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Cancer Immunology, Immunotherapy

, Volume 55, Issue 6, pp 672–683 | Cite as

Vaccination with mRNAs encoding tumor-associated antigens and granulocyte-macrophage colony-stimulating factor efficiently primes CTL responses, but is insufficient to overcome tolerance to a model tumor/self antigen

  • Paul R. Hess
  • David Boczkowski
  • Smita K. Nair
  • David Snyder
  • Eli Gilboa
Original Article

Abstract

Immunization of mice with dendritic cells transfected ex vivo with tumor-associated antigen (TAA)-encoding mRNA primes cytotoxic T lymphocytes (CTL) that mediate tumor rejection. Here we investigated whether direct injection of TAA mRNA, encapsulated in cationic liposomes, could function similarly as cancer immunotherapy. Intradermal and intravenous injection of ovalbumin (OVA) mRNA generated specific CTL activity and inhibited the growth of OVA-expressing tumors. Vaccination studies with DNA have demonstrated that co-administration of antigen (Ag)- and cytokine-encoding plasmids potentiate the T cell response; in analogous fashion, the inclusion of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA enhanced OVA-specific cytotoxicity. The ability of this GM-CSF-augmented mRNA vaccine to treat an established spontaneous tumor was evaluated in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mouse, using the SV40 large T Ag (TAg) as a model tumor/self Ag. Repeated vaccination elicited vigorous TAg-specific CTL activity in nontransgenic mice, but tumor-bearing TRAMP mice remained tolerant. Adoptive transfer of naïve splenocytes into TRAMP mice prior to the first vaccination restored TAg reactivity, and slowed tumor progression. The data from this study suggests that vaccination with TAA mRNA is a simple and effective means of priming antitumor CTL, and that immunogenicity of the vaccine can be augmented by co-delivery of GM-CSF mRNA. Nonetheless, limitations of such vaccines in overcoming tolerance to tumor/self Ag may mandate prior or simultaneous reconstitution of the autoreactive T cell repertoire for this form of immunization to be effective.

Keywords

CTL mRNA vaccine GM-CSF SV40 large T antigen Tolerance 

Abbreviations

Ag

Antigen

APCs

Antigen-presenting cells

AT

Adoptive transfer

BMDC

Bone marrow-derived dendritic cells

CaP

Prostate carcinoma

CTL

Cytotoxic T lymphocyte

CTLA-4

Cytotoxic T lymphocyte antigen-4

E:T

Effector: target

GFP

Green fluorescent protein

GM-CSF

Granulocyte-macrophage colony-stimulating factor

GMTV

Gene-modified tumor vaccine

HA

Hemagglutinin

ID

Intradermal

IL

Interleukin

IV

Intravenous

IVT

In vitro transcribed

OVA

Ovalbumin

pDNA

Plasmid DNA

PI

Postinjection

PIN

Prostatic intraepithelial neoplasia

PSA

Prostate-specific antigen

SQ

Subcutaneous

TAA

Tumor-associated antigen

TAg

SV40 large T antigen

TRAMP

Transgenic adenocarcinoma of mouse prostate

wt

Wild type

Notes

Acknowledgments

We are grateful to Duane Mitchell, Brenda Faiola, Carmen Wong, Charu Adlakha, Justin Hart, and Catherine McLaughlin. We also thank Erning Li for help with statistical analysis, and Xu Lin, Barbara Foster, and Norman Greenberg for their assistance with the TRAMP mouse model.

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Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • Paul R. Hess
    • 1
    • 2
    • 3
  • David Boczkowski
    • 2
  • Smita K. Nair
    • 2
  • David Snyder
    • 2
  • Eli Gilboa
    • 2
  1. 1.Department of Microbiology, Pathology, and Parasitology, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  2. 2.Department of Surgery, and Center for Genetic and Cellular TherapiesDuke University Medical CenterDurhamUSA
  3. 3.Department of Clinical Sciences, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA

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