Prolonging Remission in Anti–PD-1 Refractory Melanoma With Tumor-Infiltrating Lymphocyte Therapy

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For the first time in a multicenter randomized trial, T-cell therapy has been shown to improve outcomes in a solid tumor. In the phase III M14TIL trial, first-line or second-line treatment with tumor-infiltrating lymphocytes (TIL) led to a 50% reduction in disease progression or death from advanced melanoma as compared with treatment consisting of the anti–CTLA-4 antibody ipilimumab. Almost all patients had experienced disease progression on drugs targeting PD-1. The results were presented at a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2022.1

“This multicenter study shows, for the first time in a randomized, controlled trial, that cell therapy can be efficacious and beneficial for patients with solid cancers,” said John B. Haanen, MD, leader of the immunotherapy group of the Netherlands Cancer Institute, Amsterdam. “TIL could become a possible new treatment option for patients with advanced melanoma.”

John B. Haanen, MD

John B. Haanen, MD

George Coukos, MD

George Coukos, MD

With TIL therapy, immune T cells are grown from a tumor sample while the patient undergoes lymphodepleting chemotherapy. The personalized product is infused back into the patient, with the TILs recognizing the tumor cells as abnormal and killing them.

“TIL therapy is an extraordinary therapy,” commented George Coukos, MD, of Lausanne University Hospital and the Ludwig Institute for Cancer Research, Lausanne, Switzerland, in an ESMO press release. “TIL is a new paradigm for treating cancers, and, as these results clearly demonstrate, it’s efficacious and feasible at large scale. The findings raise hopes for the management and potential cure of metastatic solid tumors…. The results could potentially lead to regulatory approval that would be practice-changing.”

TIL Therapy Is Not New

According to Dr. Haanen, evidence of TIL’s activity in solid tumors was established in the 1980s at the National Cancer Institute by pioneering immunologist Steven Rosenberg, MD, PhD, with ­formal publication of his laboratory’s work in 2002.2 Subsequently, several small phase I and II trials further supported the efficacy of this therapy, but interest waned with the development of checkpoint inhibitors.

This multicenter study shows, for the first time in a randomized, controlled trial, that cell therapy can be efficacious and beneficial for patients with solid cancers.
— John B. Haanen, MD

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Dr. Haanen and colleagues initiated their study about 8 years ago, without pharmaceutical support and using Dr. Rosenberg’s protocol. Today, several commercial entities are developing their own TIL therapies.

“There was no interest from pharma when we started our study. That’s changed,” he said. The agreement between the funding agency—the Ministry of Health in the Netherlands—and the trial investigators paved the way for TIL therapy to become available in that country in January 2023, if the results of this study were positive. Efforts to obtain approval from the European Medicines Agency is underway, Dr. Haanen added.

About M14TIL

The phase III M14TIL trial randomly assigned 168 patients with unresectable stage IIIC–IV melanoma to receive immunotherapy with ipilimumab (3 mg/kg every 3 weeks for up to four doses) or TIL therapy. Most patients (86%) had experienced disease progression on anti–PD-1 agents (30% received the drugs in the adjuvant setting). Patients randomly assigned to TIL therapy underwent resection of a melanoma lesion for ex vivo outgrowth and expansion of tumor resident T cells, undergoing lymphodepleting chemotherapy before infusion of at least 5 x 109 TILs. Patients also received up to 15 doses of high-dose interleukin-2. The entire treatment process took about 8 weeks.

“It’s important to highlight that this was a particularly good patient population, as shown by their good performance status [> 80% World Health Organization performance status of 0] and the fact that just 10% had LDH [lactate dehydrogenase] levels two times the upper limit of normal,” Dr. Haanen explained.

TIL therapy is an extraordinary therapy. As these results clearly demonstrate, it’s efficacious and feasible at large scale.
— George Coukos, MD

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Initial Results

The study’s first results, reported at the ESMO Congress 2022, were based on 33 months’ median follow-up, showing TIL therapy to be associated with a doubling in progression-free survival and objective response rates. Median progression-free survival was 7.2 months compared with 3.1 months for ipilimumab (hazard ratio [HR] = 0.50; P < .001). Response rates were 48.8% and 21.4%, respectively, with corresponding complete response rates of 20.2% and 7.1%.

