Ipilimumab and a poxviral vaccine targeting prostate-specific antigen in metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial

Summary

Background

Therapeutic cancer vaccines have shown activity in metastatic castration-resistant prostate cancer (mCRPC), and methods are being assessed to enhance their efficacy. Ipilimumab is an antagonistic monoclonal antibody that binds cytotoxic T-lymphocyte-associated protein 4, an immunomodulatory molecule expressed by activated T cells, and to CD80 on antigen-presenting cells. We aimed to assess the safety and tolerability of ipilimumab in combination with a poxviral-based vaccine targeting prostate-specific antigen (PSA) and containing transgenes for T-cell co-stimulatory molecule expression, including CD80.

Methods

We did a phase 1 dose-escalation trial, with a subsequent expansion phase, to assess the safety and tolerability of escalating doses of ipilimumab in combination with a fixed dose of the PSA-Tricom vaccine. Patients with mCRPC received 2×10⁸ plaque-forming units of recombinant vaccinia PSA-Tricom subcutaneously on day 1 of cycle 1, with subsequent monthly boosts of 1×10⁹ plaque-forming units, starting on day 15. Intravenous ipilimumab was given monthly starting at day 15, in doses of 1, 3, 5, and 10 mg/kg. Our primary goal was to assess the safety of the combination. This study is registered with ClinicalTrials.gov, number NCT00113984.

Findings

We completed enrolment with 30 patients (24 of whom had not been previously treated with chemotherapy) and we did not identify any dose-limiting toxic effects. Grade 1 and 2 vaccination-site reactions were the most common toxic effects: three of 30 patients had grade 1 reactions and 26 had grade 2 reactions. 21 patients had grade 2 or greater immune-related adverse events. Grade 3 or 4 immune-related adverse events included diarrhoea or colitis in four patients and grade 3 rash (two patients), grade 3 raised aminotransferases (two patients), grade 3 endocrine immune-related adverse events (two patients), and grade 4 neutropenia (one patient). Only one of the six patients previously treated with chemotherapy had a PSA decline from baseline. Of the 24 patients who were chemotherapy-naive, 14 (58%) had PSA declines from baseline, of which six were greater than 50%.

Interpretation

The use of a vaccine targeting PSA that also enhances co-stimulation of the immune system did not seem to exacerbate the immune-related adverse events associated with ipilimumab. Randomised trials are needed to further assess clinical outcomes of the combination of ipilimumab and vaccine in mCRPC.

Funding

US National Institutes of Health.

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.