Precision Immunotherapy Program at Argos Therapeutics Utilizes HemaCare Leukopak Products for their Therapeutic Cell Manufacturing Workflow

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Introduction
Cancer immunotherapy is big news in the medical world these days, and rightly so. The FDA has now approved the very first “CAR T-cell” treatments, based on some truly astonishing positive results in patients who previously had little hope of survival. These cellular therapies are aimed at “teaching” a patient’s own immune system to fight their cancer, and they are the result of more than a decade of painstaking research and clinical trials. Argos Therapeutics is one of several pharmaceutical companies that helped lay the groundwork into developing such precision therapeutics, which are based on the guided manipulation of living cells.

Argos has operated for years in the personalized immunotherapy space, using cellular material collected from both patients and healthy donors to carry out clinical trials based on using dendritic cells to trigger a targeted, patient-specific immune response.[1] Dr. Fred Miesowicz joined Argos in 2003, guiding their research and development efforts as Chief Operating Officer and VP of Manufacturing for over a decade. As part of his work at Argos, Dr. Miesowicz oversaw a number of different clinical studies, including studies focused on treating HIV, and late stage kidney cancer. The raw materials used in process development for these studies came from HemaCare, who supplied the fresh leukopaks from which dendritic cells were isolated and modified prior to patient infusion.

Dendritic cell purity isolated from fresh leukopak
Fig. 1. Purity of dendritic cells isolated from a fresh HemaCare leukopak, as measured by immunomagnetic cell separation analysis. Dendritic cell purity was greater than 99% in all cases when gated on CD1c/CD45.

The Importance of High Quality Precursor Material
The clinical success of cell-based therapeutics is inextricably linked to the purity and potency of precursor raw materials. [2] In cell therapy, potency is often directly correlated with the number of healthy immune or stem cells in your finished product. To track potency, therefore, companies regularly perform quality control assays. HemaCare provides cell counts and purity data before precursor material is sent out to customers (see Figure 1), and pharmaceutical companies on the receiving end will often repeat quality control assays once they arrive in house, and at crucial points along the manufacturing workflow. Quality is just that important to the finished product.

“The quality of your precursor material to the overall development process is absolutely critical. Raw materials are everything, and I think the smart companies know that.” said Dr. Fred Miesowicz.

Donors are also critical to the process. Dr. Miesowicz notes that in his experience, male donors often had higher monocyte counts than female donors, and larger donors had higher numbers than more diminutive donors, simply as a matter of the blood volume that could be collected. Access to healthy donors is important because getting precursor material from patients is often not possible. Patients may be too weak to donate, or their immune systems could be compromised by their disease state, something Dr. Miesowicz saw frequently with his renal carcinoma patients. At Argos, the number of healthy immune cells present in the precursor material was particularly important, because they were dealing with monocytes, a cell type that doesn’t replicate. Since it can be assumed that the number of viable, functional cells takes at least a small hit with each step of the production process, starting that process with high quality material means that you’ll have a much better chance of higher efficacy downstream.

Reliable Sourcing
Consistent sourcing can be just as critical to downstream results as quality control. Dr. Miesowicz described the difficulty of coordinating a process development run in his lab at Argos. For most runs, the isolation and modification process for their therapeutic took seven days in total to complete. Many different individuals from different areas of expertise have to be ready to proceed at the same time, and timing is critical, since it potentially affects the lives of seriously ill patients. In cases like this, the importance of sourcing raw material in a timely manner can’t be overstated. Dr. Miesowicz emphasizes that this was one of the main reasons he originally decided to stick with HemaCare; not only did they supply high quality products, they also did an excellent job of coordinating development efforts.

After many years at Argos, Dr. Miesowicz decided it was time to switch gears. He is currently supervising the process development of a Canadian biopharmaceutical company based in Montreal called SpecificiT Pharma, that specializes in developing treatments for hematopoietic blood cancers. This company is developing a proprietary technology based on the use of Minor Histocompatability Antigens (“MiHAs”); short protein sequences that are presented on the surface of a cell. The MiHAs presented on the surface of a patient’s leukemic cells are often different from those presented on the surface of his or her donor stem cells and they can therefore be utilized to generate donor specific T-cells to safely eliminate leukemic cells without causing potentially life-threatening blood cell count lowering like CAR T-cell therapies do.[3] Dr. Miesowicz explains that he recommended that SpecificiT purchase HemaCare leukopaks for their work.

“When I first started consulting for SpecificiT, I found that, like many start-ups, they were relying on obtaining precursor material from local hospitals and academic apheresis labs, but that model just isn’t workable. In the first place, small academic groups generally don’t have healthy donors, which are critical to process development, and also collection is simply not dependable. If you want to get the product you need, WHEN you need it, HemaCare is the way to go.” exclaimed Dr. Fred Miesowicz.

After looking into the ongoing clinical research process at SpecificiT, it was an obvious step to recommend HemaCare products. The company will be using fresh leukopaks as a source of hematopoietic cells for their proprietary MiHA library, as well as for process development. Dr. Miesowicz sums up his experience with HemaCare in one simple quote: “Once we had HemaCare, we never went back.”

References
[1] Amin A., et al. Survival with AGS-003, an autologous dendritic cell–based immunotherapy,
in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): Phase 2 study results. Journal for ImmunoTherapy of Cancer. 3:14. 2015.
[2] Burger SR, et al. Cellular Raw Material Collection in Cell Therapy: Critical
Determinant of Product Quality. Drug Discovery World. 2014; Volume I5, Issue 3: 29-34. 2014.
[3] Dzierzak-Mietla M., et al. Occurrence and
Impact of Minor Histocompatibility Antigens’ Disparities on Outcomes of Hematopoietic Stem Cell Transplantation from HLA-Matched Sibling Donors. Bone Marrow Research. 2012.