Median overall survival was numerically higher, 25.8 months vs 18.9 months (HR = 0.83; P = .39), and data are not mature. “This was a secondary endpoint, and clearly you can see a trend for improved overall survival…. This study was also not powered to show an overall survival difference,” noted Dr. Haanen.

Health-related quality of life was also significantly improved with TIL therapy, as measured by the European Organisation for Research and Treatment of Cancer C15-PAL QLQ score, which was a mean of 7.7 points higher (P < .01). This improvement was maximized at week 18 and still present at 60 weeks.

Other Thoughts on Efficacy

The comparator was ipilimumab, which at study initiation was the only checkpoint inhibitor approved for use after disease progression on anti–PD-1 therapy. Dr. Haanen acknowledged that under the current treatment algorithm, patients who experience disease progression on anti–PD-1 agents now could receive ipilimumab plus nivolumab, but he predicted that TIL therapy may still be more effective.

In the recent phase II SWOG S1616 trial, ipilimumab plus nivolumab produced responses in 28% of patients with anti–PD-1–refractory disease, compared with 9% with single-agent ipilimumab.3 “Although the patient populations were different, TIL therapy was still better in our trial. I believe if you correct for the differences, TIL therapy is still an attractive treatment option, even compared with ipilimumab plus nivolumab,” he suggested.


  • In the phase III M14TIL trial, T-cell therapy improved progression-free survival in advanced melanoma, including in patients previously experiencing disease progression on anti–PD-1 agents.
  • Patients receiving an infusion of tumor-infiltrating lymphocytes (TILs) had a median progression-free survival of 7.2 months compared with 3.1 months for those treated with ipilimumab (hazard ratio = 0.50; P < .001).
  • The overall response rate was also doubled with TIL therapy, and the median overall survival was 25.8 months vs 18.9 months (and the data are not yet mature).
  • TIL therapy is also being investigated in other solid tumors.

Safety Profile

All patients treated with TIL therapy experienced a grade 3 or higher adverse event, as did 57% who received ipilimumab. However, according to Dr. Haanen, these side effects were manageable and mostly related to the chemotherapy given before TIL therapy.

“Most of the side effects occurred because of the interleukin-2, which can cause fever, chills, and dyspnea,” he said. Most side effects resolved after treatment was completed.

Mechanism of Action

Dr. Haanen offered a few thoughts on the possible mechanism of TIL therapy and why this approach may work after failure of checkpoint inhibitors: “We think the mechanism of resistance to anti–PD-1 treatment is mostly delivered by the tumor microenvironment,” he said. “So, when we take these cells out of their natural environment, reactivate them in the laboratory, grow them to very large numbers, and give them back to patients, we can overcome some of the escape mechanisms. That’s what we are seeing. Otherwise, TIL therapy wouldn’t work in this setting.”

The investigators believe TIL therapy has the potential to be effective in a wide range of solid tumors. Trials are underway in lung, cervical, and head and neck cancers. 

DISCLOSURE: Dr. Haanen disclosed relationships with Bristol Myers Squibb, Achilles Therapeutics, BioNTech, Immunocore, Gadeta, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Neogene Therapeutics, Roche, Sanofi, Third Rock Venture, Instil Bio, Iovance Biotherapeutics, PokeAcel, T-Knife, and Neogene Therapeutics. 


1. Haanen JB, Rohaan M, Borch TH, et al: Treatment with tumor infiltrating lymphocytes versus ipilimumab for advanced melanoma: Results from a multicenter, randomized phase III trial. ESMO Congress 2022. Abstract LBA3. Presented September 10, 2022.

2. Dudley ME, Wunderlich JR, Robbins PF, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 298:850-854, 2002.

3. VanderWalde AM, Moon J, Kendra K, et al: Ipilimumab plus nivolumab versus ipilimumab alone in patients with metastatic or unresectable melanoma that did not respond to anti–PD-1 therapy. 2022 AACR Annual Meeting. Abstract CT013. Presented April 12, 2022.


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