| According to the
annual report of Department of Health (DOH), the increasing rate (13.6%)
of the incidence of Prostate cancer is the highest among all malignant cancers
in Taiwan. Although prostate cancer is generally being diagnosed at an earlier
stage than ever before, which may explain the high increasing rate, it still
carries an overall cancer-specific, disease-free survival rate of only 51%.
It is curable only when localized and amenable to surgery and/or radiotherapy.
Unfortunately, at the time of diagnosis 50% of patients have either distant
metastases or lymph node involvement. Also, of those individuals treated
for local disease, 30% will develop local recurrence or metastases.
Clearly, there is a need to
develop strategies that will both increase local tumor control and treat
systemic disease. This proposal explores gene immunotherapy approaches
aimed at increasing the probability of increasing local control of prostate
cancer with radiation therapy while at the same time combating micrometastatatic
disease outside the treatment field. The aim of this project is to devise
novel strategies that can channel tumor cell death resulting from radiation
therapy into the generation of an effective anti-tumor immune response.
The focus will be on IL-3 gene immunotherapy. It is hypothesized that
radiosensitization of tumors as a result of IL-3 expression is due largely
to mobilization and recruitment of radiation resistant antigen presenting
cells to the tumor that are highly efficient at processing tumor antigens
and presenting them to the immune system. A powerful anti-tumor immune
response result and a massive influx of immune lymphocytes into the irradiated
tumor bed. The immunity that is generated aids irradiation in achieving
local tumor control and, at the same time, combats systemic micrometastatic
disease.
The project will employ a
murine model of prostate cancer (TRAMP) and adenoviral vectors to express
IL-3 intratumorally. The effect of IL-3 expression on the tumor response
to radiation therapy, the nature of the intratumoral host cell infiltrate,
and the level of systemic immunity that is generated, will be measured.
The mechanism by which IL-3 regulates the recruitment of host-derived
immune cells to irradiated and non-irradiated tumor sites will be determined,
as will the requirement for this process for the generation of systemic
immunity. The cells recruited by IL-3 and their ability to process and
present prostate tumor antigens after radiation therapy will be characterized,
both phenotypically and functionally. Finally, the therapeutic potential
of a novel Cannon-secreted IL3 fusion protein in the treatment of prostate
cancer by radiation will be explored. The findings should contribute to
future improvements in the efficacy of radiation therapy as a modality
for the treatment of locally advanced and metastatic prostate cancer.
This project is a collaboration
with Dr. William H. McBride in UCLA, USA. We are expecting to have many
pictures (RPA results and histological pictures) transmitted between UCLA,
USA and NTHU, Taiwan.
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IL-3
Transduced Tumor Cell vaccine Therapy