Ins and outs of tumour-infiltrating lymphocytes therapy in metastatic melanoma

Dr Tom Seijkens (Netherlands Cancer Institute, the Netherlands) talked about the use of tumour-infiltrating lymphocytes (TIL) therapy in patients with metastatic melanoma. He discussed patient selection, the trajectory that has to be followed by patients, and the expected outcomes of TIL therapy.

“In cell therapy, we use immune cells as medication,” Dr Seijkens began his presentation [1]. “On the one hand, the option is CAR T-cell therapy, and another option is TIL therapy.” Dr Seijkens focussed on the latter. With TIL therapy, one uses the lymphocytes present in the tumour. “Since we do not apply genetic modification in TIL therapy, the product is heterogeneous,” added Dr Seijkens. He explained that TILs could not perform optimally in the tumour environment due to a lack of nutrients and exhaustion. Also, TILs are slowed down by checkpoint proteins and are limited in number. “With TIL therapy, we extract the TILs from the tumour environment to increase their fitness and number in a laboratory,” explained Dr Seijkens. The product is heterogeneous, consisting of neoantigen-reactive T cells, shared antigen-reactive T cells, and bystander T cells [2].

TIL therapy: from collection to confusion

TIL therapy can be administered to patients with stage 4 melanoma [1]. The process starts with a screening period, in which the patient’s medical history is evaluated with a particular focus on heart and lung function. “TIL therapy is an intensive treatment, and we need to know whether a patient is fit enough to endure the treatment,” explained Dr Seijkens. Next, surgery is performed to collect TILs from the tumour. Then, the patient is hospitalised for about 2–3 weeks to receive high-dose chemotherapy, TIL infusion, and IL-2 therapy. “This trajectory takes about 3 months,” added Dr Seijkens (see Figure).

Figure: TIL therapy trajectory for metastatic melanoma [1]



CT, computerised tomography; IL, interleukin; TIL, tumour-infiltrating lymphocytes.

To estimate the potential efficacy of TIL therapy in a patient, it is important to understand the type of prior therapies received, the tumour size, and the anticipated rate of disease progression. “A TIL therapy trajectory takes about 3 months. For patients with a very aggressive tumour, in whom the disease is expected to progress rapidly, TIL therapy is not a viable option,” said Dr Seijkens. He further mentioned that brain metastases need to be treated prior to initiating TIL therapy to prevent patients from developing symptomatic brain metastases during TIL therapy. Also, sufficiently large and accessible metastases are needed to collect TILs. “After surgery for TIL collection, it takes about 4–6 weeks to produce enough TILs (5–200 billion),” continued Dr Seijkens. “If these conditions are met, we can produce a good TIL product in about 95% of the patients.”

Meanwhile, patients receive high-dose chemotherapy in preparation of the TIL infusion. “We usually administer cyclophosphamide for 2 days followed by fludarabine for 5 days,” said Dr Seijkens. This regimen instigates leukopenia, including both lymphopenia and neutropenia. In response to leukopenia, the body produces lymphoproliferative cytokines, creating a favourable cytokine profile in the plasma for lymphocytes [3]. Subsequently, chemotherapy-induced lymphopenia prevents plasma lymphocytes from using the available cytokines. Finally, this leads to the depletion of immunosuppressive cells, such as regulatory T cells, to prevent them from inhibiting the anti-tumour activity of TILs. “Most patients experience fever during chemotherapy,” according to Dr Seijkens. “It is unclear whether this is a normal reaction to the chemotherapy or whether patients have an infection. If possible, avoiding broad-spectrum antibiotics would arguably be better for the outcome of TIL therapy. However, we often have to administer antibiotics to these patients.”

According to Dr Seijkens, the TIL infusion itself only takes about 15 minutes and rarely comes with side effects. However, the IL-2 treatment given in the same period as the TIL infusion is usually burdensome for patients. “IL-2 therapy works as a growth factor, further increasing the number of TILs in vivo,” outlined Dr Seijkens. This treatment is given a maximum of 5 times in the 48 hours after TIL infusion. Common side effects are fever, dyspnoea, hypotension, and fluid retention. “The side effects are usually quite intense with IL-2 therapy,” according to Dr Seijkens. “Nonetheless, we usually successfully administer 4 to 5 IL-2 treatments to our patients.”

Efficacy of TIL therapy

The results of a systematic review showed that the objective response rate of patients with melanoma receiving TIL (n=410) is 41%, with a complete response rate of 14% and a median duration of response of 21 months [4]. “We also see that patients with a complete response are unlikely to relapse,” added Dr Seijkens. In patients who received prior checkpoint inhibitors (n=66), the objective response rate was 36%, with a complete response rate of 5.2% [5].

In another study, TIL was compared with ipilimumab monotherapy in 168 patients, of whom 86% had PD-1 refractory disease. The median progression-free survival was 7.2 months in the TIL group versus 3.1 months in the ipilimumab group. Moreover, the objective and complete response rates in the TIL arm were 49% and 20%, respectively [6]. “We have not seen a direct comparison between TIL therapy and ipilimumab plus nivolumab in this population,” added Dr Seijkens.

“TIL therapy is an additional treatment for patients with metastatic melanoma, very different from ipilimumab plus nivolumab,” concluded Dr Seijkens. “Patient selection with respect to disease progression is an essential factor in the TIL therapy trajectory. Until EMA approves TIL therapy, we are allowed to treat 50 patients per year with this modality. In the near future, we hope to expand and improve the use of TIL therapy.”

1. Seijkens T. TIL therapie bij melanoom. Dermatologendagen 2024, 11–12 April, Amsterdam, the Netherlands.
2. Klobuch S, et al. Nat Rev Oncol. 2024;21(3):173-184.
3. Melenhorst JJ, et al.  Haematologica. 2012;97(6):867-873.
4. Dafni U, et al. Ann Oncol. 2019;30(12):1902-1913.
5. Sarnaik AA, et al. J Clin Oncol. 2021;39(24):2656-2666.
6. Rohaan MW, et al. N Engl J Med 2022;387:2113-2125.

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Posted on 31 May 20244 June 2024