Durable Response Rate of 25% With TILs in Melanoma

Zosia Chustecka

June 09, 2014

With all the excitement over the new immune-checkpoint inhibitor drugs in melanoma, many of which are not yet available, it's easy to overlook another immunotherapy — tumor infiltrating lymphocytes (TILs) — that has been resulting in dramatic and durable responses for some years now.

Research into the use of TILs as a treatment for melanoma began over 10 years ago, and this T-cell approach to therapy is now being tested on an experimental basis in a number of centers around the world.

In total, probably about 1000 melanoma patients have been treated to date with T-cell therapy at these various centers, said Patrick Hwu, MD, professor of melanoma medical oncology and associate director of the Center for Cancer Immunology Research at the University of Texas M.D. Anderson Cancer Center in Houston.

He was previously at the National Cancer Institute, where the use of TIL was pioneered by Steven Rosenberg, MD, with the first use of adoptive T-cell transfer reported in 2002. The treatment involves extracting T-cells from a patient's tumor, expanding these cells in the laboratory, and then infusing them back into the patient where they mount an immune response to the tumor.

Dr. Hwu moved to Texas to set up his own lab in 2003, because, he said, "this was a fabulous therapy and nobody was doing it.... It takes some expertise and is labor intensive, but it's not that hard," he commented in an interview with Medscape Medical News.

Other centers exploring T-cell therapy for melanoma include the Moffitt Cancer Center in Tampa, Florida, more recently also the University of Washington in Seattle, as well as the Sheba Institute in Israel, and centers in Denmark and the Netherlands.

Durable Response Rate of 25%

Dr. Hwu estimates that his team at M.D. Anderson has now treated more than 100 melanoma patients with TILs.

About half of these patients respond, and in about half of responders, the response is long-lasting, he said. So the durable response rate is about 25%, he said.

Some of the responses have been very dramatic.

One patient, a female school teacher, had metastases in the brain and lung that disappeared. "They were no longer visible on CT or MRI scans," he said. That patient is alive and well more than 5 years after the procedure.

Another patient with a long-lasting response has written about his experience of being diagnosed with stage III melanoma at the age of 15, after finding a lump behind his ear. He received various treatments, including immunophoresis in Germany, but progressed to stage IV with brain metastases. He then received T-cell therapy from Dr. Hwu in 2010. His response was rapid. Subcutaneous tumors disappeared within weeks, and scans showed that internal metastases were shrinking. The patient got his life back; he has since gone to college, and will graduate in late 2014.

Dr. Hwu noted that this patient was also treated with Gamma Knife radiosurgery for brain metastases, and he received the TILs as part of a clinical trial which, when unblinded, showed that he had also received a dendritic cell vaccine. In addition, there is chemotherapy before the T-cell infusion and then interleukin (IL)-2 after. "The treatment is intense and patient stays in hospital for about a week, sometime longer," Dr. Hwu said.

The adverse effects in this regimen are mostly due to the IL-2 infusions, he said. The TILs are natural cells and so they are safe, Dr. Hwu said.

TILs are safer than T-cells that have been bioengineered, such as a chimeric antigen receptor (CAR) inserted into the T-cell. Although this chimeric technology has been around for some time (Dr. Hwu noted that he had published on CAR in ovarian cancer back in 1995), it has really taken off in the past few years and is also showing striking responses in patients with leukemia and lymphoma.

However, some of the patients experienced severe reactions, including a cytokine release syndrome, which can include hypotension, breathing difficulties, delirium, and neurologic toxicity, and some patients needed intensive care.

The adverse events after TILs are not as severe, Dr. Hwu commented. There is often hypotension, and sometimes the TILs clump in the lungs (as that is the first capillary bed that they reach), and they may require oxygen.

The limitation, however, is that nearly all TIL therapy has been directed at melanoma, because this is the one tumor from which these cells can be grown. It has been very difficult to do this in any other tumor type, he said, although there have been some recent successes, such as 1 patient with bile duct cancer patient reported by Dr. Rosenberg's team (Science. 2014;344:641-645) and 2 patients with cervical cancer reported at the ASCO annual meeting. "We are also starting to do this, and have some success with growing TILs out of colorectal cancer, but it is much harder, in general, with these other tumor types, although not impossible," Dr. Hwu added.

The expansion of the cells is enormous. There are very few T-cells in the tumor biopsy — about a million immune cells in total — and then "we expand that to as many as we can grow, up to 150 billion T-cells per patient," Dr. Hwu said. "You want to put in as many soldiers as possible.'"

The process involved in growing  the T-cells is not that complex, and although it does need expertise training, really any center with a blood bank could it, Dr. Hwu said. "The process is portable, and we have helped other centers to set up their own systems."

But another way to make this technology more accessible to others is to set up "farming" — where the T-cells extracted from the tumor biopsy are sent away to a company that would expand and prepare the T-cells for infusion back into the patient. Several companies are interested in such a scheme, including Lion Biotechnology, with whom Dr. Hwu is in talks at present. He highlighted this as a potential conflict of interest in the future; he is talking with the firm about being a consultant.

Such farming would really increase accessibility to this technology, he said, and would also make the process more uniform. This would also help to push this technology toward approval from the US Food and Drug Administration for this approach as a salvage therapy, he said.

From a patient's point of view, having TIL therapy involves 1 visit for a biopsy, and then about 3 weeks in hospital — 1 week for preinfusion chemotherapy, then a week for the T-cell infusion and IL-2, and then a week of recovery. After the treatment, the patient is immunocompromised and so is usually given 6 months of therapy with antivirals, antibacterials, and antifungal.

Dr. Hwu said they are fine-tuning the process, and are now using lower doses of IL-2 and also investigating different chemotherapy schedules, so that it could be administered in an outpatient setting. There are also plans to use the TILs along with immune-checkpoint inhibitors to see if that enhances the responses. "These are good soldiers, but we want to make them even smarter," he said.

"This is an intense therapy, but patients recover quickly, and some have these very long-term responses," he said. These T-cells then stay in the body for a very long time, and they continue to keep the disease away, with no further therapy. Some patients have complete remission of their metastatic melanoma, and they get their lives back.


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