However, allogeneic cell and gene therapy development has started outpacing autologous development over the past year.3 Allogeneic approaches provide hope to solve common challenges associated with currently approved autologous treatments, including the high cost, complex supply chain, and heterogeneity in manufacturing when working with highly pretreated patient cells.
Allogeneic approaches are not without their challenges, including the potential for graft-versus-host disease (GVHD), donor cell persistence, variability in donor starting material, and manufacturing expansion.
During The ONE Forum 2022 in November, four cell and gene therapy leaders came together to discuss the realities of autologous and allogeneic cell and gene therapy from a clinical and industry perspective.4
Timing is everything with autologous CAR-T
The approved autologous CAR-T therapies bring incredible opportunities for treating patients who have failed previous therapies or have a disease that is not responding to chemotherapy or immunotherapy. However, not every patient eligible to receive CAR-T therapy goes on to get it.
Availability remains a major challenge for the two approved autologous CAR-T therapies for multiple myeloma. Patients must join wait lists with no guarantee that a slot will become available when they need the therapy.5
But autologous CAR-T therapies, in general, have another factor that can work against them—time. Time for clinicians to receive insurance approval. Time to get an apheresis slot for cell collection from the patient. And time for product manufacturing.
Yi Lin, MD, Ph.D., consultant and associate professor in the Division of Hematology and Experimental Pathology at Mayo Clinic, Rochester, specializes predominantly in lymphoma and multiple myeloma and has an NIH-fund laboratory and clinical research program in tumor immunology, immunotherapy, and biomarkers development, with a cell therapy focus.
She said while insurance approval time has shortened, payers approve a specific product versus giving broad approval for CAR-T for the disease, which isn’t ideal. “If we want to switch the product for some reason or there’s a manufacturing challenge, that does add wait time [to get approved for a different CAR-T product],” she said.
Veronika Bachanova, MD, Ph.D., professor of medicine in Hematology, Oncology and Transplantation and cell therapies clinical director at the University of Minnesota Medical School, specializes in lymphoma and leads a research team focused on emerging CAR-T cell and natural killer (NK) cell therapies.
She explained that one of the biggest disadvantages of autologous CAR-T therapy is that the product is not available on hand. In her experience, it can take a week for an apheresis slot to open, and the manufacturing wait time is anywhere from 18 to 25 days.
“That waiting for patients means a lot of things. It can mean [the patient] needs a different therapy because the lymphoma is progressing,” Dr. Bachanova said.
Autologous cell therapy supply chain complexity and wait times are also challenges for cell and gene therapy developers.
Jennifer Collins, vice president of Supply Chain at Poseida Therapeutics, gave an example from her organization. Poseida had two autologous programs in early-phase clinical trials. She pointed to the limited availability of manufacturing slots and concerns about missing the slot if enrollment or apheresis collection was delayed.
Turnaround time post-manufacturing was lengthy due to a 14-day sterility test regulatory requirement. Adding time for patient lymphodepletion meant another week or so before infusion.
Collins said she believes the lessons learned have been beneficial for their allogeneic programs, two of which are in Phase 1 clinical trials.6 “We learned a lot about the challenges. It gave us a much better jumping-off point for our allogeneic programs,” she said.
Because allogeneic cell therapies are off the shelf, the wait time to infusion is significantly shorter. If a patient meets enrollment criteria, Collins said a clinician typically has the allogeneic product in hand within a week.
Allogeneic cell therapies hold advantages … and drawbacks
The reduction in wait time to therapy infusion is a definite allogeneic cell therapy advantage. Another may be lower toxicity, particularly with NK cell therapies.
“[NK cells] have the same killing machinery as T cells, but to our knowledge, they don’t give the same toxicities. The good news is there’s no CRS [cytokine release syndrome]. There is no obvious neurotoxicity that we know about,” explained Jeffrey Miller, MD, the deputy director of the University of Minnesota Masonic Comprehensive Cancer Center, who has more than 25 years of experience studying the biology of NK cells and other immune effector cells and their use in clinical immunotherapy.
