BRONX,
N.Y., May 8, 2024 /PRNewswire/ -- Researchers at
the National Cancer Institute-designated Montefiore Einstein
Comprehensive Cancer Center (MECCC) have shown that a breakthrough
therapy for treating blood cancers can be adapted to treat solid
tumors—an advance that could transform cancer treatment. The
promising findings, reported today in Science Advances,
involve CAR-T cell therapy, which supercharges the immune system to
identify and attack cancer cells.
"CAR-T cell therapy has revolutionized the treatment of blood
cancers such as leukemia and lymphoma but hasn't worked well
against solid tumors," said Xingxing
Zang, Ph.D., the paper's senior author. "We found that our
changes to standard CAR-T cell therapy can significantly boost its
effectiveness against solid tumors, including often-fatal
pancreatic cancer and glioblastomas." Dr. Zang is a member of MECCC
Cancer Therapeutics Research Program and professor of microbiology
& immunology, of oncology, of medicine, and of urology, the
Louis Goldstein Swan Chair in Cancer Research and the founding
director of MECCC's Institute for Immunotherapy of Cancer at
Albert Einstein College of Medicine.
The first author of the paper is Christopher Nishimura, an M.D./Ph.D. student in
Dr. Zang's lab.
Developing Personalized Cancer Killers
Dr. Zang and his colleagues created five CAR-T therapies that
they tested on mice implanted with several types of solid human
tumors. One of the therapies—which used two novel components—proved
superior in safely and effectively shrinking not only glioblastoma
and pancreatic tumors but lung cancer tumors as well.
CAR-T cell therapy, short for chimeric antigen receptor (CAR)-T
cell therapy, is a marvel of genetic engineering that transforms T
cells (a type of immune cell) into cancer-seeking missiles
programmed to attack on contact. The therapy involves extracting
the patient's own T cells and equipping them with a single gene
that codes for several different proteins. ("Chimeric" comes from
the Chimera of Greek mythology with its lion's head, goat's body,
and serpent's tail.) The genetically modified T cells are allowed
to multiply and are then infused back into the patient.
Their specially designed gene enables the infused T cells to
express synthetic CAR receptors on their surface. The CARs can
recognize specific proteins, known as antigens, that protrude from
cancer cells. Thanks to their new CARs, the T cells are able to
home in on cancer cells and then switch to attack mode.
CARs contain four key proteins, and Dr. Zang and his colleagues
achieved success against solid tumors by altering two of them. (See
illustration of CAR-T cell receptor below.)
Five CAR-Ts Confront Three Types of Cancer
All five CAR-T therapies developed by the Zang team used the
same novel targeting protein: a monoclonal antibody that binds to
B7-H3, a cancer-cell antigen widely expressed on most solid tumors
and their blood vessels. Dr. Zang had previously helped to discover
that B7-H3 allows tumors to evade immune attack by interfering with
T cells.
"We wanted our CARs to not only attach T cells to solid tumors
but also—by binding specifically to B7-H3—to prevent B7-H3 from
interfering with the T cells' ability to attack and destroy cancer
cells and their blood vessels," said Dr. Zang.
Simply attaching CAR-T cells to tumor cells isn't enough to kill
them. CARs must also include a costimulatory protein to help
activate T cells once they've made contact with cancer cells. Four
of the five CAR-T cell therapies developed by Dr. Zang's lab used
previously deployed costimulatory proteins. But their fifth therapy
used a protein never before tried in CAR-T cell therapy. In 2015,
Dr. Zang discovered that T cells possess a receptor he called
TMIGD2 that activates T cells when stimulated. He later realized
that incorporating TMIGD2 into CAR-T cells might enable them to
overcome the challenges posed by solid tumors.
"Factors such as low-oxygen levels and immune checkpoints inside
solid tumors make for a hostile microenvironment that can strongly
suppress immune attack by T cells—which also have trouble
penetrating solid tumors' dense connective tissue network," Dr.
Zang said. "It seemed possible that using TMIGD2 as a costimulatory
protein could give CAR-T cells the activation boost they need to
reach cancer cells and persist within solid tumors."
These novel CAR-T therapies were tested on mice bearing three
solid human tumors: pancreatic, lung, and glioblastoma. All were
equally likely to bind their T cells to cancer cells, since their
CARs all possessed the same novel antibody aimed at the B7-H3
antigen. The most effective one possessed both the novel antibody
and the TMIGD2 protein—a CAR that Dr. Zang calls a TMIGD2
Optimized Potent/Persistent (TOP) CAR.
The TOP Choice
The CAR-T therapy with TOP CAR proved best at keeping mice with
pancreatic, lung, and glioblastoma tumors alive. For example, TOP
CAR treatment enabled 7 out of 9 mice with glioblastoma tumors to
survive, compared with a maximum survival of 3 out of 9 mice
achieved by any of the other CAR-T therapies. It was also superior
with respect to key effectiveness and safety parameters.
Dr. Zang plans to further develop TOP CAR into an "off-the
shelf" platform that can simultaneously target B7-H3 as well as
other tumor antigens and can readily be tailored for treating many
different types of solid tumors. Einstein has intellectual property
protection for a portfolio of Dr. Zang's research and is interested
in securing commercial partners to help to move his novel TOP CAR
therapy into clinical trials in the near future, including for
cancer of the brain, liver, pancreas, ovary, prostate, lung,
bladder, colon, and others. Over the past several years, Dr. Zang
has developed two other anti-cancer drugs that are being evaluated
in phase 1 and phase 2 clinical trials in the United States and other countries.
The paper is titled "TOP CAR with TMIGD2 as a safe and effective
costimulatory domain in CAR cells treating human solid tumors."
Other Einstein authors are Devin
Corrigan, M.S., Xiang Yu
Zheng, B.S., Phillip M. Galbo
Jr., Ph.D., Shan Wang, M.D.,
Yao Liu, Ph.D., Yau Wei, M.D., Linna
Suo, M.D.,Wei Cui, Ph.D. and
Deyou Zheng, Ph.D. Other authors are
Nadia Mercado, Sc.M., of
Brown University School of Public
Health and Cheng Cheng Zhang, Ph.D., of the University of Texas Southwestern Medical
Center.
Dr. Zang and Mr. Nishimura are inventors of two pending patents:
Chimeric antigen receptors comprising a TMIGD2 costimulatory domain
and associated methods of using the same; and Chimeric antigen
receptors targeting B7-H3 (CD276) and associated methods. Dr. Zang
is an inventor of a pending patent: Monoclonal antibodies against
IgV domain of B7-H3 and uses thereof. Other authors declare no
conflicts of interest.
About Montefiore Einstein Cancer Center
Montefiore Einstein Cancer Center (MECC) is a national leader in
cancer research and care located in the ethnically diverse and
economically disadvantaged borough of the Bronx, N.Y. MECC combines the exceptional
science of Albert Einstein College
of Medicine with the multidisciplinary and team-based approach to
cancer care of Montefiore Health System. Founded in 1971 and a
National Cancer Institute (NCI)-designated Cancer Center since
1972, MECC is redefining excellence in cancer research, clinical
care, education and training, and community outreach and
engagement. Its mission is to reduce the burden of cancer for all,
especially people from historically marginalized communities.
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SOURCE Montefiore Einstein Cancer Center