and what the results mean. Regulatory bodies have not established specifications for how much testing may be required and how to go about doing it.

    The presentation focused on the potential for single-use materials to be additive and, specifically, on two problems. The first is extractables—compounds forced to migrate from a molded product under highly exaggerated conditions, such as exposure to “aggressive” solvents, extreme temperatures, sterilizing irradition, high pressure, the presence of stabilizers, colorants, and plasticizers, for example, and factors related to packaging that can lead to off-gassing. The second concern is leachables—materials that migrate into the final product or an intermediate at typical or somewhat exaggerated conditions.

    Dr. Granchelli presented a risk-based approach that involves assigning a risk for each component to the final product and, where there may be risk, determining if extractable/leachable data is already available and otherwise performing the appropriate assays. He described how vendors can help with this approach if they have already tested their single-use products under a range of conditions and can make the data available to customers.

  • 10 Most Significant Events in Cell Therapy in ’12

    Ed Field, vice chairman of the Alliance for Regenerative Medicine (ARM) and COO of Cytomedix, counted down the top 10 most significant events of 2012 in the cell therapy field:

    10. U.S. District Court (for the District of Columbia) decision in July in favor of the FDA, granting its motion for summary judgment against Regenerative Sciences and issuing a permanent injunction against the use of the company’s Regenexx Procedure, which involves removal, culture, and reinjection of a patient’s stem cells to treat joint, muscle, tendon, or bone pain; Regenexx argued the treatment is a procedure, while FDA contended it is a drug.

    9. Cytori was awarded an up to $106 million contract by Biomedical Advanced Research and Development Authority (BARDA) in September to develop cell therapies for the treatment of thermal burns combined with radiation injury; about $80 million of total is for clinical work.

    8. October launch of StemBANCC, a five-year research program to develop human induced pluripotent stem cells as a platform for drug discovery; includes 10 major pharmaceutical companies and academic institutions from 11 countries.

    7. Publication of promising Phase I and interim results for central nervous system and eye disorders, including results from Advanced Cell Technology from clinical studies of its human embryonic stem cell (hESC)-based retinal pigment epithelial therapy to treat macular degeneration; interim results were reported for the pilot investigation of stem cells in stroke trial using genetically engineered neural stem cells to treat ischemic stroke earlier this year; and Phase I goals were met in a study of lumbar intraspinal injections of fetal-derived neural stems cells in patients with amyotrophic lateral sclerosis (ALS), for example.

    6. Smith and Nephew announces acquisition of bioactive woundcare company Healthpoint Biotherapeutics for $782 million in November.

    5. Organogenesis’ Gintuit cell therapy product for oral tissue regeneration received FDA approval in March; first cell-based product from allogeneic human cells and bovine collagen; for topical application to surgical site to treat mucogingival conditions.

    4. Cell therapy and cell-based regenerative medicine raised more than $1 billion in 2012, based on all forms of funding.

    3. Approval of Osiris Therapeutics’ Prochymal stem cell therapy for the treatment of acute graft-vs-host disease in children in Canada in May and in New Zealand in June.

    2. John Gurdon, University of Cambridge, U.K., and Shinya Yamanka, Kyoto University, Japan, are awarded the Nobel Prize in Physiology or Medicine.

    1. University of Pennsylvania and Novartis sign a licensing deal valued at $20 million to develop an autologous T cell-based immunotherapeutic for cancer based on chimeric antigen receptor technologies.


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