New Phase 3 Clinical Trial for Pleural Mesothelioma Patients

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Virotherapy Clinical Trial for Pleural Mesothelioma Treatment

Imagine this: a virus, genetically engineered to boost the immune system, turning mesothelioma tumors into cancer-fighting machines. It sounds like a page out of a science-fiction novel, but it’s the culmination of more than two decades of mesothelioma research.

This type of immunogene therapy, also called virotherapy, is the subject of a new Phase 3 clinical trial for patients diagnosed with malignant pleural mesothelioma. The trial is specifically for those who have already tried and failed first-line chemotherapy treatment.

Mesothelioma Hub spoke with Dr. Daniel H. Sterman, Director of the Multidisciplinary Pulmonary Oncology Program at New York University’s Langone Health, to learn more about the trial and process. Along with Dr. Steven M. Albelda, a researcher at the University of Pennsylvania Perelman School of Medicine, Sterman created and has studied this specific immunogene therapy for more than 20 years.

Mesothelioma Hub: Why use viruses for cancer treatment?

Dr. Sterman: Viruses have adapted over millions of years to be the perfect mechanism to deliver cargo to cells. In this study, we’re using a genetically-modified adenovirus to deliver new DNA into human cells. When we engineered this virus, we wanted to accomplish two things: remove the genes that allow it to replicate itself, and deliver the specific gene we put into it.

MH: What is that specific gene?

Dr. Sterman: It’s called interferon alpha-2b, and it’s a compound that already exists in low levels within the body. When we get an infection, our white blood cells produce more interferon to fight the infection. This gene stimulates multiple aspects of the immune system.

In this trial, the adenovirus containing the interferon gene is delivered directly into mesothelioma tumors. Once there, the virus breaks down and leaves the gene behind to do its work. The tumor cells pick up the interferon gene and translate this new DNA, and the tumor starts secreting high amounts of interferon. Essentially, we’ve created a vaccine in a virus. It turns tumors into cancer-fighting factories.

MH: How is the study organized?

Dr. Sterman: This study is a Phase 3 clinical trial, so there will be two treatment arms: a randomized group, and a control group. Only 50 percent of mesothelioma patients will receive immunogene therapy. However, both groups will receive a two-week treatment of Celebrex, an anti-inflammatory medication normally used for conditions like arthritis, which has been shown to be a tumor-modulating drug.

All patients will then have a course of gemcitabine, a chemotherapy drug that also showed some synergy with the adenovirus. According to our research, these three therapies work well together. It’s a multi-pronged approach to fighting cancer.

The first day, the randomized treatment group will receive the adenovirus injected through a tube into the chest cavity. There are 300 billion viruses in just one dose. Patients in both groups will receive Celebrex for two weeks, then an intravenous injection of gemcitabine on day one and day eight on a 21-day cycle.

All patients will receive chest scans every nine weeks to assess their response. It’s important to note that unlike other studies where there’s a placebo group, every patient will receive some clinical benefit.

MH: Why gemcitabine?

Dr. Sterman: When you administer chemotherapy to cancer patients, we talk about lines of treatment. On newly diagnosed mesothelioma patients, you use first-line therapy, for example, a combination of ALIMTA and cisplatin or carboplatin. For years, this combination has been the standard in the United States.

Not all patients respond well to this first-line therapy, so doctors will try second-line therapy. We do not have an FDA-approved chemotherapy drug in second-line therapy for mesothelioma. However, there are many drugs that have been used and studied in some fashion and have some modicum of benefit. Gemcitabine, which is commonly used to treat colon and lung cancer, is one of the drugs that is recommended.

Gemcitabine is unique. Dr. Albelda and I have substantial data from our research at the University of Pennsylvania that gemcitabine offers more than just standard chemotherapy properties. It’s a modulator of the immune system, which means it makes immune responses work in the right chemical settings. We’ve tested the gemcitabine with this immunogene therapy, and it showed synergy with the adenovirus. They appear to work together.

MH: This immunogene therapy has been successful in the past. What were the results of your Phase 2 study of this adenovirus?

Dr. Sterman: We published a study at the University of Pennsylvania three years ago, where we worked with both patients who had never received treatment and those who received first-line chemotherapy treatment that didn’t work.

In second-line patients, survival time increased around 17 months after they entered the study and received the three-pronged approach of the adenovirus, Celebrex, and gemcitabine. Historically, second-line chemotherapy has at most a survival of six to eight months. It doubled survival time in about 25 percent of mesothelioma patients, which gave us evidence that this is safe and efficacious.

MH: Are you anticipating any side effects?

Dr. Sterman: In some patients, this could trigger an autoimmune disease. There’s a chance the adenovirus will attack not just the mesothelioma tumors, but other healthy tissues in the body. In general, immunogene therapy is extremely well-tolerated, but we will be monitoring this in patients.

MH: How many hospitals and patients are participating in this Phase 3 trial?

Dr. Sterman: So far, we have 55 hospital sites, and we’re hoping to increase that number to 80. Eleven or 12 or those sites are here in the United States. The rest are located around the world in Europe, Australia, and Russia.

One site at the University of Toledo is already up and running but has not administered any of the adenovirus injections yet. Here at NYU Langone Health, we plan to start accruing pleural mesothelioma patients starting next week.

Upwards of 300 patients will be randomized for this trial, which is expected to last around seven years. We’re hoping to show the overall survival of patients.

MH: What are your thoughts on immunogene therapy and the future of cancer treatment?

Dr. Sterman: It’s taken more than ten years, and this is something we never thought would never come to fruition. Now, immunotherapy is a first-line therapy. This is just one way of manipulating the immune system to fight cancer. Immunology is here to stay. It’s the end of the beginning, and we’re trying to determine other ways to harness the immune system to help the body fight cancers like mesothelioma.

MH: This clinical trial is the culmination of nearly 25 years of mesothelioma research. What are your personal thoughts?

Dr. Sterman: It’s exciting and daunting. As a young doctor working in the lab, I helped develop a concept that is just turning into a study that will take seven years to complete. It’s an entire lifetime’s worth of work, but it tells you how long it takes to make this work.

I believe it’s an exciting opportunity for the mesothelioma community, where Phase 3 clinical trials are rare. To make any advances in mesothelioma treatment, to get there, you need more research. We hope this will help the entire community.

Learn more about clinical trials for mesothelioma treatment.

Last updated on January 30th, 2023 at 10:08 pm

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