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 researchers. Their  findings (“Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors”), made in laboratory mice, are in Nature Communications.

“Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To date, most studies have focused on tumor-intrinsic properties that render them “immune-excluded.”

“Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constrains their antitumoral activity, despite expression of activation markers IFNγ and granzyme B.

“Mechanistically, chemotherapy induces the release of prostaglandin E2 (PGE2) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinders dendritic cell maturation. Upon pharmaceutical blockade of PGE2 release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This “iDAMP blockade” approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy.

“These findings provide a compelling rationale to evaluate this drug combination in future clinical trials.”

The team’s 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 discovered 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 lab 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.

The researchers believe they 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, but it also sensitized bladder tumors toward chemoimmunotherapy, providing a long-lasting response,” Hayashi pointed out.

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.

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