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Cancer Immunology, Immunotherapy

, Volume 63, Issue 9, pp 901–910 | Cite as

Preclinical evaluation of IL2-based immunocytokines supports their use in combination with dacarbazine, paclitaxel and TNF-based immunotherapy

  • Francesca Pretto
  • Giuliano Elia
  • Nadia Castioni
  • Dario NeriEmail author
Original Article

Abstract

Antibody-cytokine fusion proteins (“immunocytokines”) represent a promising class of armed antibody products, which allow the selective delivery of potent pro-inflammatory payloads at the tumor site. The antibody-based selective delivery of interleukin-2 (IL2) is particularly attractive for the treatment of metastatic melanoma, an indication for which this cytokine received marketing approval from the US Food and drug administration. We used the K1735M2 immunocompetent syngeneic model of murine melanoma to study the therapeutic activity of F8–IL2, an immunocytokine based on the F8 antibody in diabody format, fused to human IL2. F8–IL2 was shown to selectively localize at the tumor site in vivo, following intravenous administration, and to mediate tumor growth retardation, which was potentiated by the combination with paclitaxel or dacarbazine. Combination treatment led to a substantially more effective tumor growth inhibition, compared to the cytotoxic drugs used as single agents, without additional toxicity. Analysis of the immune infiltrate revealed a significant accumulation of CD4+ T cells 24 h after the administration of the combination. The fusion proteins F8–IL2 and L19–IL2, specific to the alternatively spliced extra domain A and extra domain B of fibronectin respectively, were also studied in combination with tumor necrosis factor (TNF)-based immunocytokines. The combination treatment was superior to the action of the individual immunocytokines and was able to eradicate neoplastic lesions after a single intratumoral injection, a procedure that is being clinically used for the treatment of Stage IIIC melanoma. Collectively, these data reinforce the rationale for the use of IL2-based immunocytokines in combination with cytotoxic agents or TNF-based immunotherapy for the treatment of melanoma patients.

Keywords

Immunocytokines Interleukin-2 Oncofetal fibronectin Vascular targeting 

Abbreviations

CTLA-4

Cytotoxic T-lymphocyte antigen 4

DEXA

Dexamethasone

DTIC

Dacarbazine

EDA

Extra domain A of fibronectin

EDB

Extra domain B of fibronectin

FDA

Food and drug administration

ID

Injected dose

IL2

Interleukin-2

NK

Natural killer cells

NOVA

Metamizole

OCT

Optimal cutting temperature compound

PARA

Paracetamol

PBS

Phosphate buffered saline

PTX

Paclitaxel

SE

Standard error

SIP

Small immunoprotein

T/C

Tumor growth inhibition ratio

TNF

Tumor necrosis factor

Notes

Acknowledgments

The authors thank Kathrin Schwager for her help with biodistribution and immunofluorescence experiments. The study was supported by Swiss National Science Foundation, the Swiss Federal Institute of Technology (ETH), the European Union (FP7 ADAMANT and PRIAT Project) and the Kommission für Technologie und Innovation (KTI MedTech Award to Philochem).

Conflict of interest

Dario Neri is founder and shareholder of Philogen, a biotech company that owns the F8 antibody. Francesca Pretto and Giuliano Elia are Philochem employees. Nadia Castioni declares no conflict of interest.

Supplementary material

262_2014_1562_MOESM1_ESM.pdf (78.4 mb)
Supplementary material 1 (PDF 80271 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Francesca Pretto
    • 1
  • Giuliano Elia
    • 1
  • Nadia Castioni
    • 2
  • Dario Neri
    • 2
    Email author
  1. 1.Philochem AGOtelfingenSwitzerland
  2. 2.Department of Chemistry and Applied BiosciencesSwiss Federal Institute of Technology (ETH)ZurichSwitzerland

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