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A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma

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Abstract

Antigen-specific immunotherapy was studied in a multi-institutional phase 1/2 study by combining decitabine (DAC) followed by an autologous dendritic cell (DC)/MAGE-A1, MAGE-A3 and NY-ESO-1 peptide vaccine in children with relapsed/refractory solid tumors. Patients aged 2.5–15 years with relapsed neuroblastoma, Ewing’s sarcoma, osteosarcoma and rhabdomyosarcoma were eligible to receive DAC followed by DC pulsed with overlapping peptides derived from full-length MAGE-A1, MAGE-A3 and NY-ESO-1. The primary endpoints were to assess the feasibility and tolerability of this regimen. Each of four cycles consisted of week 1: DAC 10 mg/m2/day for 5 days and weeks 2 and 3: DC vaccine once weekly. Fifteen patients were enrolled in the study, of which 10 were evaluable. Generation of DC was highly feasible for all enrolled patients. The treatment regimen was generally well tolerated, with the major toxicity being DAC-related myelosuppression in 5/10 patients. Six of nine patients developed a response to MAGE-A1, MAGE-A3 or NY-ESO-1 peptides post-vaccine. Due to limitations in number of cells available for analysis, controls infected with a virus encoding relevant genes have not been performed. Objective responses were documented in 1/10 patients who had a complete response. Of the two patients who had no evidence of disease at the time of treatment, one remains disease-free 2 years post-therapy, while the other experienced a relapse 10 months post-therapy. The chemoimmunotherapy approach using DAC/DC-CT vaccine is feasible, well tolerated and results in antitumor activity in some patients. Future trials to maximize the likelihood of T cell responses post-vaccine are warranted.

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Abbreviations

ALT:

Alanine aminotransferase

ANC:

Absolute neutrophil count

AST:

Aspartate aminotransferase

CGGs:

Cancer germline genes

CTCAE:

Common terminology criteria for adverse events

CTL:

Cytotoxic T lymphocytes

C1W1:

Cycle1-week1

DAC:

Decitabine

DC:

Dendritic cell

ECG:

Echocardiogram

ES:

Ewing’s sarcoma

GCSF:

Granulocyte colony-stimulating factor

GFR:

Glomerular filtration rate

GM-CSF:

Granulocyte macrophage colony-stimulating factor

HLA:

Human leukocyte antigen

NB:

Neuroblastoma

OS:

Osteogenic sarcoma

PBMCs:

Peripheral blood mononuclear cells

RMS:

Rhabdomyosarcoma

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Acknowledgments

We thank the clinical research staff at the Dana-Farber Cancer Institute (DFCI), Kosair Charities Pediatric Clinical Research Unit and Penn State Children’s Hospital. The work was supported by funds from Hyundai Hope on Wheels, Solving Kids’ Cancer, The Andrew McDonough B + Foundation, the Pierce Phillips Charity and the Dana-Farber Cancer Institute (DFCI) Neuroblastoma Fund. We thank all the patients enrolled in this trial and their families for their participation in the study.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Pediatrics, Hematology/Oncology, University of Louisville, 571 South Floyd Street, Suite 445, Louisville, KY, 40202, USA

    Deepa K. Krishnadas, Fanqi Bai, Janice E. Sullivan, Alexandra C. Cheerva & Kenneth G. Lucas

  2. Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Boston Children’s Hospital, Harvard Medical School, Dana 640E, 450 Brookline Ave, Boston, MA, 02215, USA

    Suzanne Shusterman, Lisa Diller & Rani E. George

Authors
  1. Deepa K. Krishnadas
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  2. Suzanne Shusterman
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  3. Fanqi Bai
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  4. Lisa Diller
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  6. Alexandra C. Cheerva
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  7. Rani E. George
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  8. Kenneth G. Lucas
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Correspondence to Rani E. George or Kenneth G. Lucas.

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Krishnadas, D.K., Shusterman, S., Bai, F. et al. A phase I trial combining decitabine/dendritic cell vaccine targeting MAGE-A1, MAGE-A3 and NY-ESO-1 for children with relapsed or therapy-refractory neuroblastoma and sarcoma. Cancer Immunol Immunother 64, 1251–1260 (2015). https://doi.org/10.1007/s00262-015-1731-3

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  • DOI: https://doi.org/10.1007/s00262-015-1731-3

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