Role of high-dose interleukin-2 for melanoma in the age of cellular therapy

Abstract

Interleukin-2 (IL-2) was one of the first immunotherapies in the treatment of patients with cancer. High-dose bolus IL-2 (HD IL-2) can induce durable complete or partial tumor regression in a small proportion of advanced melanoma and renal cell carcinoma patients. However, its potential for life-threatening side effects and requirement for inpatient administration limits its use to patients with excellent organ function treated at experienced centers. In 2024, following decades of foundational work at the National Cancer Institute, lifileucel became the first FDA-approved tumor-infiltrating lymphocyte (TIL) therapy for cancer. HD IL-2 is routinely given after TIL infusion to promote the survival and proliferation of the T cell product. In this context, fewer doses are given, and the parameters for holding an IL-2 dose are more conservative, as compared with HD IL-2 monotherapy, which has now fallen out of routine use. The lower number of doses, and possibly the effects of the preparative lymphodepletion, result in much less cytokine-related toxicity. Nevertheless, concerns related to HD IL-2 toxicity persist and possibly impact decisions to offer TIL when indicated. Here, we discuss the differences in the administration of HD IL-2 as a monotherapy vs an adjunctive therapy following TIL infusion, in an effort to demystify the toxicity of HD IL-2 in the era of cellular therapy.

Introduction

High dose IL-2

Interleukin-2 (IL-2) is a cytokine produced by T cells which stimulates T, B, and NK cells by binding to the IL-2 receptor. T regulatory cells (Tregs) and recently activated tumor-specific effector cells express high levels of all three chains of the IL-2 receptor (αβγ) resulting in high-affinity binding to IL-2. Other T cells and NK cells express high levels of IL-2Rβγ, which has intermediate affinity for IL-2. The exact mechanisms responsible for IL-2’s antitumor effects remain unclear, but high doses are required for optimal antitumor effects in both preclinical models and in advanced cancer patients, presumably because higher doses broadly expand CD8+tumor-specific populations and favor immune stimulation.1,6 High-dose IL-2 also expands and activates NK and other T cell populations and leads to the production of secondary cytokines, which may be important for antitumor activity but also contribute to toxicity.^{7 8}

High-dose bolus IL-2 (HD IL-2), administered at 600,000 or 720,000 IU/kg every 8 hours on days 1–5 and 15–19, received FDA approval for patients with advanced renal cell carcinoma (RCC) in 1992 and metastatic melanoma in 1998 after it was demonstrated to produce meaningful and durable responses.^{9 10} In a review of RCC patients treated with HD IL-2, a response rate of 14% was observed with 5% complete responses (CR) and 9% partial responses (PR).¹¹ In melanoma, a review of 270 patients treated on phase II studies of HD IL-2 demonstrated an overall response rate of 16% with 6% CR and 10% PR.¹² Importantly, in both of these studies, many of the responses observed were durable, with most of the CRs ongoing at the time of study publication.¹³

The need for and use of HD IL-2 was eclipsed by the introduction of immune checkpoint inhibition (ICI) for patients with melanoma and RCC (and now with many other tumor types as well). Retrospective data demonstrate that HD IL-2 can be used safely after ICI failure, and its modest efficacy is retained. In a retrospective analysis of melanoma patients, the response rate to HD IL-2 following CTLA-4 inhibition was 21%.¹⁴ A similar analysis of metastatic melanoma and RCC patients showed a response rate of 23% for melanoma and 24% for RCC patients treated after PD-1 pathway inhibition.¹⁵ Both of these analyses demonstrated similar toxicities and an equivalent median overall survival to patients who received HD IL-2 prior to ICI.

Tumor-infiltrating lymphocyte therapy

Early trials involving the expansion and infusion of tumor-infiltrating lymphocyte (TIL) demonstrated promising clinical efficacy in patients with advanced melanoma. However, the implementation of this adoptive cellular therapy was only possible at a few select centers due to the need to manufacture TIL directly from patient’ tumors and keep the cells viable.^{16 17} In 2024, lifileucel, a TIL therapy produced in a central lab, was approved by the FDA for the treatment of patients with advanced melanoma that has progressed after ICI and, if indicated, BRAF targeted therapy. In an initial cohort of patients lifileucel demonstrated an overall objective response rate of 36% and a disease control rate of 80%.^{18 19} A larger expanded cohort of 153 patients had an overall response rate of 31% with a median duration of response that was not reached after 27.6 months of follow-up.¹⁸

The role of TIL in the era of ICI was further demonstrated in a clinical trial comparing TIL therapy versus single-agent CTLA-4 inhibition in patients with advanced melanoma refractory to PD-1 blockade. In this trial of 168 patients, the median PFS was 7.2 months in the TIL group and 3.1 months in the CTLA-4 inhibitor group. The median OS was 25.8 months in the TIL group and 18.9 months in the CTLA-4 inhibitor group,²⁰ demonstrating a benefit for TIL in the second-line treatment setting for patients with advanced melanoma.

