Researchers shorten manufacturing time for CAR T cell therapy
A new approach allowed scientists to alter immune cells within 24 hours
versus the standard of up to two weeks

Date:
March 29, 2022
Source:
University of Pennsylvania
Summary:
A new approach could cut the time it takes to alter patients' immune
cells for infusion back into the body to find and attack cancer. The
cell manufacturing process for this type of immunotherapy that was
pioneered at Penn -- CAR T cell therapy -- typically takes nine
to 14 days. In a pre-clinical study, scientists have abbreviated
this process and generated functional CAR T cells with enhanced
anti-tumor potency in just 24 hours.



FULL STORY ==========================================================================
A new approach from Penn Medicine researchers could cut the time it
takes to alter patients' immune cells for infusion back into the body
to find and attack cancer. The cell manufacturing process for this type
of immunotherapy that was pioneered at Penn -- CAR T cell therapy --
typically takes nine to 14 days. In a pre-clinical study published in
Nature Biomedical Engineering, a team in the Perelman School of Medicine
at the University of Pennsylvania abbreviated this process and generated functional CAR T cells with enhanced anti-tumor potency in just 24 hours.


========================================================================== These results demonstrate the potential for a vast reduction in the
time, materials, and labor required to generate CAR T cells, which
could be especially beneficial in patients with rapidly progressive
disease and in resource-poor healthcare environments. The study was led
by Center for Cellular Immunotherapies researchers Michael C. Milone,
MD, PhD, anassociate professor of Pathology and Laboratory Medicine
and Saba Ghassemi, PhD, a research assistant professor of Pathology and Laboratory Medicine.

"While traditional manufacturing approaches used to create CAR T cells
that take several days to weeks continue to work for patients with
'liquid' cancers such as leukemia, there is still a significant need to
reduce the time and cost of producing these complex therapies" 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 is a testament to the
potential to innovate and improve the production of CAR T cell therapies
for the benefit of more patients." CAR T cell therapy is a type of immunotherapy used to fight cancer with a patient's own altered immune
cells. T cells are taken from a patient's blood and changed in the lab
by adding a gene for a receptor (called a chimeric antigen receptor or
CAR). The CAR T cells are then infused back into a patient to find, bind
to, and destroy cancer cells. However, when removed too long from the
body during the engineering process, T cells can lose their ability to replicate, which is central to their effectiveness as a living drug. Thus,
the Penn research team sought to shorten the process without sacrificing
the T cell potency.

In animal models, the researchers learned that the quality, rather than
the quantity, of the CAR T cell product is an important determinant
of their efficacy. Their experiment provided evidence that a smaller
number of high- quality CAR T cells that are generated without
extensive expansion outside the body is superior to a higher number
of reduced-quality CAR T cells that are extensively expanded before
returning to the patient.

Traditional manufacturing approaches require T cells to be stimulated
(or "activated") in a way that induces the cells to replicate and expand
in number.

A key to the Penn researchers' manufacturing approach is the lentiviral
vector that delivers the CAR gene to the T cells. Lentiviral vectors,
which are derived from the human immunodeficiency virus (HIV), are
able to transfer genes like the CAR to cells without the need for
this initial "activation" step, but the efficiency of this process was
low. Using engineering approaches that built in part upon knowledge of
how HIV naturally infects T cells, the Penn researchers developed a way
to overcome this requirement for T cell activation and deliver genes
directly to non-activated T cells freshly isolated from the blood. This
had a dual benefit of expediting the overall manufacturing process while
also maintaining T cell potency. Patients are not being infected with
HIV through this process.

The process of engineering T cells is costly and time-intensive, since
the treatment must be manufactured for each individual patient. The
team hopes that cutting manufacturing time could make the therapy more cost-effective and accessible to more patients.

"This innovative approach is remarkable in that it may be able to
help patients who might otherwise not be able to benefit from CAR
T cell therapy such as those with rapidly progressing cancer due to
significant time currently need to generate these therapies," Ghassemi
said. "Efficient reprogramming of T cells with a CAR in as little as 24
hours in a more simplified manufacturing process without T cell activation
or extensive culture outside the body also offers the possibility of
expanding where and when these therapies are produced. Not only might it improve the production capacity of centralized manufacturing facilities,
but if simple and consistent enough, it might be possible to produce
these therapies locally near the patient, which could be tantamount
to addressing the many logistical challenges that impede delivery
of this effective therapy especially in resource-poor environments."
This study is a catalyst for more clinical research to investigate how
the engineered CAR T cells, through this shortened approach, work in
patients with specific cancers.

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

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


========================================================================== Story Source: Materials provided by University_of_Pennsylvania. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Saba Ghassemi, Joseph S. Durgin, Selene Nunez-Cruz, Jai Patel, John
Leferovich, Marilia Pinzone, Feng Shen, Katherine D. Cummins,
Gabriela Plesa, Vito Adrian Cantu, Shantan Reddy, Frederic
D. Bushman, Saar I.

Gill, Una O'Doherty, Roddy S. O'Connor, Michael C. Milone. Rapid
manufacturing of non-activated potent CAR T cells. Nature Biomedical
Engineering, 2022; 6 (2): 118 DOI: 10.1038/s41551-021-00842-6 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220329114723.htm

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