Sipuleucel-T is an immunotherapy indicated for the treatment of metastatic prostate cancer. It offers a new mechanism to treat prostate cancer without the side effects of hormone therapies and chemotherapies. In previous studies sipuleucel-T did not delay disease progression, but demonstrated an overall survival benefit compared to placebo. While clinical trials have evaluated the effects of sipuleucel-T on overall survival and progression, more studies are needed to evaluate its effectiveness and role in the management of prostate cancer. The objective of this study is to identify the incidence and possible predictors for disease progression in patients receiving sipuleucel-T. A retrospective review of patients who received sipuleucel-T between 1 September 2010 and 11 October 2011 was conducted (n = 36). Patients who changed therapy or died within 120 days were classified as experiencing rapid progression. Potential predictors of rapid progression were examined using logistic regression. Seven patients met criteria for rapid progression. Progression occurred in 72.2% of all patients. The median days to progression was 158. No significant predictors of rapid progression were identified. Currently no predictors have been found to be associated with rapid progression in prostate cancer patients on sipuleucel-T. Full article

Prostate cancer is the most common cancer in men, both in the USA and Europe. Although incurable, metastatic disease can often be controlled for years with anti-androgen therapy. Once the disease becomes castrate resistant, the median survival is 18 months. There is growing evidence that the immune system, and in particular cytokines, play an important role in prostate cancer immunosurveillance and progression. Here, we have undertaken a clinical investigation of the role of two closely related cytokines, IL-4 and IL-13 in prostate cancer. In the largest series studied to date, we show that serum IL-4, but not IL-13 is significantly elevated in castrate resistant, compared to androgen sensitive disease. Notably however, serum IL-4 levels are also raised in patients with benign prostatic disease. Analysis of benign and malignant prostate tissue demonstrates that the source of IL-4 is epithelial cells rather than infiltrating leukocytes. Together, our data are consistent with a dual role for IL-4 in prostate cancer development. In benign disease, our data add to the evidence that IL-4 serves a protective role. By contrast, the data support a direct role for IL-4 in the progression of prostate cancer from androgen responsive, to advanced castrate-resistant disease. Full article

Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies. Full article

Active immunotherapy is dependent on the ability of the immune system to recognize and respond to tumors. Despite overwhelming evidence to support a cell-mediated immune response to prostate cancer, it is insufficient to eradicate the disease. This is likely due to a high level of suppression at the tumor site from a variety of sources, including immunosuppressive cells. Immune cells entering the tumor microenvironment may be inhibited directly by the tumor, stromal cells or other immune cells that have been induced to adopt a suppressive phenotype. The resurgence of interest in immunotherapy following the approval of sipuleucel-T and ipilimumab by the Food and Drug Administration has brought about new strategies for overcoming tumor-mediated suppression and bolstering anti-tumor responses. Improved understanding of the immune response to prostate cancer can lead to new combination therapies, such as the use of vaccine with small molecule and checkpoint inhibitors or other immunotherapies. Full article

Despite recent advances in cancer immunotherapy, no prospectively validated intermediate biomarkers exist to predict response. These biomarkers are highly desirable given modern immunotherapy’s paradoxical pattern of clinical benefit; that is, improvement in overall survival without short-term change in progression. Immunotherapy clinical trials have evaluated biomarkers that may correlate with clinical outcomes. Many of them are performed on peripheral blood to evaluate the systemic response, such as tumor-targeted humoral and cellular immunity, and cytokine responses. Accumulating evidence suggests that immune infiltrates in tumors may suggest evidence for the therapy’s mechanism of action, and have greater potential for providing prognostic and predictive information. In addition, a non-immunologic biomarker, such as tumor growth kinetics, may explain this paradoxical pattern of clinical benefit, and predict survival in patients treated with an immunotherapy. Prospective assessment and validation of these and other intermediate markers would be required to better understand their potential clinical role. Full article

Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients’ own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for immunotherapy, patient selection and best sequencing with other prostate cancer therapies remain to be determined. A better understanding of immune response may help address these issues. Full article

Prostate cancer (PCa) is the most common noncutaneous cancer diagnosis and the second leading cause of cancer-related deaths among men in the United States. Effective treatment modalities for advanced metastatic PCa are limited. Immunotherapeutic strategies based on T cells and antibodies represent interesting approaches to prevent progression from localized to advanced PCa and to improve survival outcomes for patients with advanced disease. CD8⁺ cytotoxic T lymphocytes (CTLs) efficiently recognize and destroy tumor cells. CD4⁺ T cells augment the antigen-presenting capacity of dendritic cells and promote the expansion of tumor-reactive CTLs. Antibodies mediate their antitumor effects via antibody-dependent cellular cytotoxicity, activation of the complement system, improving the uptake of coated tumor cells by phagocytes, and the functional interference of biological pathways essential for tumor growth. Consequently, several tumor-associated antigens (TAAs) have been identified that represent promising targets for T cell- or antibody-based immunotherapy. These TAAs comprise proteins preferentially expressed in normal and malignant prostate tissues and molecules which are not predominantly restricted to the prostate, but are overexpressed in various tumor entities including PCa. Clinical trials provide evidence that specific immunotherapeutic strategies using such TAAs represent safe and feasible concepts for the induction of immunological and clinical responses in PCa patients. However, further improvement of the current approaches is required which may be achieved by combining T cell- and/or antibody-based strategies with radio-, hormone-, chemo- or antiangiogenic therapy. Full article