CAR-T cell cancer immunotherapy gets personal
Fine-tuning stimulation doses to deficiencies in patient-specific CAR-
T cells, using artificial antigen-presenting scaffolds, enables manufacturing of more potent CAR-T cell products

Date:
February 10, 2023
Source:
Wyss Institute for Biologically Inspired Engineering at Harvard
Summary:
Scientists have demonstrated that personalizing CAR-T cell
stimulation during manufacturing can significantly enhance the
consistency and potency of the resulting CAR-T cell products. By
using artificial antigen-presenting cell mimicking scaffolds
(APC-ms), the team was able to fine-tune the levels of T cell
stimulation to match the phenotype of T cells obtained from
leukemia patients, and significantly enhanced their ex vivo and
in vivo tumor-clearing abilities.


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FULL STORY ==========================================================================
New adoptive T cell therapies -- in which T cells, the immune system's
natural hunters patrolling the body for foreign adversaries, are retrieved
from cancer- riddled patients, super-charged and amplified outside the
body, and then infused back into the same patient -- are changing the
prospects of cancer patients. Since 2017, when CAR (chimeric antigen receptor)-T cells were green- lighted as the first modified therapeutic
cells by the Federal Drug Administration (FDA) to treat leukemia, five
similar products have since been approved and more than 20,000 people
have been treated with this game-changing immunotherapy.


========================================================================== CAR-T cells are engineered to carry synthetic membrane-spanning receptor molecules that use their outside-facing portion to bind to antigens on
cancer cells, which their inside-facing portion responds to by switching
on a powerful tumor cell-destroying program. However, not all patients
respond equally well to CAR-T cell therapies, and cancer immunologists
have been trying to figure out what makes them work well or fail. Despite
a budding understanding of differences between cancer patients' T cells
and healthy individuals' T cells, these insights have not been taken
into account in CAR-T cell manufacturing processes. All processes use
a similar type of stimulation with T-cell specific agonists and general immune-stimulating cytokines to create infusible CAR- T cell products, irrespective of variations in the original T cells' phenotype.

Now, a collaboration between bioengineers at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard
John A.

Paulson School of Engineering and Applied Sciences (SEAS) led by David
Mooney, Ph.D. and cancer-immunologists at the Dana-Farber Cancer
Institute (DFCI) led by Catherine Wu, M.D., Ph.D. has demonstrated
that personalizing CAR-T cell stimulation during manufacturing can significantly enhance the consistency and potency of the resulting
CAR-T cell products. By using artificial antigen- presenting cell
mimicking scaffolds (APC-ms), the team was able to fine-tune the levels
of T cell stimulation to match the phenotype of T cells obtained from
leukemia patients, and significantly enhanced their ex vivo and in
vivo tumor-clearing abilities. The findings are published in Nature Communications.

"We show that CAR-T cell products made from T cells derived from cancer patients are generally less functional than CAR-T cells products
derived from healthy individuals," said Founding Wyss Core Faculty
member Mooney. "Matching the CAR-T cell antigen-stimulation dose to
the phenotype of patients' T cells using a precisely controllable
biomaterials approach that closely mimics natural antigen presentation
can significantly improve their function. This approach could further personalize CAR-T cell therapy and remove an existing inadequacy from
current T cell manufacturing." Mooney also is Robert P. Pinkas Family
Professor of Bioengineering at SEAS, and a lead of the NIH-funded Immunomaterials to Improve Immunotherapy (i3) Center coordinated at the
Wyss Institute. This project was conceived at the Center, and Wu is one
of its Principal Investigators.

Cutting the keys for personalized CAR-T therapies The team investigated
the phenotypes of T cells that they isolated from samples obtained from patients suffering from acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL), as well as from healthy donors. Next, they utilized APC-ms to provide the T cells with different doses of anti-CD3/ anti-CD28 antigen stimulation and thus created a CAR-T cell library. All
CAR- T cell products contained in the library were then probed again for functional differences, including their ability to kill cancer cells in
vitro. The researchers directly compared their approach with one that
is commonly used in CAR-T cell manufacturing, which presents the same
antigens on rigid magnetic beads (Dynabeads) to T cells.

