Mark Bonyhadi, Eric Roos and Brian Newsom, Cell Therapy Business Development leads for immunotherapy, stem cell therapy and tissue engineering, share their experiences in cell therapy and talk about recent developments and challenges.

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2009 - A year to celebrate?
So far this year, we have seen some major advancements:

• Dendreon™ announced remarkable survival data from their pivotal phase 3 study, offering next-term potential for cell therapy's first-ever blockbuster
• At the other end of the clinical development spectrum, the FDA allowed the first patients to be treated with an embryonic stem cell–based therapy, Geron, a technology platform broad enough to offer greater therapeutic potential than monoclonal antibodies
• Outside of the clinic, rapid strides are being made in induced pluripotent stem cell (iPSC) technology, which offers the potential to overcome two key hurdles in the path of hESC-based treatments—potential immunologic reactions and ethical issues—though perhaps introducing a new challenge related to genetic manipulation and stability
• From an indication standpoint, many groups including Eyecyte with the backing of Pfizer, Advanced Cell Technology, who plan to file an IND soon, and a cadre of academic groups hoping for a slice of newly announced state and federal funding are settling on the eye as a site to try their stem cell–based therapeutic approaches, in the hope of minimizing immunologic reactions and having a back-up organ (the other eye) should anything go wrong

One reason for targeting the eye for pluripotent stem cell–based approaches is the potential for teratoma formation by residual undifferentiated stem cells. Although multiple strategies are being employed, in our work with the Buck Institute (as well as work funded by CIRM at Novocell), we found a way to remove the “problem children”—potential remaining pluripotent stem cells—is to fish these cells out using an antibody to a common marker and coupling this to magnetic beads. While we don't consider this a complete solution to the teratoma issue, we do believe it is a valuable weapon to address a key challenge in the development of ESCs and iPSCs; making safer stem cell therapies.

Our community hasn't been immune to the impact of the turmoil in financial markets. Venture capital firms are struggling to keep their existing portfolio companies afloat, let alone fund new ventures. Several groups have either substantially scaled back or completely discontinued operations. Perhaps of little solace, this effect is not unique to cell therapy–focused venture capital. Government funding provides a measure of compensation. CIRM has secured financing through 2010 and is now distributing multimillion dollar awards (of which we were a minor and grateful recipient). Governments outside of California are joining the fray, including New York State (NYStem) and a well-deserved $7.2 million to cell therapy pioneers Organogenesis from Massachusetts. Even the U.S. government has joined the party with a remarkable $10.4 billion uptick in NIH funding, much of which will be focused on stem cells and regenerative medicine, now that it's okay to for us to work on this kind of stuff.

What does cell therapy mean to you?
Cell therapy to me represents long-term and potentially target-specific intervention for disease, which is significantly different from the use of radiation or chemical-based therapies which are transiently applied or rapidly cleared.


What are the key challenges faced by the cell therapy community?
I think cost of goods, cost of services, reimbursement of cost, and commercialization of cell therapies are some of the key challenges faced by cell therapy community. Cell-based therapies have yet to demonstrate efficacy. One of the challenges is acceptance of cell-based therapies by the clinical and pharmaceutical industry. Pharmaceutical companies are facing financing challenges for developing cell-based therapies.


What is the industry trend in cell therapy?
The trend is towards bulk products and then towards patient-specific products. There is also a great drive towards combination cell therapies associated with drugs or chemotherapy, and not cells alone.


What range of reagents/materials can be used in GMP cell manufacturing, with regard to their quality levels? If GMP materials are available, but would increase the cost of manufacture to a non-tenable level, can non-GMP materials be used? From your point of view, how does the FDA look at this issue?
FDA regulations go up exponentially between Phase I and Phase III clinical trials. Prior to market approval, all cell-based products need to be fully GMP/GTP-compliant. Regulatory authorities tend to be more flexible with reagent requirements in Phase I/II, depending on the severity of the disease. If the disease is life threatening, the FDA is less strict. The FDA also looks at the availability of GMP raw materials, and if not available, it might approve the use of non-GMP raw materials provided safety test such as sterility, mycoplasma and adventitious agent testing have been conducted. The FDA also looks at how long the cell-based products are in the patient; short-duration products may not raise the same level of concern as longer-duration products or products that undergo substantial differentiation and expansion in vivo. For example, dendritic cell-based tumor vaccines may be less of a carcinogenicity concern than stem cell-based products.


What are most recent developments in cell therapy that makes it so promising?
Dendreon™ Provenge prostrate cancer therapy has shown to significantly improve survival in men. Osiris’ Prochymal™ (treatment) is a form of mesenchymal adult stem cell for treating acute graft versus host disease (GvHD).

FDA approval for the clinical trial of GRNOPC1 in patients with acute spinal cord injury will be the first study of a human embryonic stem cell-based therapy in humans, and it has set the bar for this technology.  

Recent news on City of Hope stem cell-based therapy for HIV with sustained expression of siRNA has raised hopes for gene therapy. The recent reversal in the position on federal funding for embryonic stem cell research will open up discovery and exploration in this field.

What’s your background and how did you get into cell therapy?
I obtained my PhD in stem cell bioengineering in 2006 from MIT. I was appointed Chief Scientific Officer of AuxoCell Laboratories, Inc., after completing my post-doctoral training from MIT and the Boston Biomedical Research Institute in 2008. Before that, I obtained my bachelors of science in chemical engineering from the University of Massachusetts, Amherst, in 2000. I have spent the past 10 years working to bring stem cell based therapies to clinical practice, with the aim of helping patients suffering from various diseases and cancers. I have worked extensively in adult stem cells, especially human hematopoietic stem cells


How has Invitrogen made a difference in the work your company has been doing?
One of the main concerns while passing mesenchymal stem cells is to maintain normal karyotype and high viability of the cells. One morning I was preparing to passage six different flasks while working with Wharton's Jelly derived mesenchymal stem cells.

After a wash with HBSS, I added 1 mL of GIBCO® TrypLE™ Express to the last of the six flasks when suddenly the fire alarm went off in my building. Not knowing what had set off the fire alarm, I decided to attempt to save the cells by placing the flasks in the incubator to quickly detach the cells and subsequently dilute the TrypLE™ with HBSS. I placed the flasks in the incubator, but did not have the opportunity to dilute them with HBSS, since a fireman came to the cell culture room I was in and asked me to evacuate the building. So I had no choice but to leave the cells in the incubator in 1 mL of TrypLE .

It turned out that our generator room had flooded due to heavy rains overnight. It was not until 2:30 p.m. that we were allowed to re-enter the building. I took my flasks out of the incubator, prepared for the worst, but decided to proceed as normal in an attempt to save the cultures and was expecting significant cell lysis and poor cell viability.

When I looked at the cells under the microscope, to my pleasant surprise, the cells were intact (suspended in the TrypLE™), and more notably, viable—as viable as they would have been under normal conditions (~98%). I passaged the cells and the cultures continued propagating without any significant problems. Fortunately, I was using TrypLE™ to detach my cells (and not trypsin-EDTA) and was able to save my cultures, even though the cells were in TrypLE™  for 4+ hours. If I was using trypsin-EDTA, undoubtedly, the cells would have lysed in 20 minutes and I would have had to start my month-long experiment from the beginning.