Immunotherapy combination helps patients with resistant melanoma

Separate immunotherapies work well together, pumping up the impact of immune system attack on tumors, an unprecedented clinical trial shows this week in the Journal of Clinical Oncology.

Capturing tumor-homing T cells from a patient’s blood, expanding and priming them in the lab, and then giving the cells back, along with a drug that keeps them from getting turned off, improved the prospects of patients with metastatic melanoma.

Seven of 10 patients treated with that combination in a clinical trial responded. Two had a complete response, two had their tumors shrink substantially and three others had stable disease. A separate paper on one of the complete responders was published in the Journal of Experimental Medicine.

Trial results, in a small sample, indicate the combination helps patients whose disease resisted those treatments separately. In addition to the T cells, patients were treated with ipilimumab, the original immune checkpoint inhibitor, which blocks a protein on T cells that shuts down immune response.

“Our goal is to develop combination therapies that provide a clear path for T cells to do their business,” says Cassian Yee, M.D., professor of Melanoma Medical Oncology and senior author of the trial, which was conducted initially at Fred Hutchinson Cancer Center in Seattle.

T cells are the targeted troops of the adaptive immune system, recognizing and binding to antigens – abnormalities found on bacteria, viruses or abnormal cells that mark them for attack. T cells track down and kill cells bearing the antigen that they’ve bound to and then remember them for future reference.

The combination clinical trial continues at MD Anderson, where Yee arrived in 2013 after developing the process for collecting, identifying and sorting tumor-targeting T cells from peripheral blood, enhancing them in the lab with interleukin-21, and then re-infusing them in patients.

It’s similar to another technique for gathering T cells directly from a patient’s tumor, called tumor-infiltrating lymphocytes or TIL. Yee’s method doesn’t require surgery to collect cells and is a milder regimen of treatment.

“Expanding this process beyond melanoma to other cancers is really my mandate for coming to MD Anderson,” Yee says. “There are things I can do here that could not be done at another center. Other clinical departments are open to treating patients with T cells.”

Among the new alliances is one with Gastrointestinal Medical Oncology,with an early focus on colorectal and pancreatic cancers. A clinical trial will open applying Yee’s T cell therapy to those two cancers, which so far have been largely resistant to immunotherapy.

In addition to testing combinations and applying T cell therapy to new cancers, another focus is to compress the time it takes from the gathering of T cells to re-infusing the expanded and primed cells, which can take up to 12 weeks. Yee expects to get that process down to five-six weeks.

Yee also is co-leader of the adoptive cell therapy platform for MD Anderson’s Moon Shots Program, designed to reduce cancer deaths by accelerating the development of new treatments, prevention efforts and early detection based on scientific discoveries.

The platform supports cell-based therapy research and clinical trials across the program, including T cell-based treatments and an approach developed at MD Anderson employing natural killer cells, a different type of immune cell that generally recognizes and attacks invaders and aberrant cells.

Immunotherapy has progressed so far mainly through the checkpoint inhibitors, with ipilimumab approved by the Food and Drug Administration for advanced melanoma and a class of drugs that blocks a different set of brakes on T cells approved for advanced melanoma, lung, kidney and bladder cancer, and Hodgkin lymphoma.

Another form of T cell therapy involved genetically engineering T cells with a specific antigen found on tumors. So far, this approach, called chimeric antigen receptor T cells, has had early success in blood cancers but not in solid tumors.

While checkpoint inhibitors have produced durable responses for a significant fraction of patients in these cancers, there are still many who don’t benefit. Clinical trials continue to test these drugs against other cancer types and in combination with each other or other therapies.

“The question is what do we need to add to make these therapies more effective for patients,” Yee notes.