Allogeneic Cell Therapy Results: Delving A Little Deeper
By Mark Gergen, CEO, Poseida
As the CEO of a publicly traded genetic engineering company operating in the allogeneic cell therapy space, I spend a lot of time talking to investors, analysts, strategic collaborators, clinicians, employees, and others about not just our technology and products but also about competitive programs, approaches, and data.
Cell therapy holds immense promise for patients. The initial autologous, or personalized, cell therapies have shown remarkable results in some cancers over conventional therapeutic modalities, but those autologous approaches have limitations in terms of complexity, high cost and in some cases safety that will limit their broad use and adoption. As a result, many companies are pursuing allogeneic, or off-the-shelf, cell therapies to address and overcome these limitations. At Poseida, we believe that our unique approach to allogeneic cell therapy, powered by our differentiated and novel technology platforms, has the ability to address these challenges and unlock the potential of cell therapies broadly.
One of the most common questions I have been asked is: “What makes you confident about your allogeneic cell therapy approach, when so much of the data from others has been disappointing?” My initial answer is often focused on digging more deeply into those disappointing results from other companies and the possible insights that come from those observations.
We agree that the allogeneic cell therapy data we have seen from others has been uninspiring, but the natural follow up question is, “What about those data has fallen short and what are the likely causes for those results?” The answer is multi-faceted.
The first area of missed expectations is what I would categorize as up-front efficacy. That includes observations that the overall response rate, or ORR, and the depth of initial responses seen by many allogeneic approaches are not as strong as that seen with autologous approaches in similar indications. The next logical question is “What are the likely reasons for those results?”
While the biology of allogeneic therapies is complicated, one hypothesis is that ORR and depth of response is closely associated with the quality of the binder (often a CAR, or chimeric antigen receptor molecule). While cell type also matters, a good binder should deliver good initial ORR and good depth of response. As an example, Legend Biotech’s autologous CAR-T in multiple myeloma showed us that a good binder can deliver impressive ORR and deep responses even at relatively low doses.
With that in mind, if one looks at the binder technology used by some of the industry’s early allogeneic programs, we observe that many are using older and more traditional single chain variable fragment antibody binders. While there is no universal rule as to what makes a good binder, we know that some of the binders used broadly in cell therapy – by either academic or industry players – were simply not that good in vivo. We think this has contributed to some of the challenges with the early results from others.
Finding a great binder is not as simple as screening binders in ex vivo assays. Things like affinity and avidity alone do not predict how good a binder will perform in a CAR format – one has to test many binders in vivo to find the best binder or combination of binders. At Poseida we had that realization early and invested significant time and effort into exploring binder sources and attributes. We are confident in our allogeneic approach in part because we believe that we have selected good binders for our allogeneic programs.
There is an additional component of up-front efficacy related to the cell platform being used. In our experience, T cells are the best cells at killing cancer cells. Despite their name, natural killer cells, or NK cells, are simply not as good at killing as T cells. So, to some degree, cell type likely contributes to some of the early disappointing results as well. There are, of course, other cell types beyond T cells and NK cells being explored, including gamma-delta T cells, tumor-infiltrating lymphocytes and macrophages – but the jury remains out on those platforms.
Durability of Response
The second area where allogeneic data from others has not impressed is that of durability of response. Much of the data presented by others demonstrated limited durability and relatively quick relapses in at least some of the patients. Here again the question is: “What are the most likely reasons?” In the case of durability, the reasons underlying the results are a little more complex. Despite a number of hypotheses offered by some, the actual evidence published or shared to date has not clearly established a single cause. We think a number of factors could be at play.
First and probably foremost, we believe that “cell type matters” when seeking a durable treatment platform in cell therapy. There are a number of cell types being used for allogeneic cell therapy, with T cells and NK cells being among the most common at present. If you are assessing durability it would stand to reason that you want a cell type that will persist and live longer. If your product does not persist, the therapy will struggle with delivering and maintaining a durable response.
We have long been believers, and there is growing academic and industry support, for the premise that a T cell subset called a stem cell memory T cell, or Tscm, is the ideal cell type for allogeneic cell therapies. Tscm cells are the T cell subset that have the potential to engraft, self-renew, create waves of more differentiated cell types, and have the potential to live a long time. Other more differentiated T cell subtypes and cell types such as NK cells are known to have a much shorter life span. If durability is the goal, the Tscm cell would seem to have a distinct advantage. None of the early allogeneic cell data have had the benefit of using this cell type.
Second, we believe that the health and fitness of the cell matters. In an allogeneic cell product, you want the final product cells to be healthy and have significant proliferative capacity when administered to the patient. If a product is manufactured using older virus-based technologies, like many of the early allogeneic products, those cells are likely more exhausted and have less proliferative capacity at dosing. For others this can be a technology problem. The viral-based technologies require one to activate the cells to get infection and that activation starts the cells down the differentiation pathway and uses proliferative capacity during manufacturing. That problem can be further exacerbated by using a gene editing technology that also requires activation for efficient editing – pushing the cells even further into a differentiated and exhausted state as part of the production process. In short, companies using older technologies are likely producing a more exhausted product.
