Navigating the Challenges of Cell-Based Immunotherapies

The newly launched industry’s leading scientists warn of diverse hazards—unviable cells, contamination, supply chain complications, and excessive costs

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Sigilon’s encapsulated cells
Sigilon Therapeutics encases novel human cells in a proprietary immune-shielding matrix. When placed in the body, these cells, Shielded Living Therapeutics, produce therapeutic proteins in a programmable and durable fashion, without generating fibrosis or immune rejection. The purple spheres shown in this image are holding Sigilon’s encapsulated cells.

Cell therapy is emerging, cell by cell, into the repertoire of medical therapies. However, it still has not broken into mainstream use. For instance, there are only two FDA-approved chimeric antigen receptor (CAR) T-cell treatments in the United States: Kymirah, Novartis’s treatment for acute lymphoblastic leukemia, and Yescarta, Kite Pharma’s treatment for non-Hodgkin’s lymphoma. To get a sense of what pitfalls are holding these therapies back and how scientists are working to navigate them, GEN spoke to leaders in research, medicine, and biotech in cell-based immunotherapy. In this article, they discuss their field’s future, addressing topics such as the relative advantages of the allogeneic approach, which harvests cells from a donor, and the autologous approach, which harvests cells from the patient.

 

GEN: One outstanding question is how to effectively get cell therapies to patients all over the world. How do you approach that?

Michael Har-Noy, MD, PhD, CEO and CSO,  Immunovative Therapies: For us, when we started our Phase I trials, our living-cells-formulated composition had a shelf life of only 4 hours. To commercialize something like that would require us to formulate where the patients are, because you can’t really bring the cells very far in four hours. We identified early on that this was a bottleneck to commercialization. We advanced from 4 hours to 96 hours by optimizing the formulation, then to 120 hours, and now we’ve developed a frozen dosage course, where each dose can be frozen and stored long-term. We can mass produce the individually aliquoted doses, freeze them in liquid nitrogen, and distribute them to the pharmacies of clinics to be held in inventory. When they’re needed, they can simply be thawed and injected, rather than having to undergo complicated regional or on-site processing that adds costs and complexities to the distribution chain.

One of the problems is that these therapies have very short shelf lives. To prove that they’re sterile, USP71 (U.S. Pharmacopeial Convention) requires a 14-day culture. This means that companies and others in cell therapy have to infuse the cells because they have shelf lives shorter than 14 days. Basically, the cells are inside of the patient before we find out if they were sterile. This requires an enormous effort in terms of the aseptic processing techniques needed to reduce and mitigate the risk of contamination. You don’t want to retrospectively find out that you gave a patient a contaminated product.

Immunovative Therapies lab
Immunovative Therapies develops products based on its Mirror Effect technology, which is designed to elicit a graft vs. tumor (GVT)-like mechanism without graft vs. host disease (GVHD) toxicity. For example, the company combines a personalized anticancer vaccine protocol, which causes the release of tumor-specific markers, and the injection of bioengineered allogeneic immune cells into the lesion as an adjuvant to modulate the immune response and educate the immune system to kill other tumor cells. At Immunovative, all processing and formulation steps are conducted under a certified ISO 5 biosafety hood located within a certified ISO 7 cleanroom.

GEN: What do you see as a potential pitfall that is keeping cell-based immunotherapies from going mainstream?

Devyn Smith, PhD, COO, Sigilon Therapeutics:The biggest challenge you have with new therapies is the cost of goods, and I think a big piece of that is the supply chain manufacturing component. If you look at the supply chain element, you see that it goes from the autologous vein to manufacturing, and then from manufacturing back to the vein. I think that these supply chain elements are still a bit nascent. We’re still learning how handle them efficiently, so the cost of goods for those can be quite high, on top of the cost of manufacturing. And let’s say you have 48 hours to get that into a patient. We’re still not great at getting it across borders or even across the country, particularly within this time window, so I think there’s an efficiency piece that needs to be addressed to drive down the cost of goods.

Leo Chan, PhD, technology R&D manager, Nexcelom Bioscience: For years, cell counting has been very straightforward because for most researchers working with cell lines that are cultured in incubators, there’s not too much difference or complexity in these mainstream cultures. A common variation on cell counting is bright-field counting that uses simple light microscopy, a hemocytometer, and trypan blue for staining.

