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Less than five years ago the cell and gene therapy landscape for treating hematologic malignancies and disorders looked very different than it does now. In that short time, the FDA has approved five new autologous cell and gene therapies for pediatric or adult patients. However, creating an individual product for each patient can limit access. Autologous cell and gene therapies take time to manufacture, the autologous immune cells may have limited function due to the patient’s exposure to cytotoxic drugs, and collection of the patient’s cells may not be possible. That’s led cell and gene therapy developers to pursue allogeneic approaches, which ideally could be produced in greater quantities and be available “off-the-shelf.” While allogeneic T-cell therapies are already being explored in multiple early phase clinical studies, those using natural killer (NK) cells and cells derived from induced pluripotent stem cells (iPSCs) are creating buzz in the industry. Why the enthusiasm for NK cells? Autologous chimeric antigen receptor (CAR) T-cell therapies currently on the market have disadvantages beyond multi-week manufacturing times. They are also known to cause serious side effects, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Patients who receive allogeneic cell therapies, like HSCT or T-cell based therapies, can experience graft-versus-host disease. “Some advantages of NK cells are that they don’t cause graft-versus-host disease, which is a challenge for T-cell based therapies. In addition, they have not been associated with causing cytokine release syndrome or ICANS, so generally the safety profile appears to be favorable,” said Sarah Cooley, MD, MS, the Senior Vice President of Clinical Translation at Fate Therapeutics, who led NK-based cell therapy research at the University of Minnesota for 17 years prior to joining Fate in 2019. Additionally, the lifespan of NK cells and T-cells are different. NK cells respond immediately to threats and have a much shorter lifespan of weeks to a month. T-cells must learn what threat to recognize and may live for many years. “Understanding these nuances and how to harness the different cell types appropriately to treat different diseases or different stages of disease I think is very interesting,” Dr. Cooley added. According to Stephen Gottschalk, MD, Chair of the Department of Bone Marrow Transplant and Cellular Therapy at St. Jude Children's Research Hospital, the different roles NK cells and T-cells play may lead to another approach to allogeneic cell therapy in the future. “I think the off-the-shelf approach allows us to select the best mismatches to really push activating receptors versus inhibitory receptors. It might be that in the end, we first have to give, let’s say, CAR-NK cells to give a pro-inflammatory environment within the tumor and then follow up with T-cells to ‘get the job done.’ That would be like our normal immune system where, in the end, NK cells and T-cells work together to eradicate infections,” Dr. Gottschalk said. Stephan Grupp, MD, PhD, is the Chief of the Cellular Therapy and Transplant Section at Children’s Hospital of Philadelphia. He said the proof of concept shown in the work of Katy Rezvani, MD, PhD, at MD Anderson Cancer Center that was and that of companies like warrants the excitement. However, he cautioned that more must be known about long-term durability of NK cell therapies. “Given the complexity of manufacturing and the cost, you need something that’s going to have some legs. In my personal opinion, just another round of chemotherapy. It has to be something that lasts longer than that. And that, I think, the jury’s out on entirely.” He added that if researchers can get NK cells to do what T-cells do, NK therapies may be much safer and less toxic than T-cells. That, he said, “would be an incredible boon to patients.” The potential advantage of iPSC-derived therapies Donor-to-donor variability is one challenge in the development of many allogeneic cell and gene therapies. That’s a factor that makes iPSC-derived therapies intriguing. “I think the attractiveness of this is that you can be confident in the purity and homogeneity of your cell population,” Dr. Cooley said. That’s because a single cell can be genetically modified, cloned and extensively characterized. “You can look for successful insertion or deletion of the genes of interest, make sure they maintain their karyotypic normalcy and then select the optimal of these clones to then grow up into your master cell bank and then into manufacturing campaigns,” Dr. Cooley added. Dr. Gottschalk also said that the characterization possible at a very early stage is an important aspect of iPSC work. “I think the iPS technology might be advantageous because on a very fundamental level, you can characterize your genetically modified cells at a very early stage into all these assays which might not be possible if you, let’s