Within the International Society for Cellular Therapy’s (ISCT’s) Industry Commercialization committee, Tracey Lodie, director of immunology and stem cell biology at Genzyme, chairs the Industry Education subcommittee, which was established in May 2010. In an interview with BPI, she described the subcommittee’s objectives and how they tie into the manufacturing, testing, and commercialization challenges for cellular therapies.
Reducing the Risk
“ISCT is working toward becoming an informational hub, acting as a resource to de-risk cell therapy and get products to market. We work together in four subgroups: process/product development, clinical development/new product introduction, business models/reimbursement/COG, and industry education. We seek to aid in developing business models from early discovery to pre-clinical research through to clinical development. The goal of the education committee is to evaluate how the industry is addressing these needs, discovering where we find overlap with other societies, and bringing this information to those in the clinical field and at the research bench.
“A new goal this year for us is to select certain disease indications that ISCT members and cell therapy experts felt were good areas to focus on. There is a significant amount of preclinical data and early clinical data for certain disease areas. We want to hold discussion forums that focus on these areas with expert key opinion leaders, including medical scientists and regulatory experts. We want to identify and address the holes in technology and push the technology forward in particular indications. Once this information is available we will disseminate it trough public channels at ISCT.
“The education committee’s goal is not to promote a specific company; we do not give out proprietary information. We have assembled a core group of people who want to advance cell therapies before they want to advance a particular product for their company, realizing that one person’s success allows people to piggyback on those regulatory and clinical successes and even move on to different indications.”
Industry Challenges
Analytics: “As with any company, the main challenge for those working in cell therapy is determining how to manufacture product that will get regulatory approval. In general, the field needs to improve on cell characterization and identification to ensure from lot to lot that what you are developing is actually the same product. It’s very different from an antibody or small molecule for which you can do standard quality assurance/quality control analysis. It’s a cell, and there are going to be varying degrees of differences from batch to batch simply because of normal biologic growth.
“The field is still advancing and in need of developing additional potency assays to discern these slight variances from lot to lot in vitro testing to translating into clinical efficacy. If you had a reagent that hit a single target, I would be able to tell you the concentration that is the maximum dose. But with a cell therapy, there are always areas of gray. That is the challenge in the field. As a committee, we are reaching out to others in the field and other societies to tackle these issues and get the information out publicly to the point that regulatory agencies will adopt it. That is the goal. Right now there has been such a risk that many companies have been going into indications where the treatment may be the last effort or the treatment is very specific. For example, embryonic stem cells (hES) are being tested in the clinic in a very specific spinal cord injury population. So you either eliminate risk by going into a narrow subset of a population or by going into a population where it’s end-stage.”
Manufacturing: “It’s much more expensive to manufacture a cell therapy because of all the components that go into it, including media, serum, lab space, tissue culture space, and delivery. It’s not something standard can fit in a vial and store at room temperature or lyophilized and reconstituted. There are going to be cost-based challenges to manufacturing. For most in big pharma, it will not be sufficient to just transfer the know-how to get a product approved, it must be profitable. A process may be scalable and reproducible, but it might not be the most cost efficient and needs to be more refined. That’s where ISCT wants to come in — with industry education information that will help companies get more refined and scalable processes, learning from what has been experienced from phase 3 to approval.”
Clinical Trials: “Cell therapies undergo the same phases of clinical development as protein biologics. You still need to show efficacy, primary pharmacokinetics (PK) and pharmacodynamics (PD), animal studies, and so forth before getting into the clinic. But the challenge lies in the PK and PD of a cell therapy because it is distributed throughout the body and may or may not be incorporated into the tissue that should be treated. This is very different from an antibody or small molecule that has a certain half life. A cell therapy provides unique challenges based on the cells multifaceted mode of action.
“Biotech has taken on diseases that are difficult to tackle, and cell therapies have their own niche where other therapeutics have failed. This means clinical trials are difficult. Cells are usually added on top of an existing standard of care, so the number of patients has to be larger in order to get a significant outcome. If it’s a refractory or relapsing population, then the trial is more challenging from the outset. For example, in treatments for graft-versus-host-disease (GVHD), adult mesenchymal stem cells have gone in to either assist with bone marrow transplant reconstitution or to actually cure steroid refractory resistant GVHD.
“Adult mesenchymal stem cells have a dramatic safety profile and have shown efficacy in phase 2 clinical trials, but the field is still waiting the first approval due to the need for a conclusive phase 3 trial. Even though big pharma considers GVHD a risky indication with difficult patient populations and the larger trial size needed due to its multiorgan nature, a success comes with a big reward. The ultimate goal is an approved product to treat this unmet medical need.
“ISCT wants to get thought leaders in the field to identify bottlenecks in that development. As an information hub, we can improve this and get big pharma involved. The more big pharma is involved, the more know-how there is for getting therapies into the clinic and toward approval that is profitable. That is the lofty goal.”
Improving Business Models: “Cell therapy companies are trying to determine how to make the hurdle toward end-stage manufacturing, get more cell therapies to the clinic, and improve their business models to make it profitable. That was an issue for Genzyme with our autologous cell products. They were scaled up and processed and delivered to the patient, but the infrastructure was such that in order make it profitable, we would need to treat many more patients than we were able to treat using an autologous therapy. The therapy worked and was very efficacious,
but it was never very profitable.
“The business model is very different for allogeneic cell therapies. The cost of goods needs to be improved in terms of scalability, where you can remove fetal bovine serum and you can remove certain scale-up steps as well as certain intermediaries such as freezing to have it fine tuned. That is really where the field needs to improve.”
Intellectual Property: “When you make a recombinant protein, you make it from one source, but a lot of these cells can come from several sources. What makes the IP challenging is the different cell-surface markers for the cells that come from different organs. And the question that arises from a patent examiner is: Is this cell functionally different? People may not know the answer to that because the potency assays are not refined enough to answer that. That is where the difficultly arises. These are the challenges that lay ahead for cell therapy.”
Current Projects
“The task ISCT has set for themselves is to provide industry information and to link experts in the field to assist them to find the best indication to trial a cell therapy. ISCT wants to be a hub for information for scientific data, from both preclinical and clinical trials, and to have access to key opinion leaders in certain indications. ISCT’s goal is to have the information and the experts and link the two. Currently we are working on coordinating a two-day forum on inflammatory bowel disease to get industry, biotech, and regulatory representatives. The industry community is working on putting together plenary sessions for the ISCT annual meeting. And we will work on an announcement of that for the ISCT website.
“And we are in the process of linking ISCT with other societies, (with hopes to be completed by the end of the year) through web and face-to-face meetings. The plan is to have two-day forums twice a year of these investigator meetings in topics that the industry community and other ISCT members have deemed important, and then publish the results of those forums by webinar and ISCT website to get the information out and readily available to ISCT members”.
Author Details
Maribel Rios is managing editor of BioProcess International, 1-646-957-8884; mrios@bioprocessintl.com.