Lower toxicity could allow physicians to offer the treatment to more patients. “For patients who have comorbidities or are older and at risk of having some significant side effects [from other treatments], I’m really thinking about NK cells for those patients,” Dr. Bachanova said.
Lower toxicity might also allow for repeat dosing. That is important because allogeneic cell therapy durability remains unknown. Dr. Miller explained that the major difference between autologous and allogeneic cell therapies would likely be in-vivo persistence.
“The proof of concept is there. I think we just have to be prepared and see what our metrics are as we make this leap from individualized therapy to allogeneic therapy, which might have different pharmacokinetics and functional persistence in the body over time,” he explained.
Dr. Bachanova agreed there would be a learning curve for allogeneic cell therapy and questions that need to be answered about the best cell dose, how well the cells traffic into tumors, the persistence of the cells, and if multiple dosing will be necessary.
Because of the unknowns of allogeneic cell therapy durability, Dr. Miller suggested that the mindset may need to change from the “one-and-done” autologous cell therapy thinking. Instead, multiple doses could be the norm, but the cost would be a factor.
He also said allogeneic cell therapies could become a maintenance platform for diseases like acute myeloid leukemia, in which relapse is the predominant problem after hematopoietic cell transplantation.
Many factors impact clinical decision making
With effective commercial autologous CAR-T cell therapies available and allogeneic cell therapies in clinical trials for the same indication, clinicians face a decision. Enroll a patient on an allogeneic cell therapy clinical trial or use an approved autologous therapy?
Often, the decision comes down to patient, disease, and product factors.
For example, patient factors may include age and comorbidities. Disease factors include which therapies the patient has already received, how the patient responded to the therapies, and how quickly the patient’s disease is progressing. Product factors often come down to timing and availability.
“In my mind, a lot of what I think about is, do I have a month of waiting for a product or do I have to treat the patient in three days?” Dr. Bachanova explained. “If I see that the patient is not well enough to be in good shape in a month, we go through the eligibility to see whether any of the allogeneic products will be suitable to be offered to the patient.”
While pros and cons exist for both allogeneic and autologous cell therapies, both have one thing in common. They give clinicians options for treating patients that didn’t exist just a short time ago. And that gives more patients and families hope for the future.
About the author
Chris McClain is the senior vice president of Be The Match BioTherapies. He and his team engage with cell and gene therapy companies developing innovative therapies that can leverage the cell sourcing, cell therapy supply chain, research support and outcomes tracking capabilities of the National Marrow Donor Program/Be The Match.
Before joining Be The Match BioTherapies, Chris co-founded Nora Therapeutics. He was a guest lecturer in the University of Minnesota’s Carlson Graduate School of Management Life Sciences program, co-chaired Medical Alley’s Biotech Shared Interest Group, and is a member of the ISCT’s Market Access & Patient Advocacy subcommittee. Chris earned his master of business administration and bachelor of arts in economics from the University of California, Berkeley.
- National Cancer Institute. CAR T Cells: Engineering Patients’ Immune Cells to Treat Their Cancers. Updated March 10, 2022. Accessed December 20, 2022. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells.
- U.S. Food and Drug Administration. Approved Cellular and Gene Therapy Products. Accessed December 20, 2022. https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/approved-cellular-and-gene-therapy-products.
- Saez-Ibañez AR, Upadhaya S, Partridge T, Shah M, Correa D, Campbell J. Landscape of cancer cell therapies: trends and real-world data. Nature Reviews Drug Discovery. June 2022. doi: 10.1038/d41573-022-00095-1.
- The ONE Forum 2022. Balancing the Clinical and Commercial Realities of Allogeneic vs. Autologous Cell and Gene Therapy. Presentation. November 5, 2022.
- Goodman A. Patients With Multiple Myeloma May Face CAR T-Cell Shortages. ASCO Post. Published September 25, 2022. Accessed December 20, 2022. https://ascopost.com/issues/september-25-2022/patients-with-multiple-myeloma-may-face-car-t-cell-shortages/.
- Poseida Therapeutics. Pipeline. Accessed December 20, 2022. https://poseida.com/science/pipeline/.
Filed Under: Cell & gene therapy