TM: RHEINCELL Therapeutics was founded about three years ago, based on the expectation that iPSCs would become an important element in the development of advanced therapies. The founders had a very strong network with cord blood banks and the idea was to generate high-quality cellular starting materials derived from those sources.
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Is there growing interest in iPSCs?
BG: There has been enormous progress in iPSC technology, and we have experienced increasing demand from customers around the world asking for our cells to support their clinical strategies. The methods are well-defined. Culturing the cells is now easy and safe. Differentiating the cells is certainly not easy but there are numerous protocols that allow you to differentiate cells with high efficiency. Materials that are required for GMP-compliant manufacturing are becoming available as well. Now is the time to get started with clinical applications.
I’m interested in your thoughts on the evolution from autologous to allogeneic cell therapies. Do you think that one day allogeneic will replace autologous cell therapies?
BG: I think the autologous approach is certainly the more elegant one – you take the cells from the patient, reprogram them to iPS cells, generate the tissue of interest and you have personalized cells. But it’s laborious, expensive and time-consuming. Ultimately, we need an allogeneic approach to reach a broader patient population. This, of course, requires addressing the issue of immunosuppression. That’s what we support with our starting material based on HLA-homozygous donors.
What needs to happen for allogeneic therapies to become the standard approach?
BG: The big advantage of an allogeneic approach is that you could generate an indefinite resource of cells. You would only have to manipulate the cells once and grow large numbers. You could differentiate the gene-modified iPS cells into the cell type of interest, such as T cells to fight solid tumors, or you could use unmanipulated cells and turn them into specific tissues for cell replacement therapies. In any case, you could make large numbers of these cells and cryopreserve them in multiple units, ready to distribute to various clinics and serve many patients. I think that’s the potential of the allogeneic approach: that you can serve many more patients and in much shorter time with simplified logistics. I think it’s going to be exciting to see the field moving in this direction.
TM: In order to further evolve allogeneic strategies for cell therapy, the use of gene editing technologies to modify the corresponding gene pool responsible for tissue rejection is also gaining traction. This can be used to minimize unfavorable effects and that’s clearly something we are seeing more of in recent months.
Tell me about RHEINCELL Therapeutics’ role in the cell therapy landscape?
TM: A recent, critical element in the short history of RHEINCELL was the final certification of our facility and the manufacturing authorization to produce our iPSCs according to the GMP standard. That was a milestone. Now we can provide customers with the cellular starting material that they require to initiate their clinical programs.
BG: There’s a significant demand for GMP-grade iPS cells that can be exploited commercially. This is also an aspect that’s quite unique about our cells; we have full consent from donors to exploit these cells commercially. Furthermore, beyond supplying these cells, our long-term vision is to also provide the tissue that is transplanted into the patient.
TM: If you look at what our customers are doing today, they want to get their processes developed quickly, securely, with no risk. That’s what we try to support. Our GMP-grade cell lines are also available as non-GMP twins. That is, identical cell lines but specifically created to support the first evaluation and testing phase in a commercially feasible manner. The advantage for customers is that they don’t need to redo their experiments again when they move to GMP-grade. That’s where we think we can add real value alongside providing the GMP lines fully characterized.
You’ve mentioned the donors a few times. Can you talk a little bit about the donors? What exactly is HLA agent?
BG: As Thomas mentioned, we are currently focusing on HLA-homozygous donors. These are rare individuals in the population that have identical HLA cell recognition genes on both the paternal and the maternal chromosomes. This sets up the potential for making iPS cells from cord blood that match the genotypes of many more recipients than you would be able to with an arbitrary donor. In a cumulative sense, several of these cell lines would ultimately be sufficient to match a significant portion of the population, without the need for immunosuppression or with a significantly reduced dose of immunosuppressant agent. The basis of the approach is not having to use gene modification because of our granted access to HLA-homozygous starting material. The cells sourced from those privileged donors can serve to transplant many patients – up to 50 percent of the Caucasian population with the lines we have currently.
TM: It is also worth mentioning here that the cord blood is a neonatal material and thus, the genetic integrity of the derived iPSCs is superior. The tissue of origin has simply had minimal exposure to the environment. The result is a far lower mutation load of the final iPSCs, compared to what we see in the market, which of course improves safety.
Cytovia Therapeutics recently announced a partnership where they’re using iPSC-derived NK cells for application in solid tumors. Do you think partnerships will accelerate breakthroughs in solid tumors?
BG: Our cells have been tested and validated for being able to differentiate along the NK and T cell lineage. That means they are suitable for these iPSC-based cancer therapies. I think there’s a huge potential of CAR T or CAR NK cell therapies based on iPS cells. You could produce off-the-shelf stocks of the modified cells, differentiate them in large batches and treat many patients with just one or a few cell lines. I think the possibilities could be transformational and that’s why there’s so much interest in taking this approach. And certainly, our cells are particularly suitable for this, given their broader matchability to recipients via the HLA-homozygous lines.
What should we expect from RHEINCELL in the next 12 months?
TM: We are expanding our technical and scientific profile. To that end, we are exploring the aspect of gene editing but our biggest focus is augmenting the entire service portfolio around the iPSC workflow, from developing differentiation protocols together with our customers, bringing those protocols towards a GMP environment, and from there scaling up processes. Finally, we also certainly have plans to initiate our own clinical projects.