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Impact of minimal tumor burden on antibody response to vaccination

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Abstract

Four randomized phase III trials conducted recently in melanoma patients in the adjuvant setting have been based in part on the correlation between antibody responses in immunized patients and improved survival. Each of these randomized trials demonstrated no clinical benefit, although again there was a significant correlation between antibody response after vaccination and disease free and overall survival. To better understand this paradox, we established a surgical adjuvant model targeting GD2 ganglioside on EL4 lymphoma cells injected into the foot pad followed by amputation at variable intervals. Our findings are (1) comparable strong therapeutic benefit resulted from treatment of mice after amputation with a GD2-KLH conjugate vaccine or with anti-GD2 monoclonal antibody 3F8. (2) The strongest correlation was between antibody induction in response to vaccination and prolonged survival. (3) Antibody titers in response to vaccination in tumor challenged mice as compared to unchallenged mice were far lower despite the absence of detectable recurrences at the time. (4) The half life of administered 3F8 monoclonal antibody (but not control antibody) in challenged mice administered was significantly shorter than the half life of 3F8 antibody in unchallenged controls. The correlation between vaccine-induced antibody titers and prolonged survival may reflect, at least in part, increased tumor burden in antibody-negative mice. Absorption of vaccine-induced antibodies by increased, although not detected tumor burden may also explain the correlation between vaccine-induced antibody titers and survival in the adjuvant clinical trials described above.

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Abbreviations

mAb:

Monoclonal antibody

ADCC:

Antibody-dependent cell-mediated cytotoxicity

CDC:

Complement-dependent cytotoxicity

ELISA:

Enzyme-linked immunosorbent assay

FCS:

Fetal calf serum

NK cells:

Natural killer cells

IV:

Intravenous

KLH:

Keyhole limpet hemocyanin

PBS:

Phosphate buffered saline

sTn:

Sialyl Tn

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Acknowledgments

This work was supported by Grant PO1 CA33049 from the National Institutes of Health and by the Koodish Family Charitable Lead Trust. Dr. Livingston and Dr. Ragupathi are paid consultants and share holders in MabVax Therapeutics Inc. who has licensed the GD2-KLH vaccine from MSKCC.

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Author notes

  1. Soo-Kie Kim

    Present address: Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

  2. John Gathuru

    Present address: Vaxinnate Corporation, Cranbury, NJ, 08512, USA

  3. Fusataka Koide

    Present address: Nabi Biopharmaceuticals, Rockville, MD, 20852, USA

Authors and Affiliations

  1. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Nai-Kong Cheung

  2. Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10021, USA

    Katherine Panageas

  3. Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10065, USA

    Xiaohong Wu, Govind Ragupathi & Philip O. Livingston

Authors
  1. Soo-Kie Kim
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  2. Xiaohong Wu
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  3. Govind Ragupathi
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  8. Philip O. Livingston
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Corresponding author

Correspondence to Philip O. Livingston.

Additional information

The designations GM2, GD2 and GD3 are used in accordance with the abbreviated ganglioside nomenclature of Svennerholm [1].

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Kim, SK., Wu, X., Ragupathi, G. et al. Impact of minimal tumor burden on antibody response to vaccination. Cancer Immunol Immunother 60, 621–627 (2011). https://doi.org/10.1007/s00262-011-0975-9

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  • DOI: https://doi.org/10.1007/s00262-011-0975-9

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