New cell therapy beats immunotherapy in melanoma

Cell therapies have already had a huge impact on treating blood cancers, but progress in solid tumors has proven more difficult. Now, in a first multicenter randomized trial to compare the two, a new cell therapy has shown superior outcome to immunotherapy in patients with advanced disease. melanoma.

The cell therapy used in this trial consisted of adoptive tumour-infiltrating lymphocytes (TILs), which were made individually for each patient, as are chimeric antigen-receiving T cells (CAR T cells) 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 into the tumor, while 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 treated with TILs achieved significantly improved progression-free survival (PFS) compared to standard immunotherapy with ipilimumab (Yervoy).

Median PFS more than doubled to 7.2 months with TIL versus 3.1 months with ipilimumab (relative risk [HR]0.50; P

“We believe that TIL could eventually become a new treatment option for patients with advanced melanoma,” commented lead author John Haanen, MD, PhD, research group leader at the Netherlands Institute of Cancer in Amsterdam and Professor of Translational Cancer Immunotherapy at Leiden University Medical Center in Leiden.

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

“The results of this trial could fuel further research into TIL in other types of cancer, potentially demonstrating benefits in many other solid tumors and expanding the treatments available to 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 did not participate in the research.

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

“Although immunotherapy can produce impressive long-term responses, a substantial percentage of patients will have no response, or no lasting response, to checkpoint inhibitors,” Dimitrova said. “TIL therapy has proven efficacy in melanoma. However, no phase III trials have been performed to date to compare its efficacy to standard treatment.”

She noted that these results are consistent with previous reports of a response rate of around 50% 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 any biomarkers that could aid in 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 either TIL or ipilimumab (3 mg/kg every 3 weeks, maximum 4 doses). Patients were stratified for BRAFV600 mutation status, line and treatment centre, 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 ex vivo outgrowth and expansion of tumor-resident T cells. Before the cultured TILs were returned to the patients from whom they were made, the patient underwent lymphodepleting non-myeloablative chemotherapy with cyclophosphamide more fludarabine which was followed by high dose interleukin-2.

The primary endpoint of the study 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 compared to ipilimumab. The overall response rate also favored TIL over ipilimumab (49% versus 21%), with 20% versus 7% complete responses, respectively.

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 patients and 57% of ipilimumab patients, although Haanen noted that these were manageable and in most cases resolved by the time patients have been discharged from the hospital.

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

Ultra-Personalized

Also commenting on the study, Anthony J. Olszanski, MD, RPh, Associate Professor and Vice Chairman of Clinical Research, Department of Hematology/Oncology at Fox Chase Cancer Center, Philadelphia, Pennsylvania, agreed that treating patients with Melanoma that does not respond or progress after receiving treatment with immunotherapy is “difficult and represents an unmet need”.

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

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

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

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

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

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