A key finding was that cancer patients' T cells were much more
easily over- stimulated at antigen doses commonly used during CAR-T
cell manufacturing than "healthy" T cells. This made them lose their functionality, or become more "exhausted" as immunologists say, and
decreased their ability to proliferate.

CAR-T cells not only need to be transformed into a functional state
but also amplified by millions to be able to eliminate tumor cells and metastasis in the entire body.

"By exploring a precise, narrow range of stimulation doses made possible
with APC-ms, we show that there is something like a personalized
'sweet spot' for patient-derived T cells that maximizes functionality
and amplification, which is, on average, lower than the usual doses,"
said first-author David Zhang, who is a graduate student on Mooney's
team. "The APC-ms approach functions much more naturally than Dynabeads, because highly controllable levels of T-cell signals are embedded into
a lipid bilayer, which allows the CAR-T cells to push and pull at them
as just as T cells usually do across the 'immunological synapse' between
them and antigen-presenting cells when T cell stimulation is at its best."
From in vitro studies to cell manufacturing While the team did not observe
any significant differences between CAR-T cells created from ALL and CLL patient samples, overall their approach generated more cells with high cytotoxic potential toward tumor cells, a more balanced ratio between
cytotoxic CD8+ T cells and CD4+ T cells that support their function,
and more memory T cells that themselves are not cytotoxic but can be
activated in later responses. In a mouse in vivo study, infused CAR-T
cell products created with different levels of stimulation also exhibited significantly different abilities to control CD19-expressing Burkitt's lymphoma, with cells again stimulated at lower than usual levels during manufacturing showing the strongest potential.

"We constructed a proof-of-concept model that is based on the quantifiable relationship between the phenotype of a T cell blood sample and its
CAR-T cell products, and that outputs an optimal T cell stimulation dose
for personalized CAR-T cell production," said Wu. "Given that T cell
samples are always fingerprinted for important markers at the beginning
of the cell manufacturing process, similar strategies could be devised
to further personalize the therapy using the APC-ms approach." Wu is
the Lavine Family Chair, Preventative Cancer Therapies at DFCI, and
Professor of Medicine at Harvard Medical School.

"Dave Mooney's team in the Wyss' Immunomaterials platform is pushing
the envelope of CAR-T cell and other immunotherapies using entirely
new engineering and materials-based approaches. Hopefully, this
will eventually enable us to also mobilize the immune system against recalcitrant solid tumors for which no therapies exist yet. It's also
a great example of where less is more," said Wyss Founding Director
Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of
Vascular Biology at HMS and Boston Children's Hospital, and Hansjo"rg
Wyss Professor of Bioinspired Engineering at the Harvard John A.

Paulson School of Engineering and Applied Sciences.

Additional authors on the study are Wyss and SEAS researchers Kwasi
Adu- Berchie, Siddharth Iyer, Yutong Liu, and Joshua Brockman; DFCI
researcher Nicoletta Cieri, and Donna Neuberg, Sc.D., a data scientist
at the DFCI and member of the i3 Center. The study was funded by the
Wyss Institute at Harvard University, the Food and Drug Administration
(under award #5R01FD006589), the National Cancer Institute of the NIH
(under award #U54CA244726), as well as a fellowship from the Canadian Institutes of Health Research.

* RELATED_TOPICS
o Health_&_Medicine
# Stem_Cells # Lymphoma # Immune_System # Lung_Cancer #
Brain_Tumor # Cancer # Leukemia # Skin_Cancer
* RELATED_TERMS
o Natural_killer_cell o Gene_therapy o
Monoclonal_antibody_therapy o Adult_stem_cell o Cell_(biology)
o Somatic_cell_nuclear_transfer o Somatic_cell o Stem_cell

========================================================================== Story Source: Materials provided
by Wyss_Institute_for_Biologically_Inspired_Engineering_at
Harvard. Original written by Benjamin Boettner. Note: Content may be
edited for style and length.


========================================================================== Journal Reference:
1. David K. Y. Zhang, Kwasi Adu-Berchie, Siddharth Iyer, Yutong Liu,
Nicoletta Cieri, Joshua M. Brockman, Donna Neuberg, Catherine
J. Wu, David J. Mooney. Enhancing CAR-T cell functionality in a
patient-specific manner. Nature Communications, 2023; 14 (1) DOI:
10.1038/s41467-023- 36126-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/02/230210145803.htm

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