CAR-T for Oncology and Approaching the Allogeneic Tipping Point
The road to disruptive innovation is seldom straight and narrow. Defying conventional wisdom and going against the grain, especially in a crowded and competitive space where share of voice is hard to achieve, is an exercise in perseverance. Many give up or fail, a few persevere over time, and fewer still break through and achieve real success.
The allogeneic cell therapy space has seen that pattern play out over the last few years. Dozens of companies pursuing all manner of approaches flooded into the space over the last decade pursuing T cells, NK cells, iPSCs, and a number of other approaches – all claiming to have the best “off-the-shelf” approach. Almost all of these companies shared largely the same genetic engineering toolset in trying to create their products – lentivirus or gamma retrovirus for gene insertion and cas9-based, TALENs, or zinc finger gene editing technology. With so many people, including academic and experienced industry leaders, talking about those technologies – the noise level was deafening and anyone talking about an alternative approach or unfamiliar technology was either not heard or met with skepticism just because it was novel or different.
As it turns out – different matters.
It starts with commitment to taking a different approach.
At Poseida, we have taken a different path and did not waver or give up on our belief that our unique set of technologies and a different approach were needed for allogeneic CAR-T. We were among the first to focus on and talk about T stem cell memory, or Tscm, as the ideal cell type for CAR-T. In fact, we have been talking about Tscm essentially since our inception as a company. Tscm cells have many advantages over other cell types such as NK cells and more differentiated T cell subsets. T cells, compared to other cell types, are generally understood to be the best at eliminating other cells. Tscm in particular are ideal because they can engraft, self-renew, persist, and have high proliferative capacity – just to name a few benefits. For years, we were a voice in the wilderness on that point, but over time, others have come to share our belief in Tscm as the ideal cell type.
One benefit of being among the first in that belief is that focus and perseverance drove us to innovate and create enabling technologies, intellectual property, and manufacturing approaches that supported our vision. Conversely, we believe that most older technologies will struggle to truly create a high-Tscm enriched cell therapy product. What is needed to create and manufacture these high Tscm CAR-T products is a fundamentally disruptive toolset. We believe that our novel non-viral genetic engineering platform technologies are well suited to this task.
In the end, an alternative approach combined with a unique technology set results in a fundamentally different product. Our allogeneic CAR-T final products often have 40% to 80% Tscm compared to low single digits for other approaches based upon published data. In other words, our Tscm products are not just different – they are very different.
Telling a different story.
Over the course of the last 18 months or so, many of those pursuing allogeneic cell therapy approaches utilizing older technologies have faltered – and a number have failed outright. Those challenges have led to a resurgence in interest in autologous approaches – but the best path for patients is not to revert to autologous with all its challenges – but rather to persevere in our quest for an allogeneic solution. At the moment, the competitive noise level around allogeneic approaches has subsided, and an opportunity has emerged to tell a different story – at least for those paying attention and willing to pause and listen.
We believe that allogenic CAR-T, and especially a high Tscm product, is fundamentally different than autologous CAR-T. It is really a completely different class of product that needs to be thought of differently – in other words “Allo is not Auto.” All the advantages of an allogeneic product that can potentially deliver on the promise – immediate availability, comparable efficacy, comparable or better tolerability, ability to combine with other treatments, ability to re-dose, lower cost – contribute to thinking of the product and the allogeneic opportunity differently.
Notwithstanding that view, we are realists. We understand and recognize that the comparisons to autologous CAR-T will persist because the headline results are impressive. We welcome that dialogue – but a deeper conversation is needed than just looking at headlines. The real-world experience of autologous CAR-T is much, much different than the promoted headlines and not as favorable. While a full discussion of this reality is outside the scope of this note, beyond the manufacturing and capacity challenges that are well known, looking at intent-to-treat populations as a real measure of product, or the important and often ignored real-world experiences of clinicians and patients need serious consideration. The “reality” of autologous CAR-T cries out for a better solution.
Enter Allogeneic CAR-T.
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Checking the boxes in Allogeneic CAR-T
We, along with our partner Roche, have been continuing to press forward and are checking the boxes on what we see as the key requirements to unlock the true potential of allogeneic CAR-T for oncology. At Poseida, we believe that we are approaching the tipping point and, if we are right, it is an exciting time for patients and for our industry.
We believe that an ideal allogeneic product will have a number of attributes including: (i) a product that is immediately available off the shelf; (ii) a product that can be made reproducibly, at scale and at a ?dramatically lower cost than autologous approaches; (iii) a product that has the potential to deliver equivalent or better efficacy than autologous approaches; (iv) a product that has a safety and tolerability profile that can improve the patient experience, allow for fully outpatient dosing, and allow for combinations which are commonly used in oncology drug development; (v) a product that can explore and facilitate redosing or maintenance dosing and a host of other treatment regimens that autologous approaches can’t hope to achieve; and (vi) a product supported by clinical evidence of the benefits of the Tscm hypothesis, including cell engraftment and persistence.
We believe that our presentation of P-BCMA-ALLO1 data at ASH, along with other data we presented recently, continues to check the boxes of those desired attributes. To be fair, we are still early in development and we know we are not 100% there yet – but the boxes are being checked and our confidence is building that the differences matter. We believe we are approaching the allogeneic tipping point on the journey to bring the dream closer to reality. We have recently shared that we:
We recognize the data are early and there is more to prove, but we are excited about these data and what it can ultimately mean for patients. We also believe that many of these findings should translate directly to our other programs that share this platform including P-CD19CD20-ALLO1, our program partnered with Roche for B cell malignancies that is expected to start dosing in early 2024, as well as our solid tumor efforts including P-MUC1C-ALLO1, which is currently in a Phase 1 trial.
Allo is Awesome
Inside the company we like to say that “Allo is Awesome” and we believe that we are on a path to further unlocking that awesomeness. To be fair, our road to get here has not been straight but we continue to persevere and believe that, as we continue to check the boxes, others will begin to recognize our allogeneic CAR-T approach is truly differentiated and can present amazing opportunities to serve cancer patients.
As we have asked before, “What if We’re Right?” The answer, in part, is “If we are right then many more patients will benefit.” In the end, we aspire to make a difference for patients and by taking a different approach – and that is what really matters.
#alloisawesome
#alloisnotauto