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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Clinical Oncology Study Section (CONC)
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Song, Min-Kyung H
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Oh, David Y; Cham, Jason; Zhang, Li et al. (2017) Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire. Cancer Res 77:1322-1330
Lou, David Y; Fong, Lawrence (2016) Neoadjuvant therapy for localized prostate cancer: Examining mechanism of action and efficacy within the tumor. Urol Oncol 34:182-92
Wei, Xiao X; Chan, Stephen; Kwek, Serena et al. (2016) Systemic GM-CSF Recruits Effector T Cells into the Tumor Microenvironment in Localized Prostate Cancer. Cancer Immunol Res 4:948-958
Landegren, Nils; Sharon, Donald; Shum, Anthony K et al. (2015) Transglutaminase 4 as a prostate autoantigen in male subfertility. Sci Transl Med 7:292ra101
Kwek, Serena S; Lewis, Jera; Zhang, Li et al. (2015) Preexisting Levels of CD4 T Cells Expressing PD-1 Are Related to Overall Survival in Prostate Cancer Patients Treated with Ipilimumab. Cancer Immunol Res 3:1008-16
Small, Eric J; Lance, Raymond S; Gardner, Thomas A et al. (2015) A Randomized Phase II Trial of Sipuleucel-T with Concurrent versus Sequential Abiraterone Acetate plus Prednisone in Metastatic Castration-Resistant Prostate Cancer. Clin Cancer Res 21:3862-9
Cheng, Michael L; Fong, Lawrence (2014) Beyond sipuleucel-T: immune approaches to treating prostate cancer. Curr Treat Options Oncol 15:115-26
Khan, Imran S; Mouchess, Maria L; Zhu, Meng-Lei et al. (2014) Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J Exp Med 211:761-8
Cha, Edward; Klinger, Mark; Hou, Yafei et al. (2014) Improved survival with T cell clonotype stability after anti-CTLA-4 treatment in cancer patients. Sci Transl Med 6:238ra70
Friedlander, Terence W; Fong, Lawrence (2014) The end of the beginning: circulating tumor cells as a biomarker in castration-resistant prostate cancer. J Clin Oncol 32:1104-6

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