Genomes and Genes
AAV-Based Plasmacytoid Dendritic Cell Cancer Vaccine
Principal Investigator: Pierre Triozzi
Abstract: DESCRIPTION (provided by applicant): The objective is to develop a vaccine approach targeting carcinoembryonic antigen (CEA), an oncofetal antigen expressed by many common cancers. Although CEA vaccines have demonstrated promise in clinical trials, the induction of cellular immune responses has been inconsistent, and there has been little evidence of antitumor activity. Dendritic cells (DC) are considered the most potent antigen-presenting cells for initiating cellular immunity. There is experimental evidence suggesting that the plasmacytoid DC subpopulation (pDC) plays an important role in regulating the T-helper (Th) polarization of the immune response. The central hypothesis is that failure of CEA vaccine strategies to elicit therapeutic antitumor immunity is the result of suboptimal activation of pDC to promote Th1/cytolytic T lymphocyte responses. High levels of antigen promote pDC Th1 polarization. The vaccine approach will exploit the natural and physical properties of recombinant adeno-associated virus (rAAV) vectors to stably express high levels of CEA in the absence of competing viral vector antigens. Signaling through specific Toll-like receptors (TLR) is involved in pDC activation. The vaccine approach will also exploit potentially synergistic interactions between synthetic TLR agonists in promoting pDC Th1 polarization. Preclinical studies of this AAV-CEA immunogen-TLR agonist adjuvant approach in mouse tumor models are proposed. The specific aims are to: 1) correlate the dynamics of tumor antigen expression by rAAV-CEA vectors with pDC activation and anti-tumor immunity;2) characterize the dynamics of pDC Th1 polarization by TLR agonists;and 3) determine the role of pDC activation in anti-tumor immunity elicited by effective rAAV-CEA and TLR agonist combination vaccines. The ability of this vaccine approach to elicit CEA-specific, antitumor, cellular immunity and the mechanisms involved will be evaluated. Studies will include novel rAAV-CEA constructs and novel quantitative, real-time polymerase chain reaction assessment of the effects of rAAV-CEA and TRL agonists on pDC activation at the vaccine administration site, in regional lymph nodes, and systemically. Studies will also include the use of transgenic mice that express CEA. The results of this project may lead to an effective vaccine for the many cancers that express CEA, establish a vaccine approach that can be applied to other tumor-associated antigens, and help improve the understanding of the role of pDC in vaccine responses.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT
- Differential effects of low-dose decitabine on immune effector and suppressor responses in melanoma-bearing micePierre L Triozzi
Taussig Cancer Institute, R40, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA
Cancer Immunol Immunother 61:1441-50. 2012..Effects on host immune effector and suppressor responses have not been well characterized...
- Differential immunologic and microRNA effects of 2 dosing regimens of recombinant human granulocyte/macrophage colony stimulating factorPierre L Triozzi
Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
J Immunother 35:587-94. 2012..Serum levels of miRs are potentially useful biomarkers of these effects...
- Regulation of the activity of an adeno-associated virus vector cancer vaccine administered with synthetic Toll-like receptor agonistsPierre L Triozzi
Taussig Cancer Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
Vaccine 28:7837-43. 2010..Suppressor mechanisms, including those mediated by myeloid cells, may negatively regulate the antitumor immune response...
- Effects of interleukin-1 receptor antagonist on tumor stroma in experimental uveal melanomaPierre L Triozzi
Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio 44195, USA
Invest Ophthalmol Vis Sci 52:5529-35. 2011....
- Epigenetic regulation by decitabine of melanoma differentiation in vitro and in vivoOscar Alcazar
Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
Int J Cancer 131:18-29. 2012..Modification of decitabine dose, schedule and formulation for differentiation rather than cytotoxic objectives inhibits the growth of melanoma cells in vitro and in vivo...
- Inhibition and promotion of tumor growth with adeno-associated virus carcinoembryonic antigen vaccine and Toll-like receptor agonistsP L Triozzi
Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA
Cancer Gene Ther 18:850-8. 2011..In CEA-Tg mice, tumor growth can be promoted with rAAV-CEA and TLR agonists. Dendritic and myeloid cells play a regulatory role...