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Principal Investigator: Dr. Cynthia Leifer
Contact Information: E-mail: cal59@cornell.edu
- Phone: 607-253-3576
Sponsor: NIH-NCI
Grant Number: 1K22CA113705-01
Title: Enhancing Immunotherapy through Toll Like Receptors
Annual Direct Cost: $160,625
Project Period: 09/30/05-08/31/08
The goal of cancer immunotherapy is to elicit anti-tumor
immune responses. Injecting tumor antigens for immunotherapy results in T cell
responses that are weak and ineffective due to a lack of good adjuvants. Recent
emphasis has been on pathogen associated molecular patterns (PAMPs) as
candidate vaccine adjuvants. PAMPs are molecular signatures that define classes
of microorganisms and induce potent immune responses. The long-term goal of the
proposed studies is to understand the molecular mechanisms of activation of
PAMPs on their receptors, Toll like receptors (TLRs). Modulation of TLRs and
modification of PAMPs will greatly enhance cancer vaccine adjuvanticity thereby
improving immunotherapy of cancer. In this grant period we will determine
control mechanisms for PAMP recognition and receptor trafficking in a subfamily
of Toll like receptors (3, 7, 8 and 9). These transmembrane Toll like receptors
share the properties that they are not expressed at the cell surface and that
they recognize nucleic acids such as dsRNA (TLR3), ssRNA (TLR7 and TLR8) and
CpG containing DNA (TLR9). We hypothesize that nucleic acid recognizing Toll
like receptors share localization, trafficking and PAMP recognition mechanisms
that are controlled by discrete sequences in the cytoplasmic and ectodomains.
We will test the hypothesis in two specific aims. First, we will determine the
molecular mechanisms of localization and trafficking of nucleic acid
recognizing Toll like receptors in response to PAMPs. Second, we will determine
the specific binding regions on TLRs for the corresponding PAMP ligand. This
information will fill gaps in the knowledge of Toll like receptor-PAMP biology:
the molecular basis of ligand recognition, and the role of cellular targeting
in controlling signaling. This information will allow the development of novel
therapeutic strategies to modulate the immune responses to improve cancer
vaccine adjuvants. This career transition grant will allow me to develop a
research program focused on new ways to exploit TLR-PAMP biology for the
treatment of human cancer.
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