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Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma

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An Erratum to this article was published on 25 September 2014

Abstract

Background

Ipilimumab can induce durable disease control and long-term survival in patients with metastatic melanoma. Identification of a biomarker that correlates with clinical benefit and potentially provides an early marker of response is an active area of research.

Patients and methods

Ipilimumab was available upon physician request for patients aged ≥16 years with stage III (unresectable) or IV cutaneous, ocular or mucosal melanoma, who had failed or did not tolerate previous treatments and had no other therapeutic option available. Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. Tumour assessments were conducted at baseline, Week 12 and Week 24 using immune-related response criteria. Patients were monitored continuously for adverse events (AEs), including immune-related AEs. Candidate immunological markers were evaluated in peripheral blood and sera samples collected at baseline and Weeks 4, 7, 10 and 12.

Results

Among 95 patients treated with ipilimumab 3 mg/kg, the immune-related disease control rate at Week 24 was 38 %. With a median follow-up of 24 months, median overall survival was 9.6 months. Both disease control and survival were significantly associated with decreasing levels of lactate dehydrogenase, C-reactive protein and FoxP3/regulatory T cells, and increasing absolute lymphocyte count, between baseline and the end of dosing (Week 12).

Conclusion

Ipilimumab is a feasible treatment option for heavily pretreated patients with metastatic melanoma. Changes in some immunological markers between baseline and the fourth ipilimumab infusion appear to be associated with disease control and survival, but verification in prospective clinical trials is required.

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Abbreviations

AE:

Adverse event

ALC:

Absolute lymphocyte count

BORR:

Best overall response rate

CI:

Confidence interval

CR:

Complete response

CRP:

C-reactive protein

CTLA-4:

Cytotoxic T-lymphocyte-associated antigen-4

DCR:

Disease control rate

EAP:

Expanded access programme

ECOG:

Eastern Cooperative Oncology Group

FACS:

Fluorescence-activated cell sorting

ir:

Immune-related

irRC:

Immune-related response criteria

LDH:

Lactate dehydrogenase

OS:

Overall survival

PD:

Progressive disease

PBMC:

Peripheral blood mononuclear cell

PR:

Partial response

PS:

Performance status

SD:

Stable disease

Tregs:

Regulatory T cells

ULN:

Upper limit of normal

WBC:

White blood cell

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Acknowledgments

This work was supported in part by the Italian Ministry of Health, via the Ricerca Corrente 2010. The authors would like to thank the patients and investigators who participated in the European EAP. The EAP was sponsored by Bristol-Myers Squibb. Editorial and writing assistance was provided by StemScientific, funded by Bristol-Myers Squibb (BMS).

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Authors and Affiliations

  1. Unit of Melanoma, Cancer Immunotherapy and Innovative Therapy, IRCCS, Istituto Nazionale Tumori Fondazione “G. Pascale”, Via Mariano Semmola, 80131, Naples, Italy

    Ester Simeone, Giusy Gentilcore, Antonio M. Grimaldi, Corrado Caracò, Marcello Curvietto, Assunta Esposito, Miriam Paone, Marco Palla, Ernesta Cavalcanti, Fabio Sandomenico, Antonella Petrillo, Gerardo Botti, Franco Fulciniti, Gennaro Ciliberto, Nicola Mozzillo & Paolo A. Ascierto

  2. Regina Elena National Cancer Institute, Rome, Italy

    Diana Giannarelli & Virginia Ferraresi

  3. National Research Council, Sassari, Italy

    Giuseppe Palmieri

  4. San Martino Hospital, National Institute for Cancer Research, Genoa, Italy

    Paola Queirolo & Maria Pia Pistillo

  5. Dermopathic Institute of the Immaculate IDI-IRCCS, Rome, Italy

    Paolo Marchetti

  6. Sant’Andrea Hospital, University Sapienza, Rome, Italy

    Paolo Marchetti

  7. “Paolo Giaccone” Polyclinic University Hospital, Palermo, Italy

    Gaetana Rinaldi

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  1. Ester Simeone
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  2. Giusy Gentilcore
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  23. Paolo A. Ascierto
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Corresponding author

Correspondence to Paolo A. Ascierto.

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Simeone, E., Gentilcore, G., Giannarelli, D. et al. Immunological and biological changes during ipilimumab treatment and their potential correlation with clinical response and survival in patients with advanced melanoma. Cancer Immunol Immunother 63, 675–683 (2014). https://doi.org/10.1007/s00262-014-1545-8

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  • DOI: https://doi.org/10.1007/s00262-014-1545-8

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