With the rise of cell therapy, assessments of cell samples are becoming more complex. Immune cells are coming from patients and being treated and transduced to express certain markers, and these cells are supposed to be returned to the patient’s body. There’s a very strong emphasis on making sure whatever things you’re putting back into the patients should be healthy. You don’t want to put dead cells back into the patient’s body.

We’ve found that trypan blue has a huge effect. We have captured evidence showing that trypan blue bursts dead or dying cells, so they become this ballooned, very diffuse shape, which doesn’t get picked up in a light microscopy system. So these [dead] cells remain unseen. Using the trypan blue system would underestimate the number of dead cells, and could overestimate your viability.

 

GEN: How can the cost of cellular therapy be reduced? What needs to change to make it more affordable?

Dr. Har-Noy: This is the real elephant in the room in our industry. There isn’t really a solution, so we don’t like to talk about it. It’s like something being developed in the back. And it’s limited to really niche hematological malignancies, and that’s probably where there are expectations that it can be scaled up and produced for even solid tumors. We’re a long ways away from being able to do that technically, let alone to mass produce those products so they can be distributed to a larger market like solid tumors. At least the hematological malignancies are a very small market. You can set up specialized options, and the patients may come to you.

Patrick Hanley, PhD, director of GMP for immunotherapy, Children’s National Medical Center: A bone marrow transplant costs a couple hundred thousand dollars at the hospital. What would the transplant cost if Novartis were in charge of the bone marrow? It would cost four times as much. What if you were to manufacture CAR T cells at the economic centers? The cells would cost 1/10th what they would if they came from Novartis.

Given the expertise in the field right now, there’s not enough people for [immunotherapy treatment] to be widespread, but I think bone marrow transplant is a great model for all of this. You don’t have 20 bone marrow transplant centers in one city, you have one or maybe two centers of excellence, and everybody is driven to those hospitals because you know there really aren’t that many patients.

Dr. Chan: This is a very tough question because we don’t know what’s going to happen in the future. Genome technology will keep advancing, so the way people manufacture these immune cells is going to improve, just like semiconductors. I used to be in the semiconductor industry, and that industry has improved over the years, simplifying the mass production of televisions, for example, and reducing their costs. There are so many researchers working now to optimize the entire cell manufacturing process. I believe that once everything is optimized, and manufacturers are producing as much as possible, the costs can come down.

Knut Niss, PhD, CTO, Mustang Bio: It’s interesting when you look at the whole picture. You see that the manufacturing of the product is just one item. When we started our process development, we kept an eye on the overall cost of processing. But I don’t think too many people paid attention to the quality control side, which is equally important. Running assays more efficiently and more cost-effectively is critical. In clinical development, when we have a patient here, a patient there, it’s probably not as dramatic, but when you move toward commercial production, you have quality control release assays that you need to run for hundreds of patients. It probably makes sense to develop assays that are more cost effective.

 

GEN: What will cell-based immunotherapies look like in the future? Does the science or the market favor allogeneic treatments, which resemble traditional biologics in some ways, or autologous treatments, which are more novel?

Dr. Har-Noy: There hasn’t been a real commercial demonstration that the autologous business model is feasible. It’s more of a boutique drug market. That’s one issue. Another issue is finding a way to make cell-based therapy affordable to the masses. The autologous model is difficult with respect to this issue, too. It’s not really a drug, more like a procedure, like a bone marrow transplant procedure, not really amenable to the type of commercialization referred to earlier.

Dr. Niss: With allogeneics, the pipe dream would be to be similar to biologics, like a bioreactor environment where you make a large batch, like a 200-L bioreactor of T cells, and then get filled in to patient-specific doses. I’m not sure we’ll get there, to that scale, but the allogeneic approach is much more about emulating the biologics approach, where you are making one big batch so that you can be done.

I’m a little skeptical of the allogeneic approach in general. I think a 200-L bioreactor sounds overly ambitious simply because of what we know within the CAR T-cell space. You really don’t want to exhaust the proliferation potential or the proliferation capacity of the cells. You want to give the patients cells that are still capable of significant expansion when they react to the antigen. So, if you want to run a 200-L bioreactor, you basically run into the issue that you generate cells that are exhausted from a proliferation standpoint.
I see that as a potential challenge.

 

Dan Samorodnitsky is science editor at Massive Science.

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