Therapy using dual immune system cells effectively controls
neuroblastoma

Date:
September 23, 2021
Source:
University of North Carolina Health Care
Summary:
A newly developed immunotherapy that simultaneously uses modified
immune- fighting cells to home in on and attack two antigens,
or foreign substances, on cancer cells was highly effective in
mice implanted with human neuroblastoma tissue.



FULL STORY ==========================================================================
A newly developed immunotherapy that simultaneously uses modified
immune- fighting cells to home in on and attack two antigens, or foreign substances, on cancer cells was highly effective in mice implanted with
human neuroblastoma tissue, report researchers from the UNC Lineberger Comprehensive Cancer Center and the UNC School of Medicine. The dual
targeting restricted regrowth of the tumor as well as prevented the neuroblastoma cells from evading the attacking immune cells.


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The research findings appeared Sept. 23, 2021, in Nature Cancer.

Neuroblastoma is a cancer of immature nerve cells and occurs mainly in
children younger than six years of age. The tumors are typically found
on top of adrenal glands but can also develop in the abdomen, chest,
neck, pelvis, and bone.

Approximately 500 to 1,000 cases are diagnosed annually in the United
States.

"Tumor cells are characterized by a mixed expression of antigens, and
we engineered dual immune-system T cells to maximize their capacity to
prevent tumors from evading detection by the immune system," said Hongwei
Du, PhD, a postdoctoral fellow at UNC School of Medicine. "Furthermore,
the modified T cells were also able to receive important signals, which
is somewhat unique as there have been many challenges in getting certain
types of immunotherapies to overcome the unfriendly tumor environment
found in solid tumors." The researchers utilized CAR-T cell (chimeric
antigen receptor-T cell) immunotherapy, which involves harvesting
immune-system T cells from a patient and genetically re-engineering them
in the lab to recognize targets on the surface of cancer cells when they
are reinfused into patients.

Specifically, the scientists coupled the recognition of two antigens
expressed by the tumor cells with the combination of two key
co-stimulatory molecules: CD28, a protein expressed on T cells after
early activation, and 4-1BB, an important co-stimulatory protein that
is involved in T-cell survival and memory formation. Both CD28 and 4-1BB
have been shown to be equally effective in clinical studies in patients
with blood-borne cancers when used individually.

However, the combination of CD28 and 4-1BB co-stimulation appears to
be critical in solid tumors. Research efforts by Du resulted in ways to
deliver both signals efficiently.



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The scientists first looked at neuroblastoma cells in the laboratory
to see how they responded to a combined immune cell attack. Given
the positive results of the lab studies, the researchers then looked
at mice implanted with neuroblastoma to see how they would respond
to co-stimulation by CD28 and 4-1BB modified T cells. Indeed, the co-stimulatory cells were very effective in reducing cancer in mice
bearing large numbers of neuroblastoma tumors.

"We know that certain CAR-T therapies are safe for patients with solid
tumors, but so far treatments have not led to the degree of tumor
regression we would like to see," said Gianpietro Dotti, MD, professor
in the UNC School of Medicine Department of Microbiology and Immunology
and co-leader of the Immunology Program at UNC Lineberger. "We ultimately designed a strategy that simultaneously addresses the most challenging
tasks in solid tumors, such as generating CAR-T cells that rapidly
eliminate the tumor and persist in controlling tumor growth. Furthermore,
our system prevents tumor recurrence." If this therapeutic approach
is as promising in people as it has been in mice, the researchers
said targeting three, four or more antigens expressed by tumor cells
could be even more effective. They will proceed with caution as over- stimulation could exponentially increase side-effects. To counter this,
the researchers can use a 'safety switch' technology that Dotti, Barbara Savoldo, MD, PhD, professor of pediatrics and assistant director of the
UNC Lineberger Immunotherapy Program, and others developed to regulate
the level of CAR- T generated stimulation.

"We are currently implementing clinical studies to look at several
potential single targets," said Dotti. "If these studies prove that
the therapies are safe, we'll then progress to the next logical step,
which is looking to see if our therapy is effective against a combination
of targets." In addition to Du, Dotti and Savoldo, the paper's other
authors at UNC include Koichi Hirabayashi, MD, Yang Xu, PhD, Peishun Shou,
PhD, Xin Zhou, PhD, Elisa Landoni, Chuang Sun, PhD, and Yuhui Chen, PhD.

Disclosures This work was funded in part by NCI grants R01-CA193140-03 and R01-CA243543-01 from the National Cancer Institute; grant W81XWH-18-1-0441
from the Department of Defense (USA) and the Vicky Amidon Innovation Grant
in Lung Cancer Research from the Lung Cancer Initiative of North Carolina;
the UNC Small Animal Imaging Facility at the Biomedical Imaging Research Center; the Microscopy Services Laboratory at Department of Pathology;
the Laboratory Medicine and the Flow Cytometry Core Facilities are
supported in part by an NCI Cancer Center Core Support grant to the UNC Lineberger Comprehensive Cancer Center, grant P30- CA016086-40.

Competing interests Dotti is a paid consultant for Bellicum
Pharmaceuticals, Tessa Therapeutics and Catamaran and reports receiving commercial research grants from Cell Medica and Bluebird Bio; Savoldo
is a paid consultant for Tessa Therapeutics; Dotti and Du filed a patent
for the CAR targeting B7-H3. No other competing interests were disclosed
by the other authors.

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


========================================================================== Journal Reference:
1. Hirabayashi, K., Du, H., Xu, Y. et al. Dual-targeting CAR-T
cells with
optimal co-stimulation and metabolic fitness enhance antitumor
activity and prevent escape in solid tumors. Nat Cancer, 2021 DOI:
10.1038/s43018- 021-00244-2 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210923115601.htm

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