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Some patients with inoperable metastatic melanoma think of survival in terms of weeks and months, not years. For such patients with advanced melanoma, a new immunotherapy called lifileucel may offer hope by extending survival.

Lifileucel is an adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) that enhances a patient's own immune system and may lead to specific tumor cell killing.  Immunotherapy harnesses the body’s own immune system to attack cancer cells.

Dr. Amod Sarnaik

Dr. Amod Sarnaik, Surgical Oncologist

“Treatment options are limited for patients with advanced melanoma whose cancers have progressed on checkpoint inhibitors such as PD-1 antibody-based treatment,” said Moffitt Cancer Center surgical oncologist Dr. Amod Sarnaik. He is the lead author of an abstract presented at the 2020 American Society of Clinical Oncology (ASCO) Annual Meeting that outlined the phase 2 results of a global study of lifileucel.  The encouraging lifileucel clinical trial results reported at ASCO involve patients whose cancer has progressed on the PD-1 antibody-based treatment.

Although PD-1 antibody-based treatment initially is effective in 30 to 40% of treated patients, the responses for patients with advanced melanoma have proven to be relatively short-lived in 60 to 70%. “Unfortunately, there has not been a good fallback option for these patients. Although PD-1 was groundbreaking research and revolutionized immunotherapy for cancer, the reality is the majority of patients’ disease ultimately ends up becoming worse,” said Sarnaik.

More than 20 centers in Canada, the United States and Europe participated in the clinical trial, which services patients with an unmet clinical need. The trial results were encouraging for several reasons, which included the response rate, ease of single-treatment administration and long-lasting responses.

“The response rate of 36% in previously treated patients is remarkable, especially because we are talking about patients whose melanoma was not able to respond to current FDA-approved treatment,” said Sarnaik.

The cell therapy treatment preparation is complex, yet the treatment can be safely administered to patients at a broad variety of treatment centers. “We are not just treating patients in a facility like Moffitt; we also are treating patients in sites that are not as large or may not have as much robust resources as Moffitt has,” said Sarnaik. “It allows the treatment to penetrate patient populations in relatively remote areas, so it does not require the patient to have to travel all the way to a place like Moffitt for treatment. The trial conclusively demonstrates that treatment can be administered at a broad, regionally diverse number of medical centers. The fact that the patients are not required to come to one centralized place also allows the treatment to permeate multiple different countries, not just in the United States or Canada, but also in Europe.”

Median Duration of Response is Encouraging

Another important consideration is the length of response to the drug being tested. “The average responding patient was followed for beyond one and a half years, and the median duration of response to lifileucel has not yet been reached. This is a treatment that is given only one time, and if a patient has a response, the effect of that treatment goes beyond a year and a half. So the fact that not just overall survival but also responses were lasting more than a year and a half is hopeful,” said Sarnaik about the clinical trial that is still ongoing.

To create the TILs, a portion of the patient’s tumor is removed and the immune cells embedded within the tumor are grown in a cell therapy facility. It is possible to artificially manipulate the laboratory conditions to allow these immune cells to grow to billions in number, and those immune cells are used as the treatment. “So it is a living product, derived from a patient’s own tumor. We are able to recruit these immune cells out of the tumor in a way that cannot be done inside the patients themselves but can be done in the lab,” said Sarnaik.

Moffitt researchers are leaders in advancing the field of TIL therapy. Final commercialization was done outside of Moffitt, and later cohorts of the trial involved administering TILs processed in a single, free-standing site in order to achieve the required validated manufacturing process. In early cohorts of the trial, some of the TILs used as the lifileucel infusions were processed at Moffitt’s cell therapy facility, which played an important role in terms of optimization, validation and advancement of this technology.

As encouraging as the results are, Sarnaik would like to see additional advancements within TIL therapy.

The treatment requires chemotherapy, not to kill the cancer but rather to prepare the patient’s body to receive the cell therapy and to allow the TILs to expand.  “While the resultant toxicity is short-term and generally not life-threatening, the chemotherapy is associated with some toxicity and it is not to be understated,” said Sarnaik. “If we could come up with a strategy to deliver these cellular therapies without having to have as rigorous a side effect profile, that would be helpful.”

Additionally, before undergoing TIL therapy, all the patients require some type of surgery to harvest the tumor to grow the cells. “If there is a way to obtain these cells by a means alternative to surgery, like, for example, if we could do image-guided biopsy instead of tumor resection, or even filter out the patient’s own immune cells from their circulation, then that would potentially avoid having to do surgery at all,” Sarnaik said.

Such preclinical research to advance the field is ongoing.

Expanding TIL Therapy to Other Cancers

Future plans include expanding TIL cellular therapy beyond treatment of melanoma. “We are hoping this treatment can be applied to multiple different types of cancer; and there are ongoing clinical trials for patients with cervical cancer, head and neck cancer, lung cancer and sarcoma,” said Sarnaik. “Additionally, we are hoping to open a trial in bladder cancer.”

The trial sponsor, Iovance Biotherapeutics, provided the capital resources to develop the treatment so that it is broadly applicable, then partnered with academic centers including Moffitt to implement clinical trials. “This clinical trial could not be possible without an industry-academic partnership,” said Sarnaik.

The trial is a culmination of decades of research previously conducted and pioneered through the National Cancer Institute, with much of the advancements built upon the immunotherapy research of Dr. Steven Rosenberg, chief of the Surgery Branch at National Cancer Institute.

Contributions of both the patients and their families were essential to the success of the clinical trial to learn more about this unique technology. “The patients on the trial are subjecting themselves to uncertain side effects, and at the beginning of the trial there was uncertain clinical benefit. Over time, we became excited that the treatment was working quite well, but at the beginning we weren’t entirely sure. The patients and their families contributed greatly,” said Sarnaik. “In addition to that, there were patients who voluntarily donated their tumors, even before there was any trial at all. We took those tumors and learned how to grow the TIL.”