Different types of immunotherapy have been shown to induce both immune and clinical responses in different malignancies, but at this point, only a small proportion of patients may benefit. The goal of this project is to develop more effective immunotherapy for prostate cancer. We have demonstrated that enhancing T lymphocyte responses with an antibody to immune inhibitory molecule CTLA4 can induce clinical responses in a small proportion of patients with castrate-resistant prostate cancer. We have examined whether this treatment could be combined with the cytokine granulocyte-macrophage stimulating factor (GM-CSF), which is also being studied as an immunotherapy for prostate cancers. In a phase I clinical trial, we have shown that the combination of CTLA4 blockade and GM-CSF treatment is safe and may lead to clinical responses at a higher rate. In order for CTLA4 blockade to be further developed clinically, we must determine whether combination immunotherapy indeed results in improved clinical outcome.
In specific aim 1, we will perform a randomized phase II clinical trial where patients with hormone-refractory prostate cancer will be treated with either anti-CTLA4 antibody alone or anti-CTLA4 antibody in combination with GM-CSF. In the second aim, we will determine whether CTLA4 blockade alone or the combination leads to significant activation of effector T cells and expansion of regulatory T cells. In the final aim, we will define antigen-specific immune responses induced by the treatment. In doing so, we may validate novel tumor antigens that may represent novel vaccine candidates. Alternatively, we may define an immune response signature that may predict which patients might respond to this immunotherapeutic approach.

Public Health Relevance

Immunotherapy is an emerging modality in prostate cancer therapy. Prostate cancer patients can possess preexisting immune responses to their cancer that can be enhanced for clinical effect. Treatment with blocking antibodies to CTLA4 have been shown to augment this immune response and induce clinical responses in a small proportion of patients. Combining this treatment to cytokine therapy with GM-CSF provides an approach for enhancing these T cell responses and ultimately enhancing clinical efficacy. Defining the target proteins against which this immune response is induced may lead to improved treatments for prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136753-05
Application #
8449498
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Song, Min-Kyung H
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
5
Fiscal Year
2013
Total Cost
$292,312
Indirect Cost
$103,113
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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