Approaching The Allogeneic Tipping Point: The Emergence Of Allogeneic Cell Therapy For Oncology
By Mark Gergen, CEO, and Kristin Yarema, Ph.D., President, Cell Therapy, Poseida Therapeutics
From the perspective of allogeneic cell therapy developers, ASCO 2023 was provocative. Buzz from the impressive clinical results seen in autologous CAR-T cell therapy programs for early cancer treatment quickly spilled beyond the podium presentations into the convention’s hallways and cafes. At the same time, and often even in the same scientific session, physicians recognized that the inherent challenges of manufacturing autologous cell therapies mean that patients who could benefit from these potentially lifesaving therapies too often do not receive them today. Despite autologous manufacturers’ investment in more capacity, this situation is likely to get worse, not better, as much larger patient populations become eligible for cell-based therapies as the evidence for their efficacy mounts.
Simply put, an autologous approach that is expensive, does not scale well and results in some patients going without effective care options is not going to meet the needs and high expectations of patients, physicians, and health care systems, and payors. Bispecific antibodies, touted as another possible answer, are also expensive and difficult to manufacture and do not yet match the results of cell therapy. As a result, there is an excitement for allogeneic cell therapy products to emerge that can enable broader patient populations across multiple indications to access cell therapy at lower cost, higher reliability, and with more widespread and rapid distribution.
It was motivating to witness the focus on patients and hear firsthand about real-world experience with autologous CAR-T. The challenges of cost and manufacturing capacity are well known, but we also started to hear about significant numbers of patients who could not get access to therapy, whose autologous manufacturing failed, or who sadly progressed and died while waiting for their therapy to be manufactured. We also heard from physicians and patients about the importance of safety and tolerability – and how high levels of serious cytokine release syndrome and neurotoxicity and additional treatments to manage those side effects are challenging. It became clear during the meeting that autologous approaches are struggling to fulfill the promise of cell therapy.
Fortunately, in our view the field is approaching the tipping point where allogeneic cell therapy will come into its own. When that happens, those players with the right approach, the right technology and the right focus will quickly be recognized and rewarded.
Allo is not Auto: The Need to Think about Allogeneic Differently
To fully appreciate the role allogeneic cell therapy can play in oncology, a different perspective is needed. Too many people within the industry as well as investors want to take the autologous experiences and learnings and apply them directly to allogeneic. That simply will not work—and might lead to undersizing the opportunity. Allo is not Auto with extra gene editing. Allo should not be assumed to be inferior to Auto. That realization is starting to take hold.
As we envision an ideal allogeneic product, we think about a product that: (i) is immediately available; (ii) is dramatically cheaper than autologous approaches; (iii) will deliver equivalent or better efficacy than autologous products; (iv) has a better safety and tolerability profile to improve the patient experience and allow for combination therapies that are the clinical norm in oncology; and (v) can explore and enable redosing and other treatment options. Is an allogeneic product with all those characteristics truly possible?
We should be aspiring to an allogeneic cell therapy that has the advantages of other modalities including first generation cell therapy, biologics and antibodies, and even small molecules. There is no good reason that one cannot create an allogeneic product that is equivalent or better than what the autologous programs have delivered to date. When one thinks about what will make an exciting allogeneic product, one should focus on the patient experience. Can we get a patient into a deep response with limited toxicities and a reasonable treatment experience and keep them in response for a long period – all at a reasonable cost? The many benefits of an allogeneic product will open many paths to get to those outcomes that are not possible with autologous products – we just need to keep an open mind and not limit our thinking.
Cell Choice, Technology, and Focus Matter
The tipping point for allogeneic cell therapy is coming, but what specific factors will drive the wave of therapies that can make this modality definitively real for patients? While there are many elements to consider, a few seem key to understanding what will lead to success: “What’s the Right Cell Choice;” “What’s the Right Technology;” and “What’s the Right Focus?”.
The Right Cell Choice
There are many approaches being taken to explore allogeneic cell therapy. These include a variety of cell types such as T cells, natural killer (NK) cells, induced pluripotent stem cells (iPSCs), tumor-infiltrating lymphocytes (TILs) and macrophages, just to name a few. In theory all have advantages and disadvantages. Logic and real-world experience, however, seem to point us toward T cells as the best approach.
We believe, as do others, that the most logical choice for allogeneic cell therapy is healthy donor-derived T cells – and in the case of Poseida, the particular subtype of stem cell memory T cells. We believe that because virtually all of the impressive autologous cell therapy results are derived from patient T cells. This is not surprising, as it is well established biology that T cells are the immune system’s best killers. Further, we also know that within the T cell experience, higher percentages of stem cell memory T cells in a product correlate well with better responses in the clinic. The data seems clear that T cells, and stem cell memory T cells in particular, are the ideal cell type.
Why use healthy donor-derived T cells as the starting material for allogeneic cell therapy? In the autologous setting, the raw material is T cells from a cancer patient who is usually older, may have aberrant cells from the cancer and often has been through many rounds of pharmaceutical treatment, meaning their immune system cells are not the fittest. On the other hand, healthy donor-derived T cells (usually from a young donor) are healthier with more resilience in manufacturing and more proliferative capacity, which also correlates with clinical effect. In other words, allogeneic T cell therapy starts with better material, which we believe will result in a better product.
