Immunotherapy and Cancer

Last fall, the Baylor College of Medicine Mesothelioma Treatment Center began running a new clinical trial that looks at how to use immunotherapy and surgery together as a more effective way to treat mesothelioma – an extremely rare form of cancer caused by exposure to asbestos.

A little background: Mesothelioma usually takes decades to develop after the initial asbestos exposure. In most cases, because symptoms develop so late, the disease is diagnosed after it reaches Stage 3 or Stage 4, after it has begun spreading beyond the lining of the lungs or abdomen, where it initially develops. Because of this late-stage diagnosis, treating the disease is extremely difficult, and usually a multiple-tactic approach is taken that uses surgery, chemotherapy, and radiation.

In recent years, some newer treatments have emerged that have shown some real promise in treating mesothelioma. One of these is immunotherapy, which boosts various immune system mechanisms to enhance their ability to attack cancer. One particular immunotherapy drug that has shown positive early results is pembrolizumab (brand name Keytruda).

Up until now, immunotherapy has always been administered either as a standalone treatment or, more often, as an adjuvant therapy after surgery. With this newest clinical trial, however, researchers at Baylor College of Medicine are looking to see if using immunotherapy as a neoadjuvant therapy – that is, administered before the primary surgery – will increase the therapy’s success.

Dr. Bryan Burt, who is leading the Baylor team, had this to say about the new approach. “In this trial, checkpoint inhibitor immunotherapy is administered before surgical resection. To our knowledge, this is the first trial of this kind for patients with malignant pleural mesothelioma, in which the immune system is ‘primed’ with these agents before the patient undergoes a complete macroscopic tumor resection. Whereas a variety of earlier studies have investigated other modalities of immunotherapy, many of these strategies were not as effective as checkpoint inhibitor therapy, which has shown remarkable efficacy in a number of other solid tumors, and for which a number of preclinical studies in mesothelioma demonstrate favorable results.”

Dr. Burt
Photo from Baylor College of Medicine

As part of the trial, patients with malignant pleural mesothelioma will receive one of two checkpoint inhibitor immunotherapy regimens (anti-PD1, or combination anti-PD1 plus anti-CTLA4) before resectional surgery. Tumor tissue will be obtained before giving these drugs, and then again at the time of resection, after the immunotherapy drugs have been administered.

According to Dr. Burt, by taking tissue both before and after the immunotherapy is administered, the researchers believe they can detect how the immune system is responding to the cancer before most of it is removed through surgery. “This protocol will allow us to learn exactly how the immune response within the tumor is affected by these drugs,” Dr. Burt explained. “Secondary outcomes in this trial include studying the effect of these drugs on tumor recurrence and on long-term survival.”

To be eligible for this trial, patients must be candidates for surgical resection by pleurectomy/decortication or extrapleural pneumonectomy. Whether patients have received previous traditional chemotherapy does not influence eligibility.

Overall, these sorts of studies are important because immunotherapy currently offers one of the best attempts to find a better treatment for mesothelioma. Specifically, checkpoint inhibitor immunotherapy is changing the landscape of the treatment of solid tumors. Mesothelioma tumors develop out of inflammation, particularly when there are dense immune infiltrates with the ability to respond to these novel immunotherapeutic agents.

Nonetheless, researchers are still breaking new ground with studies like these. “Immunotherapy for mesothelioma can be considered in an early phase of development,” said Dr. Burt. “Recent human data from small clinical trials using checkpoint inhibitors in mesothelioma patients have shown promising results.”

Mesothelioma is notorious for having an extremely poor prognosis. Long-term survivors are very few and far between. Even in cases where the disease goes into remission, incidence of recurrence is very high. Dr. Burt believes that immunotherapy could change that situation.

“It is our hypothesis that preoperative checkpoint inhibitor therapy, followed by surgical resection, has potential to create immunologic memory that will be protective against disease recurrence,” Dr. Burt stated. “In other words, there are many data to suggest that checkpoint inhibitor therapy initiates an anti-tumor T-cell response.

“In this trial, checkpoint inhibitor therapy is initiated preoperatively, in the presence of the tumor against which the T-cell response should be targeting, and we anticipate that the resulting anti-tumor immune response will be long-lived. Patients then undergo complete resection of all visible tumor by seasoned mesothelioma surgeons at the Mesothelioma Treatment Center at Baylor College of Medicine. We are hypothesizing that the immunologic memory created by preoperative immunotherapy will have the ability to protect against tumor recurrence.”

The work that Dr. Burt and the team at Baylor are doing is important for those who have mesothelioma. But it is also part of the larger work being done to find more effective treatments for a variety of cancers as part of the Cancer Moonshot Initiative announced by President Barack Obama earlier this year and led by Vice President Joe Biden.