Combining immunological and androgen-directed approaches: An emerging concept in prostate cancer immunotherapy

Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231, USA.
Current opinion in oncology (Impact Factor: 4.47). 03/2012; 24(3):258-65. DOI: 10.1097/CCO.0b013e32835205a0
Source: PubMed


The autologous antigen-presenting cell immunotherapy, sipuleucel-T, was the first and remains the only US Food and Drug Administration-approved immunotherapy for prostate cancer. In this article, we will summarize recent clinical data on several additional immune-directed strategies, some of which have now entered phase 3 trials.
Multiple studies are now testing sipuleucel-T in different disease settings and/or in combination with conventional and novel hormonal therapies. In addition, a poxviral-based vaccine has shown promise in early-phase clinical studies and has now entered phase 3 testing in men with metastatic prostate cancer. Next, a DNA vaccine has been evaluated in men with biochemically recurrent prostate cancer and has shown early signs of clinical efficacy. Finally, several studies are evaluating the role of immune checkpoint blockade using ipilimumab in pivotal phase 3 trials in prostate cancer patients with advanced disease, as well as in earlier phase studies in combination with androgen ablation.
The abundance of new treatment options for men with advanced prostate cancer will challenge the role of immunotherapy in these patients. Future progress may rely on optimal combination and sequencing of various immunotherapies with androgen-directed approaches as well as with other standard prostate cancer therapies, an effort which is now just beginning.

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    • "A possible explanation is that the immune modulatory effects of ADT augmented the antitumour immune responses initiated by Prostvac-VF. The optimal timing and sequence of Sipuleucel-T with novel hormone therapies such as abiraterone and enzalutamide are currently being investigated in phase II and III clinical trials, with the results being much anticipated [37, 83]. Similarly, the development of PD1 and PDL1 immune checkpoint inhibitors has attracted much interest [63]. "
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    ABSTRACT: The mainstay therapeutic strategy for metastatic castrate-resistant prostate cancer (CRPC) continues to be androgen deprivation therapy usually in combination with chemotherapy or androgen receptor targeting therapy in either sequence, or recently approved novel agents such as Radium 223. However, immunotherapy has also emerged as an option for the treatment of this disease following the approval of sipuleucel-T by the FDA in 2010. Immunotherapy is a rational approach for prostate cancer based on a body of evidence suggesting these cancers are inherently immunogenic and, most importantly, that immunological interventions can induce protective antitumour responses. Various forms of immunotherapy are currently being explored clinically, with the most common being cancer vaccines (dendritic-cell, viral, and whole tumour cell-based) and immune checkpoint inhibition. This review will discuss recent clinical developments of immune-based therapies for prostate cancer that have reached the phase III clinical trial stage. A perspective of how immunotherapy could be best employed within current treatment regimes to achieve most clinical benefits is also provided.
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    • "One apparent drawback of immunotherapy is the fact that other treatment modalities produce measurable tumor response in addition to improving OS. Thus, the maximum clinical benefit of immunotherapies may only be realized when they are combined or sequenced with conventional treatments for prostate cancer, preferably early in the course of disease when both tumor burden and tumor-induced tolerance are minimal.5152 "
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    ABSTRACT: In recent years, immunotherapy has emerged as a viable and attractive strategy for the treatment of prostate cancer. While there are multiple ways to target the immune system, therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in late-stage clinical trials. The landmark Food and Drug Administration approval of sipuleucel-T for asymptomatic or minimally symptomatic metastatic prostate cancer set the stage for ongoing phase III trials with the cancer vaccine PSA-TRICOM and the immune checkpoint inhibitor ipilimumab. A common feature of these immune-based therapies is the appearance of improved overall survival without short-term changes in disease progression. This class effect appears to be due to modulation of tumor growth rate kinetics, in which the activated immune system exerts constant immunologic pressure that slows net tumor growth. Emerging data suggest that the ideal population for clinical trials of cancer vaccines is patients with lower tumor volume and less aggressive disease. Combination strategies that combine immunotherapy with standard therapies have been shown to augment both immune response and clinical benefit.
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    • "Although androgen ablation is typically effective in initially reducing tumor burden, because most prostate tumor cells depend upon androgens to grow and survive, disease inevitably recurs due to the outgrowth of tumor clones in which the androgen receptor signaling axis functions even in the absence of normal androgen levels or in the presence of anti-androgens.184,185 The development of autochthonous prostate tumors in mice induces T-cell tolerance to prostate-specific antigens, but - importantly - androgen ablation diminishes this effect, apparently by reducing tumor mass and hence the quantity of tumor antigen available for presentation by steady-state tolerogenic DCs.64,186 Clinical trials are currently testing the idea that T cell-based prostate cancer therapies may be most effective when administered soon after androgen ablation.187 Androgen ablation may improve the clinical outcome of immune therapy (at least in part) by reducing the number of tumor cells to be eliminated by the immune system. "
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