According to a proof-of-concept trial conducted by Cedars-Sinai Cancer researchers, combining anti-inflammatory medication with immunotherapy and conventional chemotherapy medications may enable long-term suppression of aggressive bladder tumor growth.
The findings, made in laboratory mice, were published TK in the peer-reviewed journal Nature Communications.
According to earlier research by the team, lead by Keith Syson Chan, PhD, a scientist at Cedars-Sinai who is the study’s corresponding author, the chemotherapeutic medications gemcitabine and cisplatin alone are unable to trigger a patient’s own immune response to cancer.
Additionally, they discovered that chemotherapy causes the massive production of a brake, or inhibitory signal, which slows an immune response by reversing “go” signals. To remove the brake, the researchers combined gemcitabine with the anti-inflammatory medicine celecoxib. By doing this, they were able to tip the scales in favor of the “go” signals, which enhanced the immune response in laboratory mice.
Using those results as a foundation, the researchers identified a mechanism that may be responsible for the immune-dampening effect of chemotherapy and determined how to combat it in order to stimulate a longer-lasting immunological 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.”
Harnessing the patients’ immune system to attack tumor cells has become an important tool for physicians treating cancer. With these findings, patients who don’t respond to chemotherapy and immunotherapy have the potential for better outcomes in the future.
Dan Theodorescu
According to the Urology Care Foundation, severe muscle-invasive bladder cancer is more likely to spread to other body areas. 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
Chemotherapy medications, which actively destroy cancer cells, have been the mainstay of cancer treatment since the 1940s. The most effective type of cell death, known as immunogenic cell death, which causes the release of a protein that tells the patient’s own immune cells to kill the invading cancer cells, is not, however, induced by many of the current medications.
Dendritic cells, which are immune cells, are prompted to activate T cells to destroy tumors by this “go” signal. Instead, the majority of modern chemotherapies for pancreatic, bladder, breast, and ovarian cancers are not only immune-suppressive but also non-immunogenic.
In order to aid a patient’s own immune cells in combating cancer, immunotherapy medications have been added to cancer treatment regimens recently, however 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 reason why chemotherapy and immunotherapy often fail may have been found by the researchers. Researchers discovered in their current investigation that chemotherapy caused a notable release of prostaglandin E2, a bioactive lipid linked to 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.
The researchers will then work with their clinical colleagues at Cedars-Sinai Cancer and Mount Sinai, including those investigating novel therapies for colon and pancreatic cancer, to examine the effectiveness of the new therapy in randomized, placebo-controlled human studies.
“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.”
