Personalized medicine is a promising new approach to disease treatment. The ultimate in personalized medicine is a cellular therapy manufactured specifically for an individual patient using his or her own cells. But this autologous approach to generating immunotherapies has unique manufacturing challenges. Each patient receives an individual product batch, which needs to be manufactured, tested, and released. So thousands to tens of thousands of batches could be made for each indication every year. Given the personalized nature of these therapies, the production scale remains the same for each batch. Thus, scale-up is not required; scale-out is key for meeting the demands of autologous cell-therapy manufacturing.

Manufacturing Methods

Generating autologous cellular therapies can take several approaches. In general, all involve obtaining autologous cells from a patient by procedures performed at a hospital or blood center. Depending on the therapy, those cells are either transferred to a local laboratory for further processing or shipped to a central processing facility. This starting material has limited stability, requiring immediate processing upon receipt. For proliferating cells, the desired cell type for a given therapy is typically expanded in cell culture. If the cells are terminally differentiated (nonproliferating), then cells for the therapy are typically generated by isolating precursor cells for the desired type and culturing them with appropriate cytokines for differentiation into the desired cell type.

During cellular processing, an antigen may be added to elicit a desired immune response. This may be a defined antigen (the same for every patient and process) that can be produced using traditional large-scale methods. For example, Dendreon Corporation uses a defined-antigen approach in making its Provenge (sipuleucel-T) prostate cancer treatment, which received the first and only FDA approval to date for an autologous cellular therapy in April 2010. The antigen for Provenge is a recombinant fusion protein comprising granulocyte macrophage–colony stimulating factor (GM-CSF) crosslinked to the prostate antigen prostatic acid phosphotase (PAP). This recombinant fusion protein (PAP-GM-CSF) is manufactured at large scale to provide material for multiple batches of product.

Other manufacturing approaches use an autologous antigen from each patient's tumor for oncology treatment or from a given virus for treating infectious diseases. They generate completely autologous cellular therapies tailored to each individual 's disease. They generate completely autologous cellular therapies tailored to each individual's disease. This enables adaptation of methods from one indication to another without the need to identify defined antigens for each indication. However, it also increases the complexity of the manufacturing process because an antigen needs to be processed and tested for each patient and combined with that patient's own cells.

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There are different methods for processing autologous antigens. The simplest method is to use tumor lysate, which requires relatively minimal processing, essentially a homogenization step. That provides a patient's cells directly with the proteins expressed by his or her tumor as antigens during cellular processing to generate the immunotherapy. Alternatively, tumor lysate, can be processed to isolate total RNA, enabling cells of interest to express and process it for the immunotherapy. This can be taken a step further by amplifying the mRNA in the isolated total RNA. Although that requires the most effort in terms of antigen processing, a relatively small amount of tumor is required to generate sufficient mRNA for multiple doses (or even multiple batches) of the cellular therapy.

Following cellular processing, the resulting cellular therapy may be either directly infused (so one manufacturing run generates one dose for the patient) or cryogenically preserved (in multiple doses). Once cryogenically preserved, each individual dose for a patient is then delivered using liquid nitrogen dry shippers before administration.

In early phase clinical trials, the manufacturing of cellular therapies generally uses manual processing methods transferred from research laboratories. Semiautomated commercial equipment options are available for the isolating precursor cells. Some instruments use antibody-coated bead–based methods (e.g., the CliniMACS cell separation system from Miltenyi Biotec, www.miltenyibiotec.com) for isolating precursor cells. Another is based on elutriation, also known as counterflow centrifugation (the Elutra cell separation system from CaridianBCT Inc., www.caridianbct.com). Some companies have developed their own proprietary methods for isolating precursor cells. Examples include a tangential-flow filtration method developed by Northwest Biotherapeutics, Inc. (www.nwbio.com) and a cell separation device used by Dendreon.

Options abound for the initial isolation of precursor cells. But little automated commercial equipment is available to address either the remaining cellular processing steps or the more complex antigen processing steps. Some companies are working to develop cellular therapy enabling devices, such as Miltenyi's CliniMACS Prodigy system. But a need remains for automated equipment that can handle the complexity of autologous therapy processing and enable scale-out for larger clinical trials and commercialization. Therefore, Argos Therapeutics initiated development of its own automated system to address these manufacturing challenges.

The key to scale-out for autologous cellular therapies is using functionally closed, single-use technologies and automation for processing. Such disposables minimize cleaning requirements between batches — which is critical for turnover of equipment — and eliminate concerns regarding cross contamination. Automation provides consistency and efficiency in processing using disposables.