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

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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.

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Abbreviations

BCG:

Bacillus Calmette–Guerin

CD:

Cluster of differentiation

CR:

Complete response

DCR:

Disease control rate

ECOG:

Eastern Cooperative Oncology Group

EDB:

Extra-domain B

FN:

Fibronectin

FOXP3:

Forkhead box P3

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

HIV:

Human immunodeficiency virus

HSV:

Herpes simplex virus

IFN-α:

Interferon alpha

IFN-β:

Interferon beta

IL2:

Interleukin-2

irRC:

Immune-related response criteria

LAK:

Lymphokine-activated killer

LDH:

Lactate dehydrogenase

MIU:

Million of international units

mOS:

Median overall survival

NED:

No evidence of disease

NK:

Natural killer

ORR:

Objective response rate

PBMC:

Peripheral blood mononuclear cells

PD:

Progressive disease

PR:

Partial response

RECIST:

Response criteria in solid tumors

SD:

Stable disease

TNF-α:

Tumor necrosis factor alpha

Tregs:

Regulatory T cells

WHO:

World Health Organization

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Acknowledgments

Support from the EU Seventh Framework Programme “PRIAT” (Profiling Responders In Antibody Therapies), Grant agreement no: 305309, is gratefully acknowledged.

Conflict of interests

D. Neri is co-founder and shareholder of Philogen. R. Danielli, M. Santinami and M. Maio received compensation from the Philogen group for advisory services, patient treatment and/or as coordinating investigators of this trial. The other authors declare no competing interest.

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Author notes

    Authors and Affiliations

    1. Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Siena, Italy

      Riccardo Danielli, Anna Maria Di Giacomo, Ornella Cutaia, Andrea Lazzeri, Carolina Fazio & Michele Maio

    2. Melanoma and Sarcoma Unit, Department of Surgery, National Tumor Institute, Via G. Venezian, 1, 20133, Milan, Italy

      Roberto Patuzzo, Gianfranco Gallino, Andrea Maurichi, Annabella Di Florio & Mario Santinami

    3. Section of Pathological Anatomy, Department of Medicine, Surgery, and Neuroscience, University of Siena, Siena, Italy

      Clelia Miracco

    4. Philogen S.p.A., Siena, Italy

      Leonardo Giovannoni

    5. Philochem AG, Otelfingen, Switzerland

      Giuliano Elia

    6. Swiss Federal Institute of Technology (ETH), Zurich, Switzerland

      Dario Neri

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    1. Riccardo Danielli
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    Correspondence to Mario Santinami.

    Additional information

    Riccardo Danielli, Roberto Patuzzo, Michele Maio and Mario Santinami contributed equally to the study.

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    Danielli, R., Patuzzo, R., Di Giacomo, A.M. et al. Intralesional administration of L19-IL2/L19-TNF in stage III or stage IVM1a melanoma patients: results of a phase II study. Cancer Immunol Immunother 64, 999–1009 (2015). https://doi.org/10.1007/s00262-015-1704-6

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