IL-2 toxicity

Although HD IL-2 provided durable responses for a minority of patients, the toxicity of this therapy limited its administration. Even with intense supportive care, it is uncommon for a patient to receive all intended doses due to cumulative and severe toxicity. The general strategy for the administration of HD IL-2 has been to give doses until toxicity reaches a level at which a dose needs to be skipped and only resume if toxicity resolves at the time of the next scheduled administration. A maximum of 14 doses can be administered per 5-day cycle, with most patients receiving 10–12 doses. Patients typically could receive a second 5-day cycle after a 1–2 week recovery interval.

When high-dose IL-2 was given in the past, a higher number of cumulative IL-2 doses administered per patient correlated with better treatment response.²¹ Tumor control was associated with the development of cytokine-related adverse events.²² Thus, providers gave as many doses of therapy as the patient could tolerate until toxicity made it impossible to continue. Because most toxicities were completely reversible on completion of the IL-2 course, doses were given despite rising creatinine, elevation of liver function tests, and mild to moderate capillary leak syndrome. Guidelines were established to improve toxicity management for HD IL-2 therapy, leading to improvements in patient outcomes.²³

The role of adjunctive HD IL-2 therapy following TIL infusion

The mechanism of action of HD IL-2 monotherapy is presumably dependent on stimulating pre-existing tumor-reactive T effector cells, located in the tumor or peritumoral stroma. In contrast, with TIL therapy, IL-2 is an adjunctive therapy which stimulates helper and cytotoxic T cells both in vitro during the TIL preparation and in vivo following the TIL infusion.

All trials of TIL therapy have used lymphodepleting chemotherapy and administration of IL-2 and/or other cytokine therapies following TIL infusion to stimulate and expand the TIL. Without TIL, the chemotherapy and limited IL-2 in these regimens do not have significant antitumor activity.²⁴ Without IL-2, TILs still have some activity, as demonstrated by an NCI TIL study that omitted IL-2. This trial closed due to low accrual, but preliminary results were posted, and responses were seen in 5 of 17 patients (29%) (ClinicalTrials.gov Identifier NCT 01468818).

The most standard current regimen given with TIL consists of 6 doses of HD IL-2 (600,00 IU/kg) infused every 8–12 hours over 2–3 days. Patients are still pancytopenic from the lymphodepleting chemotherapy and receiving granulocyte-colony stimulating factor, antibiotics, and transfusions during the IL-2, so fevers and other medical complications have to be carefully assessed and managed.

Recent expert consensus guidelines on TIL therapy were published by the Society for Immunotherapy of Cancer in JITC, and experts support conservative parameters for holding or discontinuing HD IL-2 in this setting. Missed doses and truncated courses of IL-2 do not appear detrimental to outcomes with TIL therapy.²⁵ Hassel et al conducted a subgroup analysis of clinical outcomes by the number of HD IL-2 doses administered.²⁶ The response rate was 37.5% with 1–2 doses, 30.8% with 3–4 doses, and 31.2% with 5–6 doses of HD IL-2. There was no significant difference in response rate (p=0.87) or duration of response based on the number of HD IL-2 doses given (p=0.25). Grade 3/4 toxicities were similar across the IL-2 dose groups; however, there were three deaths from treatment-related toxicity in the group who received 5–6 doses of HD IL-2.

Conclusions

While HD IL-2 monotherapy has a historic reputation for severe toxicity drastically limiting its use to select centers and highly selected patients, the goal of HD IL-2 with TIL therapy is to augment the TIL therapy, which can be accomplished with fewer doses and less toxicity (figure 1).

Figure 1. (A) Dosing schema for high dose IL-2 therapy and adjunctive HD IL-2 when given with TIL infusion. (B) Comparison of common toxicities between HD IL-2 dosing and IL-2 with TIL administration (adapted from Atkins et al¹² and Chesney et al¹⁸). HD IL-2, high-dose bolus IL-2.

Conservative guidelines for HD IL-2 administration with TIL are supported by data showing that the activity of TIL was not compromised in patients receiving fewer doses. Therefore, IL-2 administration and toxicity should not be a barrier to offering TIL if indicated in an individual patient. TIL therapy should still be administered by physicians familiar with IL-2 and immunotherapy toxicity, usually in conjunction with specialists with expertise in managing patients with chemotherapy-induced pancytopenia lasting days to weeks. It is expected that the number of institutions and multidisciplinary medical teams that can safely provide these regimens can be expanded with appropriate training, experience, and (in the instance of IL-2 administration) reassurance.

Finally, efforts are underway to modify and engineer the native IL-2 molecule to increase specificity for cytotoxic and helper T-cells and limit Treg signaling.²⁷ These novel compounds may provide improved methods to bring about IL-2 signaling for anti-cancer purposes and would be well suited to be incorporated into TIL therapy. At the same time, investigations are ongoing to optimize TIL selection by identifying parameters associated with response and to engineer the TIL to express functions that enhance their antitumor effects and/or produce their own cytokine, which may obviate the need for HD IL-2 as an adjunctive therapy.²⁸