TUMOR RNA TRANSFECTED DENDRITIC CELL VACCINES

Project: Research project

Project Details

Description

DESCRIPTION: (Applicant's Abstract) Extensive preclinical studies, as well as
early indications from clinical trials, suggest that vaccination with
tumor-derived mRNA transfected autologous dendritic cells (DC) represents a
potentially effective and broadly applicable treatment modality for
disseminated metastatic cancer. The underlying hypothesis of this application
is that the RNA transfected DC vaccination approach, promising as it may be in
its current form, will require significant improvements to realize it's full
potential. The purpose of the proposed studies is to explore strategies that
will augment, in a significant manner, the therapeutic impact of this
intervention modality. Animal models will be used to (a) develop improved DC
antigen presenting platforms and (b) design adjunct treatments to enhance,
qualitatively as well as quantitatively, the immune response generated by the
RNA transfected DC. In Specific Aim 1 the applicant will explore the importance
of DC maturation. Since the maturation process of DC is more complex than
initially thought and the influence of various maturation agents has not been
clearly defined, he will first determine the biological impact of various
agents on DC maturation and then correlate with their potency to stimulate T
cell responses and protective immunity. He will also follow up on preliminary
observations suggesting that calreticulin (CRT) functions as a potent
maturation agent. In Specific Aim 2, the applicant will test whether Flt-3L
mobilized DC are effective APC in a vaccination setting. The significance from
a clinical standpoint is that generation of Flt-3L mobilized DC is much simpler
compared to the generation of monocyte derived DC, which is currently used by
the applicant and others in clinical trials. In Specific Aim 3 the applicant
will explore adjunct treatments designed to expand in vivo the tumor-specific T
cell response generated by vaccination with RNA transfected DC. The applicant
hypothesizes that the inherent deficiency of vaccination with RNA transfected
DC to stimulate an effective CD4+ T cell response (T-help) will limit the
therapeutic benefit of this intervention modality. Methods to boost
tumor-specific CD4+, as well as CD8+ T cell responses will be explored by
co-administration of agents such as IL-2, IL-12, CpG ODNs, Poly I:C or
anti-CTLA4 ab. Promising strategies indicated by the murine studies will be
channeled into the applicant's ongoing clinical program. The studies proposed
in this application will set the stage for the development of improved
generation of RNA transfected DC vaccines.
StatusFinished
Effective start/end date4/1/003/31/05

Funding

  • National Cancer Institute: $242,550.00
  • National Cancer Institute: $242,550.00
  • National Cancer Institute: $242,550.00
  • National Cancer Institute: $242,550.00
  • National Cancer Institute: $242,550.00

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