“Hot Tumors” May Be the Key to Improved Immunotherapy Results in Mesothelioma Patients

Although pancreatic cancer and mesothelioma are very different cancers, the two diseases are both extremely aggressive and require equally aggressive treatments to combat the tumors.  But researchers have continually been stymied in finding an effective therapy for either of the cancers. Now, researchers believe “hot tumors” may hold the secret to enhancing the effect of immunotherapy in pancreatic cancer, and hopefully, for mesothelioma as well.

Researchers from Penn Medicine’s Abramson Cancer Center (ACC) found that the concentration of T-cells, or immune cells, within a tumor can drive the success of immunotherapy. A “hot” tumor has a higher concentration of T-cells resulting in a higher sensitivity to immunotherapy treatment. “Cold” tumors, with fewer T-cells, were found to be more resistant to the immunotherapy.

Although T-cells help fight off cancer, hot tumors, in effect, exhaust the T-cells allowing the cancer to avoid them and continue to grow. But those same T-cells may rally to help fight the cancer when an immune checkpoint blockade treatment, immunotherapy, is introduced to the hot tumor.

“There is no disputing that targeting immune cells has led to promising outcomes for many cancer patients, but not every person responds to these types of mesothelioma treatments,” said senior author Ben Stanger, MD, PhD, a professor of Gastroenterology and Cell and Developmental Biology in the Perelman School of Medicine at the University of Pennsylvania. “Every tumor is different, so we’re investigating how to use the underlying biology of tumor cells to successfully treat more cancer patients.”

Mesothelioma, caused by asbestos exposure, is diagnosed in close to 3,000 Americans each year. Research that increases the effectiveness of immunotherapy is critically important to patients diagnosed with cancers, like pancreatic and mesothelioma, that can fight off even the strongest of drugs.

Some mesothelioma patients have benefitted from the latest immunotherapy drugs, including Keytruda and Opdivo. (Read about mesothelioma warrior Mavis Nye achieving remission with Keytruda.)

Immunotherapy enhances the body’s immune response to cancer, allowing natural defense mechanisms to kick in and fight cancer tumors. However, since not all patients respond to immunotherapy, the Penn Medicine researchers looked closer at the hot tumors.

The team injected pancreatic tumors into healthy mice with a working immune system, and then observed the reaction to immunotherapy by the hot and cold tumors. All of the mice were treated with a checkpoint blockade drug, and either an anti-CD40 agonist, combined chemotherapy, or both. 20 out of 26 hot-tumor mice receiving the combination treatment survived more than six months. While the cold tumors were the most prevalent to develop in the mice, none of those tumors “cleared their cancer” with the same treatment.

The results were attributed to CXCL1 – a compound that keeps T-cells away – and is responsible for resistance to immunotherapy. When CXCL1 was knocked out in the cold tumors, T-cells became active and sensitive to immunotherapy.

“In the future, these tumor cell lines could help to further identify and optimize therapies for specific subsets of patients…” the team concluded.

Currently, there is no cure for mesothelioma,but research into treatments of other cancers is followed closely by the mesothelioma community in hopes the results are equally effective in the rare cancer.

Read the results of the study in the July 3 issue of Immunity.

Sources:

• July 3 issue of Immunity
  https://www.cell.com/immunity/fulltext/S1074-7613(18)30261-9
• Penn Medicine’s Abramson Cancer Center
  https://www.pennmedicine.org/news/news-releases/2018/june/penn-study-reveals-secrets-of-hot-and-cold-pancreatic-cancer-tumors