Saturday, December 10, 2022

Researchers shorten manufacturing time for CAR T cell therapy: A new approach allows scientists to replace immune cells within 24 hours with a standard of up to two weeks

A new approach from Penn Medicine researchers could cut the time it takes to replace patients’ immune cells for infusion back into the body to find and attack cancer. The cell generation process for this type of immunotherapy, which was a pioneer in Penn – CAR T cell therapy – typically takes nine to 14 days. In a pre-clinical study published in Nature Biomedical EngineeringA team from the Perelman School of Medicine at the University of Pennsylvania summarized this process and created functional CAR T cells with increased anti-tumor potency in just 24 hours.

These results demonstrate the potential for a drastic reduction in the time, material and labor required to generate CAR T cells, which may be particularly beneficial in patients with rapidly progressive disease and resource-poor healthcare environments. The study was led by Center for Cellular Immunotherapy researchers Michael C. Milone, MD, PhD, associate professor of pathology and laboratory medicine, and Saba Ghasemi, PhD, a research assistant professor of pathology and laboratory medicine.

“While conventional manufacturing approaches are used to make CAR T cells that continue to function for several days to weeks for patients with ‘liquid’ cancers such as leukemia, there is still time and cost to produce these complex therapies. There is a significant need to reduce” Milone said. “Building on our research from 2018 that reduced the standard manufacturing approach to three days, and now to less than 24 hours, the manufacturing method reported in this study has the potential to improve and improve the production of CAR T cell therapy.” There is a proof of the benefit of more patients.”

CAR T cell therapy is a type of immunotherapy used to fight cancer with the patient’s own altered immune cells. T cells are taken from the patient’s blood and transformed in the laboratory by adding a gene for a receptor (called a.) chimeric antigen receptor either car) CAR T cells are then injected back into a patient to find, bind to, and destroy cancer cells. However, when removed from the body for too long during the engineering process, T cells can lose their ability to replicate, which is central to their effectiveness as a survival drug. Thus, the Penn research team sought to shorten the procedure without sacrificing T cell potency.

In animal models, researchers learned that CAR T cell product quality, rather than quantity, is an important determinant of their efficacy. Their experiment provided evidence that a small number of high-quality CAR T cells generated without extensive expansion outside the body is better than a high number of low-quality CAR T cells that can be grown extensively before the patient returns. are expanded.

Traditional manufacturing approaches require T cells to be stimulated (or “activated”) in a way that prompts the cells to replicate and expand in number. Key to the Penn researchers’ manufacturing approach is the lentiviral vector that delivers the CAR gene to T cells. Lentiviral vectors, which are derived from human immunodeficiency virus (HIV), are able to transfer CAR-like genes into cells without the need for this initial “activation” step, but the efficiency of this process was low. Using engineering approaches built on the knowledge of how HIV naturally infects T cells, the Penn researchers have been able to overcome this requirement for T cell activation and generate freshly isolated non-activated T cells from the blood. developed a way to directly deliver the gene. This had the dual benefit of accelerating the overall manufacturing process while maintaining T cell potency. Patients are not getting infected with HIV through this process.

The process of engineering T cells is expensive and time-consuming, as the treatment must be manufactured for each patient. The team hopes that the reduction in manufacturing time could make the therapy more cost-effective and accessible to more patients.

Ghasemi said, “This innovative approach is remarkable in that it may be able to help patients who may not otherwise be able to benefit from CAR T cell therapy, such as those with rapidly progressing cancers.” This is what people currently need to generate these treatments.” , “Efficient reprogramming of T cells with CAR in a more simplified manufacturing process without T cell activation or extensive culture outside the body offers the possibility to expand where and when these therapies are produced, even in 24 hours. Not only can it improve There is production capacity of centralized manufacturing facilities, but if simple and consistent enough, it may be possible to produce these treatments locally near the patient, which may equate to addressing many of the logistical challenges that may be faced by particular resources. – hinders the delivery of this effective therapy in the poor environment.”

This study is a catalyst for more clinical research to investigate how engineered CAR T cells, through this concise approach, work in patients with specific cancers.

Penn scientists led the research, development and clinical trials of this pioneering CAR T therapy in collaboration with Novartis and Children’s Hospital of Philadelphia. In 2017, experimental medicine now known as Kimiriyah, Became the first CAR T cell approved by the US Food and Drug Administration (FDA) for the treatment of pediatric and young adult patients with acute lymphoblastic leukemia (ALL). The therapy was also approved in 2018 for certain types of lymphoma.

The study originated in work supported by the Novartis Institute for Biomedical Research through a research alliance with the University of Pennsylvania. It was funded by the Office of the Assistant Secretary of Health through the St. Baldrick Foundation Scholar Award, the National Blood Foundation Scientific Research Grant Award, and the Peer Reviewed Cancer Research Program (W81XWH-20-1-0417). RO1CA226983.

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