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Cancer Immunology, Immunotherapy

, Volume 64, Issue 4, pp 437–446 | Cite as

Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor β by the monoclonal antibody fresolimumab (GC1008)

  • Mario E. LacoutureEmail author
  • John C. Morris
  • Donald P. Lawrence
  • Antoinette R. Tan
  • Thomas E. Olencki
  • Geoffrey I. Shapiro
  • Bruce J. Dezube
  • Jay A. Berzofsky
  • Frank J. Hsu
  • Joan Guitart
Original Article

Abstract

Fresolimumab is an antibody capable of neutralizing all human isoforms of transforming growth factor beta (TGFβ) and has demonstrated anticancer activity in investigational studies. Inhibition of TGFβ by fresolimumab can potentially result in the development of cutaneous lesions. The aim of this study was to investigate the clinical, histological, and immunohistochemical characteristics of cutaneous neoplasms associated with fresolimumab. Skin biopsies (n = 24) were collected and analyzed from patients (n = 5) with treatment-emergent, cutaneous lesions arising during a phase 1 study of multiple doses of fresolimumab in patients (n = 29) with melanoma or renal cell carcinoma. Blinded, independent histological review and measurements of Ki-67, p53, and HPV integration were performed. Based on central review, four patients developed lesions with histological characteristics of keratoacanthomas, and of these patients, a single case of well-differentiated squamous cell carcinoma was also found. Expression of Ki-67, no evidence of p53 overexpression, and only focal positivity for human papillomavirus RNA by in situ hybridization in 4/18 cases were consistent with these findings. Following completion of fresolimumab, lesions spontaneously resolved. Therefore, benign, reversible keratoacanthomas were the most common cutaneous neoplasms observed, a finding of importance for adverse event monitoring, patient care, and optimization of therapies targeting TGFβ.

Keywords

Transforming growth factor β GC1008 Fresolimumab Keratoacanthoma Squamous cell cancer 

Abbreviations

AE/SAE

Adverse events/serious adverse events

Akt

Protein kinase B

ALK

Anaplastic lymphoma receptor tyrosine kinase

ERK

Extracellular signal-regulated kinase

HPV

Human papillomavirus

IHC

Immunohistochemical

IgG

Immunoglobulin

JNK

Jun N-terminal kinase

KA

Keratoacanthoma

Kg

Kilograms

Ki

Kinesis

KO

Knockout

Mg

Milligrams

MM

Malignant melanoma

NCI

National Cancer Institute

RAF

Rapidly accelerated fibrosarcoma

RAS

Rat sarcoma

RCC

Renal cell carcinoma

SCC

Squamous cell carcinoma

SMAD

Small body size mothers against decapentaplegic

TGFβ

Transforming growth factor β

TGFBR

Transforming growth factor β receptor

Notes

Acknowledgments

This work was supported by Genzyme Corporation and in part by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI).

Conflict of interest

Frank J. Hsu was an employee of Genzyme. Mario E. Lacouture and Joan Guitart were consultants for Genzyme. Jay A. Berzofsky received research support from Genzyme. All other authors do not have any conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Mario E. Lacouture
    • 1
    Email author
  • John C. Morris
    • 2
  • Donald P. Lawrence
    • 3
  • Antoinette R. Tan
    • 4
  • Thomas E. Olencki
    • 5
  • Geoffrey I. Shapiro
    • 6
  • Bruce J. Dezube
    • 7
  • Jay A. Berzofsky
    • 2
  • Frank J. Hsu
    • 8
  • Joan Guitart
    • 9
  1. 1.Dermatology Service, Department of MedicineMemorial Sloan Kettering Cancer CenterNew YorkUSA
  2. 2.Metabolism Branch and Vaccine Branch, Center for Cancer ResearchNational Cancer InstituteBethesdaUSA
  3. 3.Department of MedicineMassachusetts General HospitalBostonUSA
  4. 4.Department of MedicineThe Cancer Institute of New JerseyNew BrunswickUSA
  5. 5.Department of MedicineThe Ohio State UniversityColumbusUSA
  6. 6.Department of MedicineDana-Farber Cancer InstituteBostonUSA
  7. 7.Department of MedicineBeth Israel Deaconess Medical CenterBostonUSA
  8. 8.Genzyme CorporationCambridgeUSA
  9. 9.Departments of Dermatology and PathologyNorthwestern UniversityChicagoUSA

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