Poseida: New CEO, same passion for allogeneic therapies

Yarema joined the clinical-stage cell and gene therapy (CGT) firm in April 2023 as president of cell therapy. After less than a year in the role, the company appointed Yarema CEO in January 2024.

Yarema previously worked as CCO at Atara Biotherapeutics, where she led the commercialization of the world’s first marketed allogeneic T cell therapy, Ebvallo (tabelecleucel), to treat a rare lymphoma.  

Since its founding in 2014, the company has focused on the “goal” of allogeneic , or off-the-shelf, cell therapy. However, like most companies in the CGT space, Poseida first started with autologous cell therapy development.

All approved CAR T-cell therapies are autologous. Autologous products are made by taking, reengineering, and reintroducing a patient’s own cells. Autologous methods of treatment usually have a low risk of rejection but are not always suitable for all patients because of the restrictions in the quality and availability of the individuals’ cells.

Allogeneic therapies, meanwhile, can use cells or tissues from different individuals. As these are not personalized, one advantage over autologous is the relative ease to mass-produce such products and thus, improve patient access. While allogeneic treatments could potentially treat more people, it has not fully reached commercialization yet due to the risk of rejection and immunosuppressive and matching measures needed to be taken.

BioProcess Insider (BI): What is the main goal you have as CEO?

Kristin Yarema (KY): My main goal as CEO is to help guide and empower our fantastic Poseida team as we advance entirely new classes of allogeneic cell and non-viral gene therapies with the capacity to cure patients of cancer and genetic diseases.

BI: Why have you chosen to focus on allogeneic cell therapy as a principal area at Poseida?

KY: At Poseida, we focus on allogeneic CAR-Ts because we want CAR-T to be someday available to every patient and treating physician who feel it is the right choice for them.  

While autologous cell therapies have delivered impressive results, manufacturing is expensive, highly variable, and difficult to scale. Autologous CAR-T also has considerable treatment and logistical complexity and burden for the patient and hospital due to the necessary apheresis procedure for each patient, which requires time, space, transport of the individual patient material, which must maintain strict chain of custody and chain of identity controls. Sometimes, given the waiting time for auto CAR-T, patients are not able to receive the CAR-T quickly enough to benefit.

BI: What are the advantages of allogeneic therapies?

KY: Allogeneic cell therapies, including allogeneic CAR-T, are a long-awaited next-generation option addressing many of these challenges. Allogeneic cell therapy is different because it uses T cells derived from healthy donors as the starting material, rather than cells from ill and heavily pretreated patients, which in theory may result in higher quality products, which may ultimately correlate with superior clinical effect—as well as more reliable and more rapid delivery so the patient can start therapy much more quickly.  Allogeneic cell therapies hold significant promise to broaden and speed patient access, lower costs, and increase reliability and scalability of production.

BI: What allogeneic therapies are Poseida developing?

KY: We have long believed that readily produced, off-the-shelf allogeneic, T stem cell memory (SCM)-rich CAR-T products have the potential to offer a compelling efficacy and safety profile while also supporting patient access.

BI: What advantages would this have?

KY: We hope that (TSCM)- rich allogeneic CAR-T therapies may potentially offer the optimal combination of clinical results, on-demand availability, and high-volume production, while supporting broader access to CAR-T therapies.

BI: How do you intend to reach this aim?

KY: In the near term, this is all about execution and moving our clinical cell therapy programs through clinical development towards future potential commercialization and into the hands of the patients who would otherwise have limited options for care. That applies to our heme malignancy programs partnered with Roche and to our unpartnered solid tumor work.

BI: Is clinical data available to support this approach?

KY: We have made a great start with the early Phase I data from our P-BCMA-ALLO1 multiple myeloma program which we presented at American Society of Hematology (ASH) in December 2023.

The promising clinical data demonstrated patients could have high response rates—over 80% — while also achieving very deep responses with our TSCM-rich allogeneic CAR-T. What is remarkable is that these results were in a very […] heavily pretreated patient population, where the median number of prior lines of therapy was seven—meaning patients had essentially exhausted all their treatment options—and we still saw these responses, including responses in patients who had failed previous autologous CAR-T therapies.

BI: Please can you discuss your manufacturing strategy?

KY: We firmly believe that manufacturing is a critical aspect of the product and needs to be developed in lockstep with clinical development. As such, we have invested and made significant strides regarding our manufacturing platform and process science capabilities. We are currently producing products for all three clinical-stage programs at our in-house GMP facility.

BI: How important do you think it is to have a successful manufacturing approach?

KY: We intend for this to continue and to make it a real focus because we believe a robust manufacturing approach is imperative to succeed in allogeneic cell therapy. Execution in both the clinic and the plant is essential to continue our momentum toward providing therapies that could ultimately be safer, more efficacious, and more accessible than the current standards of care.

BI: What are the manufacturing limitations associated with autologous treatments?

KY: With autologous CAR-T, a single production batch is used to treat a single patient. But even with improvements and buildout of one's manufacturing capacity, it remains a monumental problem to find enough scale to meet the needs of say tens of thousands of patients each year who could be hoping for therapy for a given tumor type in just the US and major European countries alone. One other problem is understanding that market access means more than simply payment for a treatment, though we sometimes think of it that way. 

BI: What else needs to be considered regarding market access?

KY: In the case of CAR-T, we also need to consider whether a patient will receive the therapy in time to benefit from it. With autologous CAR-T, the waiting time for patients can range from several weeks to months before receiving treatment. It is important that we seek to reduce the amount of time that it takes for a given patient to be able to receive their CAR-T and increase the number of patients who can ultimately receive it.

BI: Can you explain how an allogeneic approach increases patients access?

KY: We believe allogeneic CAR-T that is produced at scale in large batches from cells provided by healthy donors is a huge part of the answer. For allogeneic CAR-T like ours, one leukopack from one single healthy donor can be used to manufacture 100 doses or more from a single manufacturing run. Moreover, the product can be cryopreserved, stored in inventory, ready to be ordered, shipped overnight, and made ready for the patient and the physician managing the treatment more easily. That means the patient can begin conditioning treatment right away and can be infused with the CAR-T cells in roughly one week's time. That stands in sharp contrast to the autologous CAR-T experience that has been reported anecdotally and in surveys from centers using autologous CAR-T. Some of these have reported that maybe one in four patients hoping to receive autologous CAR-T end up experiencing disease progression and become ineligible for treatment, pass away, or move to hospice care before they are able to receive the treatment. That is just not acceptable, and we need to find better solutions for patients.

BI: What are the challenges associated with manufacturing allogeneic CAR-Ts?

KY: We like to say there are at least four things that a company needs to do properly. First and foremost, you need the right cell type as the chassis for your CAR-T. It has become increasingly clear in the literature that for CAR-Ts to work well they need to have a high degree of stemness, meaning the cells are relatively undifferentiated. Unfortunately, many of the tools and approaches that have traditionally been used to produce autologous or allogeneic CAR-T make it difficult to get products that have a high degree of stemness.

Poseida takes a different approach and begins with the very initial stage of differentiation called the stem cell memory T cell (TSCM). We believe it is incredibly important to start therapy here as these cells are longer lived, self-renewing and have the highest degree of stemness.

This article was first published in BioProcess Insider on 26 February 2024