Alternative cell types to T cells offer some benefits, but also pose many challenges and lack strong supporting clinical evidence to date. Natural killer cells, for example, simply don’t kill as well as T cells, despite their name. In addition, while it is easy to grow NK cells to large numbers ex vivo, they simply don’t proliferate as well in vivo – likely a significant limitation for an in vivo therapy. iPSCs have also attracted attention through the theoretical advantage of being able to generate an inexhaustible supply of cells ex vivo. Understandably appealing from a manufacturing perspective, iPSCs when differentiated ex vivo don’t always look like their endogenous counterparts, giving rise to questions about characterization of the product. The list could go on.
In summary, if biologic understanding combined with all the most impressive clinical data from autologous CAR-T trials highlights T cells, and if healthy donor T cells are readily available as a robust starting material, and stem cell memory T cells in particular are correlated with best responses– why would anyone choose a different cell type? We don’t think they would.
That begs the question: “Why doesn’t everyone use healthy donor T cells if it is such an obvious and excellent choice?” The answer, in part, is that genetically modifying, developing and manufacturing T cells, especially T stem cell memory cells, is hard – really hard. Most technologies and approaches are simply not up to the task.
The Right Technology
One of the questions in cell and gene therapy is which tools and technology should be used to create them. Genetic engineering tools vary but will certainly shape and potentially limit the kind of final product that can be created. Unfortunately, the conventional tools that many in the cell therapy field have used to date are old technologies that were not really designed for these purposes – and as a result have inherent limitations.
Most cell therapy companies use viral technologies, usually lentivirus or gamma-retrovirus, to perform the gene insertion of their CAR or TCR into the cell. Those technologies are decades old, expensive, inefficient, and have serious drawbacks in terms of scalability. Issues such as the finite cargo capacity of viral vectors become increasingly important in allogeneic approaches where in addition to gene insertion, further gene editing to eliminate alloreactivity is required. Further compounding this problem, many in the industry rely on older gene editing technologies like CRISPR, TALENs, or zinc finger nucleases to do their editing, which again were not designed for cell therapy and may have challenges such as specificity and efficiency. Lastly, too many companies are seeking to shave a few days off production time of autologous cell therapies through minor adjustments of long-established processes, rather than invest in solving the bigger problem of how to radically reduce manufacturing costs and deliver large batches of product that can meet the needs of hundreds of patients and be ready in inventory so that no patient has to wait for treatment.
There are a few players in the industry that have taken a different technology path. At Poseida, we have focused completely on non-viral technologies for our cell therapies and have continued to innovate with technology advances that have been purpose-built to overcome specific challenges in allogeneic cell therapy. For example, we have developed novel tools that enable us to modify stem cell memory T cells, and to deliver multiple genes with a single editing step. In order to manufacture allogeneic cell therapy at scale, we have developed our Booster Molecule technology, which allows us to generate hundreds of doses from a single manufacturing run – potentially reducing the per dose costs to antibody-like levels. As more allogeneic cell companies mature, we hope and expect to see more innovations in these and other areas that can further unlock the promise of allogeneic CAR-T.
The Right Focus – Putting Patients First
At the end of the day the discussions at ASCO were focused on the right question: “How do we best serve patients – and many more of them – with cell therapies?”
Serving the Broader Market
We think it clear from the discussions the data at ASCO that the key to serving more patients and the broader market requires that we crack the code on allogeneic cell therapy. The autologous approaches are struggling to serve even the 3rd and 4th line patients in a few limited indications, not to mention the 1st and 2nd line patients that should be treated and other indications as well. Our healthcare system needs an allogeneic solution that can be produced at scale and a dramatically reduced cost to make these therapies available for all patients who could benefit.
Speed to Treatment
We need a solution that facilitates treating patients more quickly. Telling a cancer patient that they have to wait even two, four, or six weeks for treatment is simply not acceptable. With an allogenic solution, patients can get treated more quickly – potentially in a matter of days. That speed to treatment can make a difference in outcomes and definitely in the mental health of the patients and their loved ones.
Safety, Tolerability, and Patient Experience Matter
The patient and physician narratives from ASCO explained that safety, tolerability, and patient experience matter. These days in many cancers, patients can live with disease for years – sometimes decades. The old drug development mindset that that a certain and even high level of toxicity was acceptable if efficacy was promising enough, and that treatment might need to extend endlessly, is simply not true and not an acceptable compromise. Quality of life matters to patients. The many visits patients make to the clinic to receive treatments and manage side effects and toxicities are disruptive, physically and mentally exhausting, and constantly remind patients of how their lives are impacted by their disease.
The Tipping Point – It’s Closer Than You Think
As an organization that has been focused on the promise of allogeneic cell therapy almost since our inception, we are energized by the emerging interest among our collective community in the challenges facing autologous products and the rising hope that allogeneic approaches are drawing near. We believe that tipping point is very close. We look forward to discussions at the future medical meetings—and to the time when those discussions revolve around how patients far and wide have access to life-changing cell therapy that is ready, affordable, and waiting for each one of them.