Phase II trial of intralesional therapy with interleukin-2 in soft-tissue melanoma metastases

Abstract

The objective of the present study was to validate the use of intralesional injection of interleukin-2 (IL-2) in patients with skin and softtissue melanoma metastases. A total of 24 patients with AJCC stage III or IV melanoma and single or multiple skin and soft-tissue metastases were included. Interleukin-2 injections were administered intralesionally into the total number of cutaneous and soft-tissue metastases accessible from the skin, 2 -3 times weekly, over 1 -57 weeks. Single doses varied from 0.6 to 6 Â 10 6 IU, depending on lesion size. The clinical response was monitored by sonography and confirmed by histopathology; response evaluation was confined to the intralesionally treated tumours. Complete response (CR) of the treated metastases was achieved in 15 patients (62.5%), the longest remission lasting 38 months to date. In five patients, partial response (PR) was achieved (21%) and in another three patients, progressive disease was observed (one patient not assessable). A total of 245 metastases were treated with CR in 209 (85%), and PR in 21 (6%). The therapy was generally well tolerated; the observed adverse events were mainly of grade 1 -2 severity. Immunohistochemical studies showed the tumour cells undergoing apoptosis and revealed a mixed character of the inflammatory infiltrate. The unusual high CR rate in metastatic melanoma of 62.5% and the limited toxicity suggest that treatment of skin and softtissue melanoma metastases with intralesional injection of IL-2 may be a safe and effective alternative to conventional therapies. The optimal dosage and duration of this therapy still remain to be defined in larger prospective multicentre trials.

Melanoma Treatment with Intratumoral Electroporation of Tavokinogene Telseplasmid (pIL-12, Tavokinogene Telseplasmid)

“…However, there was no evidence of clinically meaningful systemic immune activation since regression of nontreated lesions was not observed in any patient [35]. Similar findings have been observed in patients treated with intralesional IL-2, which leads to frequent regressions of treatment lesions but not abscopal regressions of untreated lesions [36,37]. These findings are interesting but inadequate since the goal of cytokine therapy is to induce systemic immune changes that alone or in combination with additional agents could lead to durable remissions in cancer patients.…”

Intralesional Treatment of Stage III Metastatic Melanoma Patients with L19–IL2 Results in Sustained Clinical and Systemic Immunologic Responses

“…In previous studies using untargeted IL2, we reported CRs of injected metastases, according to adapted RECIST criteria, in more than 60% of patients (14,15), which is significantly higher than the CR rate of 25% according to modified irRC/RECIST observed here. In our opinion, this difference does not reflect a lower efficacy of L19-IL2 compared with untargeted IL2, but is more likely related to differences in the patient populations and trial designs.…”

“…Second, there are differences between the studies with untargeted IL2 and the present study in the treatment regimen and schedule. In IL2-based studies, the treatment schedule was two to three times weekly with a maximum daily dose of 16 MIU IL2 or variable, according to the individual tumor burden of patients (14,15). Importantly, in these trials, new lesions arising during treatment were also injected, and treatment continued until all lesions, including the new ones, finally regressed.…”

“…Different groups, including ours, have reported the promising response of melanoma metastases to intratumoral injection of IL2 (13)(14)(15)(16)(17). To improve this approach, we now considered the use of antibody-based pharmacodelivery strategies.…”

Local immunostimulation leading to rejection of accepted male skin grafts by female mice as a model for cancer immunotherapy

“…Impressive results have been obtained on cutaneous metastases of melanoma patients (27,28). Our approach focuses on the search for synergic combinations of various cytokines and TLR ligands with the aim of obtaining immune rejection with much lower dosages (50-500×) than those reported previously.…”