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

Hess, Paul; Boczkowski, David; Nair, Smita; Snyder, David; Gilboa, Eli
June 2006
Cancer Immunology, Immunotherapy;Jun2006, Vol. 55 Issue 6, p672
Academic Journal
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.


Related Articles

  • The serial engagement model 17 years after: fromTCR triggering to immunotherapy. Valitutti, Salvatore // Frontiers in Immunology;Aug2012, Vol. 3, p1 

    More than 15 years ago the serial engagement model was proposed as an attempt to solve the low affinity/high sensitivity paradox of TCR antigen recognition. Since then, the model has undergone ups and downs marked by the technical and conceptual advance-ments made in the field ofT lymphocyte...

  • Cytotoxic T lymphocyte epitopes from human heparanase can elicit a potent anti-tumor immune response in mice. Xu-Dong Tang; Guang-Ping Liang; Chuan Li; Ying Wan; Ting Chen; Ling Chen; Song-Tao Yu; Zhen Xiong; Dian-Chun Fang; Guo-Zheng Wang; Shi-Ming Yang // Cancer Immunology, Immunotherapy;Jul2010, Vol. 59 Issue 7, p1041 

    Heparanase is expressed in almost all advanced tumors, and therefore it may serve as a potential target for tumor therapy. Our previous study has shown that heparanase can serve as a potential universal tumor-associated antigen (TAA) for the immunotherapy of advanced tumors. Further study...

  • Induction of Intrahepatic HCV NS4B, NS5A and NS5BSpecific Cellular Immune Responses following Peripheral Immunization. Kuhs, Krystle A. Lang; Toporovski, Roberta; Ginsberg, Arielle A.; Shedlock, Devon J.; Weiner, David B. // PLoS ONE;Dec2012, Vol. 7 Issue 12, p1 

    Numerous studies have suggested that an effective Hepatitis C Virus (HCV) vaccine must induce strong cytotoxic and γ+ T cell responses targeting the non-structural region of the virus. Most importantly, these responses must be able to migrate into and remain functional within the liver, an...

  • Augmenting T Helper Cell Immunity in Cancer. Knutson, K. L.; Disis, M. L. // Current Drug Targets - Immune, Endocrine & Metabolic Disorders;Dec2005, Vol. 5 Issue 4, p365 

    Cancer specific immunity elicited with vaccines has traditionally focused on the activation of the CD8 cytolytic T lymphocyte (CTL) often involving direct stimulation of immunity using HLA-class I binding peptide epitopes. Recently it has become clear that activation of the CTL immune effector...

  • Efficient induction of CD25- iTreg by co-immunization requires strongly antigenic epitopes for T cells. Shuang Geng; Yang Yu; Youmin Kang; Pavlakis, George; Huali Jin; Jinyao Li; Yanxin Hu; Weibin Hu; Shuang Wang; Bin Wang // BMC Immunology;2011, Vol. 12 Issue 1, p27 

    Background: We previously showed that co-immunization with a protein antigen and a DNA vaccine coding for the same antigen induces CD40low IL-10high tolerogenic DCs, which in turn stimulates the expansion of antigen-specific CD4+CD25-Foxp3+ regulatory T cells (CD25- iTreg). However, it was...

  • Targeting the Immune System in Cancer. Chaudhuri, Devyani; Suriano, Robert; Mittelman, Abraham; Tiwari, Raj K. // Current Pharmaceutical Biotechnology;Feb2009, Vol. 10 Issue 2, p166 

    The concept of cancer immunotherapy provides a fresh perspective as it is not associated with many of the drawbacks of conventional therapies such as chemotherapy, radiotherapy and surgery. When fully activated the immune system has immense potential as is evident from mis-matched transplanted...

  • Unique Characteristics of the Intestinal Immune System as an Inductive Site after Antigen Reencounter. Kantele, Anu; Arvilommi, Heikki; Likkanen, Katja; Savilahti, Erkki; Mäkelä, Helena P.; Herzog, Christian; Furer, Emil; Kantele, Jussi M. // Journal of Infectious Diseases;1/15/2005, Vol. 191 Issue 2, p312 

    Background. Immunization prepares the body for a reencounter with the microbe. Information on the targeting of immune effector cells during secondary immune response-that is, lymphocyte homing-is scarce. In the present study, the homing potentials of lymphocytes are examined after antigen...

  • Medulloblasoma: challenges for effective immunotherapy. Sonabend, Adam; Ogden, Alfred; Maier, Lisa; Anderson, David; Canoll, Peter; Bruce, Jeffrey; Anderson, Richard // Journal of Neuro-Oncology;May2012, Vol. 108 Issue 1, p1 

    For medulloblastoma patients, the current therapeutic paradigm of surgery followed by radiation and chemotherapy can lead to long-term remission. However, the sequelae of treatment can be very debilitating, particularly in young children. Immunotherapy is an attractive treatment approach to...

  • Adoptive cancer immunotherapy: discovering the best targets. Perreault, Claude; Brochu, Sylvie // Journal of Molecular Medicine;Apr2002, Vol. 80 Issue 4, p212 

    Numerous animal and clinical studies have shown that injection of T lymphocytes from a major histocompatibility complex matched donor can cure subjects with chemotherapy-resistant hematological malignancies. This graft-versus-tumor effect, which represents the most conclusive evidence that the...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics