Intralesional administration of L19-IL2/L19-TNF in stage III or stage IVM1a melanoma patients: results of a phase II study

Abstract

The intratumoral injection of cytokines, in particular IL2, has shown promise for cutaneous melanoma patients with unresectable disease or continuous recurrence despite surgery. We recently reported that the intralesional injection of L19-IL2, an immunocytokine combining IL2 and the human monoclonal antibody fragment L19, resulted in efficient regional control of disease progression, increased time to distant metastasis and evidence of effect on circulating immune cell populations. We have also shown in preclinical models of cancer a remarkable synergistic effect of the combination of L19-IL2 with L19-TNF, a second clinical-stage immunocytokine, based on the same L19 antibody fused to TNF. Here, we describe the results of a phase II clinical trial based on the intralesional administration of L19-IL2 and L19-TNF in patients with stage IIIC and IVM1a metastatic melanoma, who were not candidate to surgery. In 20 efficacy-evaluable patients, 32 melanoma lesions exhibited complete responses upon intralesional administration of the two products, with mild side effects mainly limited to injection site reactions. Importantly, we observed complete responses in 7/13 (53.8 %) non-injected lesions (4 cutaneous, 3 lymph nodes), indicating a systemic activity of the intralesional immunostimulatory treatment. The intralesional administration of L19-IL2 and L19-TNF represents a simple and effective method for the local control of inoperable melanoma lesions, with a potential to eradicate them or make them suitable for a facile surgical removal of the residual mass.

Fig. 1

Frequency of common adverse events. Percent of patients who experienced the most common adverse events, as related to all safety-evaluable patients, is indicated. For each patient, if an adverse event occurred more than once throughout the study, only the highest-grade adverse event was considered for the calculation

Fig. 2

Evidence of bystander effect. Example of bystander effect on neighboring, non-injected lesions. Two cutaneous lesions were present at baseline on the right heel of patient 004 (a). Lesion 5 (green arrow) was injected with the immunocytokine combination, while lesion 6 (red arrow) was left uninjected. b To f illustrate the evolution of the two lesions at the end of treatment (day 22, b), week 6 (c), week 12 (d), week 18 (e) and week 24 (f). Both the injected and the not injected lesions appear to have disappeared 24 weeks after first treatment. Example of bystander effect on distant, non-injected lesions. Patient 006 presented at baseline one large cutaneous lesion and four enlarged mediastinal lymph nodes. Only the cutaneous lesion was treated as per protocol. g shows a CT scan of an axillary lymph node measuring 15 × 15 mm at baseline (white arrow). At tumor assessment performed at week 18 (h), the lymph node had shrunk (8 × 6 mm, white arrow). Normalization in size was also observed in two other lymph nodes of the same patient (not shown)

Fig. 3

Progression-free survival and overall survival a Kaplan–Meier plots of progression-free survival to new cutaneous/subcutaneous lesions (red line), lymph nodes (blue line) or distant organs (black line), respectively. b Kaplan–Meier plot of overall survival

Fig. 4

Immunohistochemical findings in two patients. Hematoxylin/eosin staining of sections from treated (a and i) or untreated (b and j) lesions. Frequency of CD8+ T cells in treated (e and m) as compared to untreated lesions (f and n). CD4+ T cells in treated lesions (c and k) as compared to untreated lesions (d and l). Tregs (g) and NK cells (o) infiltration of treated lesions as compared to untreated lesions (Tregs, h; NK cells, p). Magnification: a, b, i, and j 100×; c–h and k–p, 200×