Armed antibodies for cancer treatment: a promising tool in a changing era

Abstract

Advances in the understanding of tumor immunology and molecular biology of melanoma cells have favored a larger application of immunotherapy and targeted therapies in the clinic. Several selective mutant gene inhibitors and immunomodulating antibodies have been reported to improve overall survival or progression-free survival in metastatic melanoma patients. However, despite impressive initial responses, patients treated with selective inhibitors relapse quickly, and toxicities associated to the use of immunomodulating antibodies are not easily manageable. In this sense, the concept of using antibodies as delivery vehicles for the preferential in vivo localization of the drug at the site of disease with reduction of side effects has raised particular interest. Antibody-cytokine fusion proteins (termed immunocytokines) represent a new simple and effective way to deliver the immunomodulatory payload at the tumor site, with the aim of inducing both local and systemic antitumoral immune responses and limiting systemic toxicities. Several clinical trials have been conducted and are actually ongoing with different immunocytokines, in several tumor histotypes. In metastatic melanoma patients, different drug delivery modalities such as systemic, loco-regional and intratumoral are under investigation. In this review, the rationale for the use of L19-IL2 and L19-TNF, two clinical stage immunocytokines produced by the Philogen group, as well as opportunities for their future development will be discussed.

Fig. 1

Current treatment algorithm used at INT in metastatic melanoma patients

Fig. 2

Potential future applications and algorithms of IIT with L19-IL2/L19-TNF in metastatic melanoma patients. a IIT with L19-IL2/L19-TNF in stage IIIB/stage IIIC non-resectable melanoma both as curative or neoadjuvant intent. In case of local progression after long DCR and persistence of injectable lesions, retreatment with L19-IL2/L19-TNF may be considered. b IIT with L19-IL2/L19-TNF in stage IIIB/C patients with extensive disease or stage IV M1a, b, c melanoma and the presence of superficial injectable metastasis. Based on BRAF status wild-type (wt) or mutant, L19-IL2/L19-TNF can be administered concomitantly or sequentially with systemic immunotherapy (Ipilimumab, anti-PD1 mAb and others) or BRAF inhibitors ± MEK inhibitors. Upon progression, retreatment may be evaluated. c In the most extreme clinical scenario, IIT with L19-IL2/L19-TNF can directly be delivered into one or more visceral metastasis, for one or higher number of applications, based on disease localization