say, make off-the-shelf products from peripheral blood donors,” he said, adding, “Each product is different and you would have to characterize in very great detail all the insertion sites or, if you use gene editing, off-target effects.” Dr. Grupp said that the complete uniformity from a product created in an iPSC setting is potentially very interesting, as well as the better characterization that’s possible. But, he offered a word of caution. “The science is not there yet to fully drive how the characterization actually results in clinical benefit because we haven’t treated enough patients yet. That’s the only reason. Not that it’s not working. It’s just that we need more clinical data,” he said. Novel Allogeneic Cellular Therapies: Predictions for the Future Drs. Cooley, Gottschalk and Grupp joined Chris McClain, Senior Vice President of Sales and Business Development at Be The Match BioTherapies®, for a panel discussion at The ONE Forum 2021. They discussed NK cell therapy, iPSC therapy, and the challenges—and promise—of allogeneic cell and gene therapies.WATCH THE SESSION Allogeneic NK cell and iPS-derived cell therapies may offer another advantage: improved access With the potential for serious adverse events limiting the delivery of current FDA-approved autologous cell and gene therapies to mainly academic medical centers—and the high price tag—these therapies are not readily available to everyone who needs them. Allogeneic cell and gene therapies like NK cell and iPSC-derived therapies could change that dynamic. “With iPSC-derived cell products, the cost of goods is demonstrably much, much less. How those get priced is not my space, but the capability to do it much more cost effectively exists,” Dr. Cooley shared. She said other important points related to access involve the safety and ease of administration of these cell therapies. “One important goal would be to develop therapies that can be administered in the outpatient setting with an expectation of fewer side effects or need for admission or hospitalization,” Dr. Cooley explained. She said the safety profile of NK cells to date, with fewer side effects like CRS, graft-versus-host disease and neurotoxicity, are one reason she is so excited about the therapy. “At some point, not all patients can be treated at a quaternary care setting,” she said. “Getting therapies that can be effectively delivered in a community hospital with appropriate safety characteristics such that a community-based oncologist can provide these therapies I think is really important.” An exciting future for treating patients with hematologic malignancies and disorders HSCT was the original cell therapy and remains the gold standard of curative therapy for patients with certain blood cancers and disorders. The allogeneic and autologous cell therapies in development today offer exciting potential options to complement, supplement or replace traditional HSCT. Dr. Grupp has been an HSCT physician his entire career. He also worked with the researchers at Penn and Novartis on the development and approval of Kymriah®. He said that allogeneic transplant is very difficult for patients and they’re happy to have other treatment options. “More and more of our patients aren’t going to transplant, and that is an unalloyed good as far as I’m concerned. We want the opportunity to broaden our palette to things that might replace transplant for at least some of our patients,” he said. Dr. Cooley hopes to see allogeneic and autologous cell and gene therapies begin to be delivered earlier. “Looking to spaces where we see clinical efficacy and then trying to understand where we can perhaps move cell therapy earlier into the disease process to achieve cures and eliminate some of the long-term side effects from extensive therapy is an important potential for these types of treatment,” she said. Dr. Gottschalk echoed their statements with a reminder that we are just at the beginning. He likened CD19 CAR-T therapy to what Gleevec likely was for the small molecule field in the mid-90s. “It will take a lot of innovation to make these therapies successful for other disease like AML, solid tumors and brain tumors. It will take some time. It will not happen tomorrow,” he said. But, he said, “Within the next five to 10 years, we will have effective therapy for some of these cancers where early phase cell therapy studies currently are not very effective. I’m confident we will achieve that with continued innovation.” Helping cell and gene therapy companies accelerate therapy development Be The Match BioTherapies® offers allogeneic and autologous cell and gene therapy developers proven solutions that are built on 30+ years of experience delivering the first cell therapy—HSCT. Our solutions are optimized to support companies from early-stage development though commercial delivery and outcomes data collection and analysis.EXPLORE OUR SOLUTIONS

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