By Mark Gergen, CEO, Poseida Therapeutics
Cell Therapy – Success and Progress in Oncology
Over the last decade, cellular therapies have transformed some areas of cancer care as the genetic engineering of living human cells has for the first time enabled new and better therapeutics. Most of the early success has come in hematologic malignancies, sometimes referred to as liquid tumors, and primarily through the use of modified T cells using chimeric antigen receptors, called CAR-T therapies. Some of the early results have been truly extraordinary with response rates and complete responses seen at previously unimaginable levels in some indications.
Most of the progress has come in B cell malignancies targeting CD19, a receptor expressed on cancer cells in some of these indications, and in multiple myeloma targeting B cell maturation antigen, or BCMA. It makes sense that these indications would be easier to target to a degree because the tumor cells are present in the blood (and the marrow in the case of BCMA) and therefore more accessible. Currently four CAR-T therapies are approved by the U.S. Food and Drug Administration, although broad commercial success has yet to be demonstrated, in part due to logistics and costs associated with these personalized approaches.
These early successes in cell therapy have been with autologous CAR-T, which is a highly personalized approach of genetically modifying a patient’s own T cells to create the therapeutic. The initial focus on autologous therapy was, in part, because it avoids issues of rejection of the treatment or the risk of graft versus host disease, which could be a safety issue. In time, most expect a move toward allogeneic, or “off-the-shelf,” approaches to CAR-T, where a cell therapy is made from a healthy donor and developed and modified so that it can be given to many patients. While still emerging, allogeneic cell therapy promises to be the next wave of innovation.
What About Cell Therapy in Solid Tumors?
Despite the remarkable responses in autologous CAR-T for hematological indications, success has not yet translated into solid tumor indications, which represent a much larger opportunity in oncology. The question is “Why and how do we get there?”
There are many explanations offered for this difficulty including: (i) access by T cells to the site of the solid tumor; (ii) tumor microenvironment factors, including checkpoint inhibition; (iii) hypoxia in the center of the tumor; and (iv) lack of well understood and compelling solid tumor targets. Some have concluded that cell therapy just won’t work well in solid tumors – but I disagree.
While the data set is limited, we can glean insights from anecdotal reports of complete responses in solid tumors with CAR-T. For example, there was a published report in the New England Journal of Medicine1 of a complete response, or CR, in glioblastoma and a report by Eureka Therapeutics of a CR in hepatocellular carcinoma using CAR-T, which was published in the Journal of Clinical Oncology.2 In both these cases, patients were treated with multiple rounds of high-dose CAR-T that eventually resulted in a CR. There are other reports emerging of activity as well with CAR-T and T cell receptor, or TCR, therapies, but the case reports noted above of CRs in difficult-to-treat populations are particularly intriguing. What the data so far suggests is that CAR-T can work in solid tumors, but it may be harder than what has been observed in liquid tumors.
Moving Toward Cell Therapy Success in Solid Tumors
Knowing that efficacy in solid tumors is achievable with cell therapy, how do we translate that knowledge into broader success? There are several things we can learn from those examples and other learnings.
Eliminating solid tumors with cell therapies may take more time on therapy. In other words, to achieve the desired deep responses the cells need to be present to continue to chip away at the solid tumor until the tumor is eliminated. Clearly, if the cells do not continue to be present, they cannot continue to kill cancer cells and desired efficacy will be elusive. In the examples above, CRs were achieved by giving repeat administration of the CAR-T over time. However, in many cases and for many patients, generating enough cells through an autologous process to achieve that goal may not be possible, so other options will be needed. The first is to move to an off-the-shelf allogeneic approach, where many doses can be created from a healthy donor so multiple doses can be readily available at an affordable cost to treat the patient until a deep response is achieved. The second, and perhaps better option is to create the product from a cell type that would persist in the patient long enough to eradicate the tumor. Third, ideally combining this more durable and persistent cell type with the allogeneic benefits of cost and scale would be the best solution.
Options in Pursuing the Goal
With our goal now identified, what are some of the key considerations we need to explore? They fall into three buckets: (i) how to choose the best cell type for the application; (ii) what targets and target modalities may be needed; and (iii) how to identify the best technology for the task and what innovation may be needed.
Cell Type Matters
There are a number of cell types in development for cell therapies today. Let’s take a quick look at two of the most common approaches – T cells and Natural Killer (NK) cells.
In basic biological terms, it is widely understood that T cells are the best killers of the immune system. They also have the potential to be durable and last a lifetime. For example, if a person is infected with yellow fever as a child – and again reinfected 30 years later – it is the T cells that will “remember” the original infection and respond. As a result, if the goal is to find the cell with the best potential for persistence, T cells may be the ideal choice – although not all T cells are created equally.
