ArticlesIpilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial
Introduction
Until recently, docetaxel with prednisone was the only standard treatment for patients with metastatic castration-resistant prostate cancer (mCRPC). This cancer results in more than 250 000 deaths worldwide each year, highlighting the need for additional treatments.1 However, several additional agents have recently emerged that improve survival in mCRPC.
One such agent, sipuleucel-T (Dendreon, Seattle, WA, USA), is a vaccine based on antigen-presenting cells that has shown an overall survival benefit in two phase 3 trials.2, 3 On the basis of these findings, the US Food and Drug Administration (FDA) approved sipuleucel-T for the treatment of mCRPC.4
Another vaccine that has shown a survival advantage in mCRPC is PSA-Tricom (Prostvac, developed by the US National Cancer Institute [NCI], licensed to BN Immunotherapeutics, Mountain View, CA, USA). This vector-based vaccine, which expresses transgenes for prostate-specific antigen (PSA) and three T-cell co-stimulatory molecules, showed an 8·5 month improvement in overall survival relative to placebo (p=0·006) in a multicentre randomised phase 2 trial.5 In a similar but smaller trial at the NCI, PSA-Tricom was shown to generate an antigen-specific immune response, which was associated with favourable survival outcomes.6 A multicentre phase 3 trial of PSA-Tricom in mCRPC is underway.7
On the basis of these findings, investigations are underway to further augment the immune response generated by these vaccines, with the goal of substantially enhancing clinical outcome. Among the strategies being assessed is combination therapy with agents that inhibit immune checkpoints that serve as the body's natural mediators of immune response. Although cancer vaccines might induce an antigen-specific T-cell response, once activated, T cells upregulate cytotoxic T-lymphocyte-associated protein 4 (CTLA4), a negative regulatory molecule. Preclinical studies in mice have shown that CTLA4 blockade can delay turning off an immune response and increase T-cell avidity, leading to enhanced T-cell-mediated immune responses to the vaccine.8, 9, 10 The key role of CTLA4 in regulating immune response is evident in CTLA4 knockout mice, which cannot modulate immune responses. These animals live only 3–4 weeks before succumbing to massive organ infiltration by unchecked autoreactive T cells.11
Ipilimumab (Bristol-Myers Squibb, New York, NY, USA) is an antagonistic anti-CTLA4 monoclonal antibody that blocks the activity of CTLA4. Ipilimumab has been extensively studied in melanoma and has also been assessed in the treatment of prostate cancer, in which a minority (about 20%) of patients had significant PSA declines.12, 13, 14 A phase 3 randomised trial of ipilimumab in patients with metastatic melanoma showed a significant improvement in overall survival relative to an active control group.15
The PSA-Tricom vaccine is designed to enhance T-cell co-stimulation through enhanced expression of the transgenes of PSA and three T-cell co-stimulatory molecules (CD58, CD80, and ICAM1) on antigen-presenting cells engaging their respective ligands on T cells. CD80 is known to react with CD28 on T cells for positive co-stimulation, and CTLA4 for negative immune checkpoint inhibition. The antagonist monoclonal antibody anti-CTLA4 was designed to interrupt this negative signal and enhance immunity. It is thus unclear how a vaccine such as PSA-Tricom, with its positive co-stimulation, would interact in terms of safety and efficacy with an anti-CTLA4 monoclonal antibody designed to block negative co-stimulatory signals, especially in view of the immune-related adverse events noted in patients receiving anti-CTLA4 alone. Therefore, we designed a study to assess fixed doses of PSA-Tricom with escalating doses of ipilimumab, with the aim of establishing the safety and tolerability of these combined treatments.
Section snippets
Participants
Between August, 2005, and July, 2008, we did a phase 1 trial to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. All patients we enrolled had a histologically confirmed diagnosis of mCRPC. Patients had no bone pain that needed treatment with narcotics and we required them to have a life expectancy greater than 6 months and an Eastern Cooperative Oncology Group performance status of 0–1. We also required patients to
Results
We enrolled 30 patients in four cohorts over the course of our study (table 1). Their baseline characteristics are shown in table 2. We did not record any dose-limiting toxic effects during the period we assessed dose-limiting toxic effects (to 2 weeks after the second infusion of ipilimumab) and thus did not expand any cohort for this reason. Toxic effects for our combination regimen were primarily local grade 1 and 2 injection-site reactions (three patients with grade 1 events, 26 with grade
Discussion
As expected, the range of toxic effects we identified exceeded those in single-agent studies involving PSA-Tricom, where grade 1 or 2 local injection-site reactions were most common.2, 6, 24 However, the proportion of patients affected by grade 3–4 toxic effects in our study (eight [27%] of 30 patients) was similar to previous phase 1 trials involving ipilimumab (panel).25, 26, 27 Our data suggest that the combination of a vaccine that enhances immune co-stimulation with an immune checkpoint
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These authors contributed equally