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Novel Cell Therapy Beats Immunotherapy in Melanoma

PARIS — Cell therapies have already had a huge impact on the treatment of blood cancers, but progress in solid tumors has proved more difficult. Now, in a first multicenter randomized trial to compare the two, a novel cell therapy showed a superior outcome to immunotherapy in patients with advanced melanoma.

The cell therapy used in this trial was composed of adoptive tumor infiltrating lymphocytes (TIL), which were made individually for each patient, just as chimeric antigen receptor T cells (CAR T cells) are for patients with blood cancers. However, the process involved is somewhat different, as TILs are made from lymphocytes that have infiltrated the patient’s tumor and are obtained by surgery in the tumor, whereas CAR T cells are made from circulating blood cells. 

The phase 3 trial involved 168 patients with unresectable stage IIIC-4 melanoma, and showed that patients who were treated with TILs achieved a significantly improved progression-free survival (PFS) when compared with standard immunotherapy with ipilimumab (Yervoy).

The median PFS was more than doubled to 7.2 months with TILs vs 3.1 months with ipilimumab (hazard ratio [HR], 0.50; P < .001).

“We do think that TIL could possibly become a new treatment option for patients with advanced stage melanoma,” commented lead author John Haanen, MD, PhD, research group leader at the Netherlands Cancer Institute in Amsterdam and a professor in translational immunotherapy of cancer at Leiden University Medical Center in Leiden.  

He presented the findings at a presidential symposium during the 2022 Congress of the European Society for Medical Oncology (ESMO) in Paris, France.

“The results of this trial may fuel further research of TIL in other cancer types, potentially demonstrating benefit in many other solid tumors and expanding available treatments for patients,” said Maya Dimitrova, MD, medical oncologist at NYU Langone Perlmutter Cancer Center, New York City. She was approached for comment by Medscape Medical News and was not involved in the research.

Immune checkpoint inhibitors and targeted therapies have become the standard of care for advanced melanoma and greatly improved patient outcomes, she said. But as about half of patients treated with these agents will not achieve a durable benefit, there remains a need for new treatment options.

“Although immunotherapy can yield impressive long-term responses, a substantial percentage of patients will have no response, or no durable response, to checkpoint inhibitors,” said Dimitrova. “TIL therapy has proven effectiveness in melanoma. However, no phase III trials have been done to date to compare its effectiveness to a standard of care regimen.”

She noted that these results are consistent with past reports of an approximately 50% response rate with an impressive 20% complete response rate in the TIL group. Data from a phase 2 trial reported last year, for example, showed an objective response rate of 36.4%.

“It will be important to determine the persistence of antitumor activity and whether there are biomarkers that could help with patient selection given the resource intensity of the therapy,” Dimitrova said. “TIL therapy will likely become a new standard of care in metastatic melanoma refractory to immune checkpoint inhibitors.” 

Superior to Immunotherapy

In the current study, Haanen and colleagues randomly assigned 168 patients to TIL or ipilimumab (3 mg/kg every 3 weeks, maximum 4 doses). Patients were stratified for BRAFV600 mutation status, treatment line and center, and the majority (86%) were refractory to anti-PD-1 treatment.

Patients in the TIL group underwent resection of a melanoma lesion (2-3 cm) for the ex vivo outgrowth and expansion of tumor-resident T cells. Before the cultured TILs were infused back into the patients from which they were made, the patient underwent nonmyeloablative, lymphodepleting chemotherapy with cyclophosphamide plus fludarabine that was followed by high-dose interleukin-2.

The study’s primary endpoint was progression-free survival and secondary endpoints included overall and complete response rate, overall survival, and safety.

At a median follow-up of 33 months, TIL significantly improved progression-free survival as compared to ipilimumab. The overall response rate also favored TIL compared with ipilimumab (49% vs 21%), with 20% vs 7% complete responses, respectively.

The median overall survival was 25.8 months for TIL and 18.9 months for ipilimumab (HR, 0.83; P = 0.39).

Grade 3 or higher treatment-related adverse events occurred in all TIL and 57% of ipilimumab patients, although Haanen noted they were manageable and, in most cases, resolved by the time patients were discharged from the hospital.

“There were no new safety concerns with TIL,” said Haanen, “And these toxicities are driven by the chemotherapy and interleukin-2 that are part of the TIL regimen. There were no long-term sequelae in patients treated with TIL and health-related quality of life was higher in patients treated with TIL.”


Also commenting on the study, Anthony J. Olszanski, MD, RPh, associate professor and vice chair of clinical research, Department of Hematology/Oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania, agreed that the treatment of patients with melanoma who do not respond to or progress after receiving treatment with immunotherapy is “challenging and represents an unmet need.”

“TIL therapy is, in some ways, ultra-personalized therapy because we harvest immune cells from the patient’s tumor, expand them outside of the body, and then re-infuse them,” he said. “This trial, which randomized patients between TIL vs the CTLA-4 inhibitor, ipilimumab, has shown an impressive progression-free survival and overall response rate benefit and will help establish TIL therapy as a viable treatment strategy for some patients.”

The study was supported by the Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society, and Capital Region of Denmark Research Foundation.

Haanen and several of the co-authors have declared multiple relationships with industry as noted in the abstract. Olszanski reports participation in advisory boards for BMS, Merck, and Instil Bio and he reports running trials for them.

2022 Congress of the European Society for Medical Oncology (ESMO): Abstract LBA3. Presented September 10, 2022.

Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.

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