Within the T cell family there are various subtypes of cells, including T stem cell memory cells, T central memory cells, T effector memory cells and T effector cells. Among these subtypes, it is the T stem cell memory, or Tscm, cells that have the properties most associated with duration and persistence. Tscm cells have the ability to engraft in the body, are long lived, self-renewing, multi-potent, and give rise to all the other T cell subsets. In essence, a Tscm cell is like a pro-drug that can create wave-after-wave of more differentiated cells that can then attack and kill the cancer. If you can create a CAR-T product that is comprised of Tscm cells, those cells should persist and last longer than other cell types. Even among the T cell family, the other types of T cells do not engraft and persist as well as the Tscm cell.
While many believe that Tscm cells are the ideal cell type, they can be hard to modify and expand ex vivo while preserving their stemness, which has led many companies to other approaches. T cells are sensitive to manipulation and many older genetic engineering technologies will not work to create these products – especially if you are desiring the Tscm cell subtype. While there are technological challenges, solutions are emerging.
Natural Killer Cells
NK cells have generated a following in part because they are naturally semi-allogeneic than some other cell types and can be expanded through many cycles creating large numbers of cells. In other words, they are easier to work with than T cells and thus have potential benefits. The expansion attributes are quite attractive from a manufacturing scale up perspective if you can be assured that those cells remain stable and true to phenotype long-term. Because NK cells are naturally less immunogenic, it potentially allows you to minimize genetically editing otherwise needed to create an allogeneic product.
There are of course challenges with NK cells as well. Despite the name, Natural Killer cells simply don’t kill as well as T cells. Additionally, NK cells do not persist for long periods in vivo which works against the desire for a persistent cell – especially for solid tumors applications. Some pursuing the NK approach are looking for ways to improve persistence by modifying those cells in various ways, which may help address that inherent liability, or one could explore redosing, which may work in some indications or settings.
Choosing Good Targets in Solid Tumors
Once we move beyond the choice of cell type, we must consider the choices of targeting modality and specific targets have the potential to be effective in our indications of interest. As noted above, in the hematological indications to date companies have used CD19 in the case of B cell malignancies or BCMA in the case of multiple myeloma, because those molecular targets are cell surface markers that can be addressed with a CAR. In solid tumors, the choices are likely to be more complex with many companies exploring both CAR targets, for cell surface markers, as well as T cell receptors, or TCRs, to try to reach internal, or non-cell surface, targets of interest. Much work is being undertaken by academia and industry to identify the most effective targets for a variety of solid tumor indications.
It remains unknown which molecular targets may emerge as the most desirable or relevant for solid tumors. Because of the complexity and diversity of the solid tumor indications, in some cases multiple targets may be necessary. In addition, some indications may require including both CAR and TCR targets in the therapeutic or including other molecules or features, sometimes called armoring, to address things like persistence or tumor microenvironment factors. If more components or features would be valuable to include in the genetically modified cell, that could be challenging or impossible for those using older technologies that are constrained by cargo capacity or other limitations. Here again, a focus on discovery and innovation will be needed.
Technology and Continuing Innovation
As we think about cell type, targets and approach, the question for industry becomes what technologies and approaches are best suited or required to make those choices actionable? While the initial success was achieved with older technologies like lentivirus or gamma-retrovirus for gene insertion, the limitations of those systems will not likely be able to meet the demands of more specific and complex genetic engineering going forward. Newer technologies like transposon-based gene insertion approaches or cleaner gene editing hold promise for the next wave of cell therapies, it is clear that ongoing innovation will be needed to improve upon the first generation of virus-based technologies.
Genetically engineered cell therapies hold immense promise for the treatment of cancer, including solid tumor indications and potentially other diseases. While early results are exciting and encouraging, we are only scratching the surface of what is possible in unlocking the true potential of these technologies and approaches.
At Poseida, we are excited to be part of the journey to redefine what these therapies can mean for patients and the treatment of cancer, including solid tumor indications, and eventually many other human diseases. We believe that cell and gene therapies will be at the forefront of new medicines for years to come and embrace the potential and the challenge to make the dream of single treatment cures a reality. We and others in our industry are motivated and passionate about solving these challenges because patients are waiting.
 Brown CE et al. Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med. 2016;375:2561-2569. Link: https://www.nejm.org/doi/full/10.1056/nejmoa1610497
2 Liu C et al. ET140202 t-cells: A novel therapy targeting AFP/MHC complex, that is both safe and effective in treating metastatic hepatocellular carcinoma. J Clinical Oncology. 2019;37:15_suppl, e15614-e15614. Link: https://ascopubs.org/doi/abs/10.1200/JCO.2019.37.15_suppl.e15614
About the Author
Mark Gergen is Chief Executive Officer of Poseida Therapeutics, Inc., a clinical-stage biopharmaceutical company utilizing proprietary genetic engineering platform technologies to create cell and gene therapeutics. Its oncology pipeline includes CAR-T product candidates with high levels of stem cell memory T-cells, or Tscm cells, which are enabled by its novel technology. Its first two allogeneic CAR-T programs, including its P-MUC1C-ALLO1 solid tumor program, are expected to have have initial clinical data in the second half of 2022.
Mr. Gergen was appointed CEO of Poseida 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. Previously 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.