Additive Intralesional Interleukin-2 Improves Progression-Free Survival in a Distinct Subgroup of Melanoma Patients with Prior Progression under Immunotherapy

SIMPLE SUMMARY: Despite the immense progress in systemic treatment of advanced unresectable melanoma with immunotherapies, there is still an unmet need for patients showing primary resistance. We show that addition of intratumoral injections of the immune modulator Interleukin-2 can overcome primary resistance in a distinct subset of patients and this effect is associated with an intratumoral increase of certain inflammatory cells supporting the paradigm of turning a “cold” into a “hot” tumor. ABSTRACT: A considerable amount of melanoma patients show primary resistance to PD-1 and CTLA-4 inhibitors. We have previously reported a beneficial role of intralesional Interleukin-2 (IL-2) in 9 melanoma patients developing new locoregional metastases under immunotherapy. We have now expanded this retrospective cohort to 27 patients. Patients were evaluated for their tumor characteristics, treatment response and progression-free and overall survival (PFS/OS). In 16 patients, tumor biopsies before and under IL-2 treatment were evaluated for immune markers. The median follow-up time was 16 (1–59) months from start of IL-2 treatment. Treatment response of locoregional metastases was seen in 74% of all patients and response of distant organ metastases in 37% of stage IV patients, respectively. A prolonged PFS and OS was significantly associated with absence of active distant metastases (p = 0.008), response of locoregional metastases (p = 0.002), increase of absolute eosinophil count (AEC) (p < 0.001) and an influx of CD8(+) tumor infiltrating lymphocytes (TILs) (p = 0.003). Additional intralesional treatment with IL-2 in patients with locoregional progression under immunotherapy is a well-tolerated, easily feasible therapeutic option especially in patients lacking active distant metastases. A careful patient selection can lead to an improved PFS and OS.