Potential therapy may boost chemoimmunotherapy response in bladder
cancer
Date:
March 28, 2022
Source:
Cedars-Sinai Medical Center
Summary:
Adding an anti-inflammatory medication to immunotherapy and standard
chemotherapy drugs may provide long-term suppression of aggressive
bladder tumor growth, according to a proof-of-concept study.
FULL STORY ========================================================================== Adding an anti-inflammatory medication to immunotherapy and standard chemotherapy drugs may provide long-term suppression of aggressive
bladder tumor growth, according to a proof-of-concept study led by
Cedars-Sinai Cancerinvestigators. The findings, made in laboratory mice,
were published TK in the peer-reviewed journal Nature Communications.
==========================================================================
The researchers' previous work, led by Cedars-Sinai scientist Keith
Syson Chan, PhD -- the study's corresponding author -- found that the
combined use of the chemotherapy drugs gemcitabine and cisplatin is
unable to activate a patient's own immune response to cancer. They also
found that chemotherapy prompts the overwhelming release of an inhibitory signal, or brake, that suppresses an immune response by counteracting "go" signals. When the investigators added the anti-inflammatory drug celecoxib
to gemcitabine to remove the brake, they were able to shift the balance
toward the "go" signals, improving the immune response in laboratory mice.
Building on those findings, the researchers discovered a mechanism that
may drive the immune-dampening effect of chemotherapy and determined how
to counteract it, therefore activating a longer-lasting immune response.
"These results are significant because the novel drug combination
of an anti- inflammatory medication like celecoxib, chemotherapy and immunotherapy potentially can increase the chemoimmunotherapy response in patients with muscle-invasive bladder cancer," said Fotis Nikolo, PhD,
a project scientist at Cedars-Sinai Cancer and first co-author of the
study. "We're also hopeful that our findings will be relevant to other
cancer types." Muscle-invasive bladder cancer is aggressive and more
likely to spread to other parts of the body, according to the Urology
Care Foundation. Each year, more than 83,000 new U.S. cases of bladder
cancer are diagnosed in men and women.
About one quarter of those newly diagnosed have the muscle-invasive type.
Past and Present Treatments Since the 1940s, the main treatment
for killing cancer cells has involved chemotherapy drugs, which kill
the cells directly. But many of the current drugs fail to induce the
most efficient form of cell death, known as immunogenic cell death,
which activates the release of a protein that instructs the patients'
own immune cells to kill the invading cancer cells. This "go" signal
prompts immune cells -- called dendritic cells -- to activate T cells to eradicate tumors. Instead, most current chemotherapies for pancreatic,
bladder, breast and ovarian cancers not only are non-immunogenic, they
suppress the immune system.
==========================================================================
In recent years, immunotherapy drugs have been added to cancer treatment regimens to help a patient's own immune cells attack cancer, but the
response rate is low. Currently, about 70% to 80% of patients taking immunotherapy drugs fail to respond to them, Nikolo said.
Unlocking the Puzzle The researchers may have discovered why the
combination of chemotherapy and immunotherapy often fails. In their
current study, the investigators found that chemotherapy induced a
remarkable release of prostaglandin E2, a bioactive lipid associated with inflammation and cancer. Called an inhibitory damage- associated molecular pattern, or iDAMP, prostaglandin E2 blocks dendritic cells from maturing
and fighting cancer, explained Kazukuni Hayashi, PhD, a study co- author.
To counteract that effect, the researchers added to the chemoimmunotherapy
the drug celecoxib. The anti-inflammatory medication targets the
protein COX-2, which promotes the release of prostaglandin E2,Hayashi explained. This drug combination allows killer T cells to infiltrate
the tumor core and kill the tumor cells.
"The addition of the celecoxib not only worked well with chemotherapy,
it also sensitized bladder tumors toward chemoimmunotherapy, providing
a long-lasting response," Hayashi said.
========================================================================== Next, the researchers plan to test the efficacy of the new treatment in randomized, placebo-controlled human trials in collaboration with their
Cedars- Sinai Cancer and Mount Sinai clinical colleagues, including
those researching new treatments for colon and pancreatic cancer.
"Harnessing the patients' immune system to attack tumor cells has become
an important tool for physicians treating cancer," said Dan Theodorescu,
MD, PhD, director of Cedars-Sinai Cancer and a study co-author. "With
these findings, patients who don't respond to chemotherapy and
immunotherapy have the potential for better outcomes in the future."
Additional Cedars-Sinai Cancer co-authors include Xen Ping Hoi; Mark
Alonzo; Armine Kasabyan; Hideki Furuya, PhD; Charles Rosser, MD; Dolores
Di Vizio, MD, PhD; and Jlenia Guarnerio, PhD. Collaborators at Mt. Sinai,
NCI, and Moffitt Cancer Center also contributed to the study.
Research reported in this study was supported in part by theNational
Cancer Institute under award numbers R01CA255609-01A1, F31CA247257, T32GM088129, and the U.S. Department of Defense, under award numbers
CA181002, CA200750, and CA210889.
========================================================================== Story Source: Materials provided by Cedars-Sinai_Medical_Center. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Fotis Nikolos, Kazukuni Hayashi, Xen Ping Hoi, Mark Ellie Alonzo,
Qianxing Mo, Armine Kasabyan, Hideki Furuya, Jane Trepel,
Dolores Di Vizio, Jlenia Guarnerio, Dan Theodorescu, Charles
Rosser, Andrea Apolo, Matthew Galsky, Keith Syson Chan. Cell
death-induced immunogenicity enhances chemoimmunotherapeutic
response by converting immune-excluded into T-cell inflamed
bladder tumors. Nature Communications, 2022; 13 (1) DOI:
10.1038/s41467-022-29026-9 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220328090017.htm
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