Investigators Michel Sadelain (left) and Prasad Adusumilli
In 2013, Science magazine named cancer immunotherapy the scientific breakthrough of the year. It featured two active fields of study at Memorial Sloan Kettering as leading areas of research.
One of those fields is chimeric antigen receptor (CAR) therapy, which is based on the premise that a patient’s own immune cells can be trained to recognize and attack cancer cells. This approach has shown early potential in treating certain kinds of blood cancer, but researchers have yet to determine the best way to apply it to treating solid tumors.
A study published earlier this month in Science Translational Medicine suggests how this technique might be applied to tumors of the pleural cavity, the area in the chest found just outside the lungs. The pleural cavity is the most common location in the body for rare, aggressive tumors called mesotheliomas and is also a frequent site of metastasis for other tumor types, including lung and breast cancers.
“Every year in the United States, about 150,000 new patients are diagnosed with cancer in the pleural cavity, and about 1.5 million procedures are done as a result of these tumors,” says MSK thoracic surgeon Prasad Adusumilli, the first author of the new study. “I’ve focused much of my work the past several years on finding better ways to treat these tumors.”
Finding the Right Target
In CAR therapy for leukemia, immune cells called T cells are genetically engineered to recognize the CD-19 protein, which is found on the surface of blood cells called B cells. Since CD-19 is not present in pleural tumors, investigators needed to identify another target — a protein that’s present in these tumors yet not in most other cell types — in order to protect healthy cells from attack.
They found these attributes in a protein called mesothelin. Mesothelin is present in almost 90 percent of mesotheliomas, as well as 60 percent of lung adenocarcinomas and 35 percent of triple-negative breast cancers (the most difficult-to-treat type of breast cancer). Previous studies conducted by the MSK team showed that the presence of mesothelin indicates that a cancer is more aggressive and less likely to respond to other treatments, such as radiation or chemotherapy.
Putting the Pieces in Place
For the CAR therapy research to move forward for pleural tumors, the investigators spent several years developing mouse models that closely mimic this type of cancer — the first ever developed.
They also focused on finding ways to manufacture T cells engineered to recognize the mesothelin protein, work led by MSK’s Cell Therapy and Cell Engineering Facility under the direction of Isabelle Rivière.
CAR T cell therapy works by filtering out a patient’s T cells and — outside the body — introducing a new gene into the cells. That gene encodes a receptor that enables the T cells to recognize a protein present on the surface of cancer cells — in this case, the mesothelin protein.
A Superior Immune Response
In CAR therapy for leukemia, the engineered cells are reintroduced to the patient through the bloodstream, but for pleural tumors the investigators found another way.
“We thought this was going to be a pretty run-of-the-mill animal study, but it turned out to yield a big surprise,” says Michel Sadelain, Director of MSK’s Center for Cell Engineering and the study’s senior author. “We discovered that when we infused the T cells directly into the pleural cavity, the response was 30 times better than infusing them intravenously. The intrapleural infusion was superior in terms of eliminating local tumors, and it yielded a superior overall immune response.”
“We learned that when we administer the T cells directly into the pleural cavity, they all see the cancer immediately,” Dr. Adusumilli adds. “The T cells get activated and divide more quickly. Furthermore, they are able to enter the bloodstream and travel throughout the body, finding and killing cancer cells that are present in other locations.”
In the majority of mice, the tumors were eradicated and didn’t come back. And two further experiments — conducted 100 or 200 days after the mice had been infused with T cells — showed that the immune cells had persisted and still were able to kill the cancer when new tumors were introduced.
Moving Forward to Trials
Based on the mouse studies, the investigators plan to launch a clinical trial in early 2015 to find out if the treatment is safe for people with solid tumors in the chest cavity.
“Ultimately, patients are the reason we do this research,” Dr. Sadelain concludes. “I’m very proud to work at MSK, where we can develop this kind of approach in the research lab and implement it in the clinic, thanks to our facilities and the depth of our clinical programs.”