A third reason for durability challenges is the possibility of some biologic response that is cutting off or blunting the response in the patient. There are a number of hypotheses, including a possible NK response, some type of neutralizing antibody response or a cytotoxic response – although the data and evidence to date is far from conclusive in any direction. From the allogeneic data to date, it is not clear whether one or any of these hypotheses are real – but are offered more as theoretical reasons for the results. One question that should be asked in at least some cases, is whether it was some biological response that led to the disappointing result or whether the product itself was just an exhausted cell type with a less than optimal binder. Even if such biologic challenges are real, there are solutions to dealing with those challenges if you have the technology platforms that enable you to address them. We believe that we do.
As discussed, durability is a complex question that can also be impacted by other factors such as antigen loss (in some indications) and we appreciate that complexity. We believe that cell type, and specifically Tscm, does make a difference and may be the real key to effectively treating certain cancers.
The bottom line is that Poseida’s approach and our resulting products are not just a little different from others, they are significantly different and so we are confident of a different and potentially better outcome.
What Does Success Look Like for Allogeneic Cell Therapy?
Often the follow up question to the discussion above is, “What does success look like for allogeneic cell therapy?” If we take the longer-term view, we need to look at multiple factors including up-front efficacy, durability, safety, and access as well as health economics (i.e., cost). The end goal should be to make transformative allogeneic CAR-T cell therapies available to as many patients who can benefit from them as possible, so all these factors come into play.
We believe that by using the right binder and the right cell type, allogeneic therapies should be able to match or surpass the efficacy of autologous therapies. How exactly up-front efficacy translates to ORR and depth of response will vary by indication, but there is no reason to believe that we cannot address the shortcomings of other allogeneic approaches. In terms of durability, we also believe that the challenges encountered by early allogeneic entrants can be addressed through a combination of the right cell type, the right genetic edits, and the right armoring and dosing strategies to deliver equivalent or better duration of response than autologous approaches.
Where allogeneic approaches should really shine, and where we are convinced that they will, is in convenience, including safety considerations and cost. The ability of allogeneic approaches to be immediately available off-the-shelf is a game changer for patients and for eventual commercial reach – especially if you can produce a product with a safety advantage, which we think is aided by the right cell type and the right technology. While some of the autologous products have delivered impressive efficacy, the logistic challenges, cost, and safety profile will limit those products once a more affordable allogeneic option becomes available.
Finally, while no one likes talking about the financial aspects of these technologies you cannot ignore the health economic factors as they relate to both patient access and commercial reach. With the right technologies to apply, allogeneic approaches should be able to eventually generate many, many doses from a single manufacturing run, bringing the cost of an allogeneic cell therapy to a level that is a fraction of the cost of autologous predecessors. As a result, if an allogeneic cell therapy option is cheaper, potentially safer, more convenient, more broadly available and even close to the level of efficacy of its autologous counterpart, that will be a game changer. We believe that day is coming soon.
So – Are We Confident or Optimistic?
Circling back to the initial question: Are we confident that we can improve on the allogeneic data seen to date from other early entrants? I am not sure if it is confidence, optimism or a bit of both, however, we do believe that a solution for allogeneic cell therapy is around the corner and that we have the technology to make that dream a reality. To be fair, this is a complicated endeavor, and it may take an iteration or two to find the ideal solution, but we are committed to finding it. We recently announced a partnership with Roche to combine our efforts to find allogeneic CAR-T solutions for hematologic malignancies and are excited to have a strong ally in that quest. Together we will delve deeper into exploring the learnings from our own work and from the early allogeneic entrants that have struggled, and we are optimistic that we are on the right path. While the journey and the research are not over, we are excited about the potential these therapies hold for patients in oncology. Let’s keep asking the deeper questions until the dream becomes reality.
About the Author
Mark Gergen was appointed Chief Executive Officer of Poseida Therapeutics, Inc. in February 2022. He joined Poseida in February 2018, initially serving as Chief Business Officer and Chief Financial Officer before being named President and Chief Business Officer in July 2020. Prior to Poseida, he served as Senior Vice President and Chief Operating Officer of Halozyme, Inc. and Executive Vice President and Chief Operating Officer at Mirati Therapeutics, Inc. Before that he served in senior management positions, including as Senior Vice President of Corporate Development at Amylin Pharmaceuticals, Inc. He also served in senior management positions at CardioNet Inc., Advanced Tissue Sciences, Inc., and Medtronic, Inc. Mr. Gergen received a J.D. from the University of Minnesota Law School and a B.A. in business administration from Minot State University.