Ipilimumab (Anti-cytotoxic T-lymphocyte Antigen 4 [CTLA-4], MDX-010)
T-cell activation depends on the ability of T-cell receptors to recognise antigenic peptides expressed by APCs, such as dendritic cells. Two receptors, CD28 and CTLA-4, expressed on the surface of T-cells are responsible for ligand recognition and regulation of activation. While ligand binding to CD28 may stimulate T-cells, the interaction between CTLA-4 and the ligand may inhibit stimulation of T-cells . CTLA-4 binds B7.1 and B7.2 (expressed on APC) and mediates negative signalling, which triggers inhibition of T-cell activity
The hypothesis relies on the use of an antibody to prevent interaction between CTLA-4 and its ligands, to enhance the immune response against these antigens. Therefore, blocking CTLA-4 represents a possible mechanism to enhance stimulation of T-cells and consequently boost the response against the tumour cells (Fig. 2).
Ipilimumab is a human anti-CTLA-4 monoclonal antibody. In a phase I trial  of ipilimumab, 14 patients with CRPC (50% had previously received chemotherapy) were treated with a single infusion of 3 mg/kg ipilimumab. Two patients had a PSA decline of ≥50% that lasted 135 and 60 days. Ipilimumab was generally well tolerated, except from one patient who developed grade 3 rash/pruritis requiring systemic corticosteroids. Most common AEs were arthralgia, malaise, bone pain, pallor, back pain, constipation, fatigue, and decreased appetite.
In a phase II study , the combination of ipilimumab with docetaxel was tested. In all, 43 patients were treated with ipilimumab at 3 mg/kg for 4 weeks × 4 doses (23 patients or ipilimumab at the same dose and a single dose of docetaxel 75 mg/m2 on day 1, 20 patients). PSA responses were observed in six patients (three in each group). The most common AEs were fatigue, pruritus, nausea, rash, constipation, and weight loss. In all, there were 52 serious AEs in 18 patients; five of these 52 seroius AEs, reported in three patients, were considered to be related to ipilimumab treatment. These included adrenal insufficiency (one), diarrhoea, colitis and melena (all in one patient), and colitis (one).
A phase I dose-escalation trial  evaluated ipilimumab-GVAX in patients with metastatic CRPC. PSA responses of >50% were seen in seven of 28(25%) patients. The most common AEs were injection-site reactions, fatigue, and pyrexia. Two patients had grade 3 hypophysitis and one patient developed grade 4 sarcoid alveolitis.
Another phase I trial  tested the PROSTVAC-ipilimumab combination and this combination did not seem to exacerbate the immune-related AEs associated with ipilimumab. Grade 3 toxicities included hepatitis, adrenal insufficiency, alveolitis, and hypophysitis. However, the maximum tolerated dose was not determined.
The addition of radiotherapy as a potential immune enhancer to improve clinical responses to ipilimumab has also been reported, in phase I and II trials, to be well tolerated [50, 51]. A randomised double-blind phase III trial comparing ipilimumab vs placebo after radiotherapy in patients with CRPC, who received prior treatment with docetaxel, has just finished the recruitment phase . In most of these studies, immune-related AEs seemed to correlate with anti-tumour activity.
Prostate-specific Membrane Antigen (PSMA) and Antibodies (J5091)
PSMA is a glycoprotein that is expressed on the membrane cell surface of both normal and prostate tumour tissue [53, 54]. It has been reported that PSMA is upregulated after androgen-deprivation therapy .
J591 is a monoclonal antibody that binds to the external domain of PSMA, and has been used combined with radionuclei for therapeutic purposes. After a phase I trial  of lutetium-177-labelled J591 (177Lu-J591) that reported biological activity in four patients with a duration ranging from 3 to 8 months, the same group presented a phase II study  with 30 patients, where 18 (60%) patients had progressed to docetaxel chemotherapy. There was a decline of >50% and 30% in PSA in 10% and 30% of patients, respectively. The most common AE was thrombocytopenia.
A randomised 2:1 double-blind phase II trial  in patients with high-risk CRPC (PSA doubling time of <8 months, and/or PSA level of >20 ng/mL) and rising PSA, is currently ongoing. The primary endpoint is 18-month metastasis-free survival.
In a phase I trial of yttrium-90-labelled J591 (90Y-J591) , there was anti-tumour activity in two patients, who had 85% and 70% PSA declines with a duration of 8 and 8.6 months, respectively. These PSA declines were associated with objective responses. Thrombocytopenia was the dose-limiting toxicity.
Anti-programmed Death 1 (PD-1; MDX-1106/BMS-936558/ONO-4538)
PD-1 is an inhibitory co-receptor expressed on antigen-activated T- and B-cells . MDX-1106, a human monoclonal antibody that blocks PD-1, has been tested in phase I trials. A maximum tolerated dose was not defined. The most common treatment-related AEs were fatigue, rash, diarrhoea, pruritus, and nausea. Drug-related AEs with potential immune-related causes included pneumonitis, vitiligo, colitis, hepatitis, hypophysitis and thyroiditis. There were no responses in the 17 patients with prostate cancer .
Several studies are currently ongoing with all of these drugs in different settings (Table 2).
Table 2. On-going clinical trials of immunotherapy for patients with metastatic castration-resistant prostate cancer
|Agent||Phase||n||Target antigen||Comparison treatment||Primary endpoint||ClinicalTrials.gov Identifier (accessed 19 November 2012)||Status|
|Ipilimumab|| || || || || || || |
|Ipilimumab plus GM-SCF||II||54||CTLA-4||Ipilimumab||PSA response||NCT01530984||Not yet recruiting|
|Ipilimumab plus GVAX||I||28||CTLA-4||–||Safety||NCT01510288||Terminated|
|Ipilimumab plus abiraterone/prednisone||I/II||25||CTLA-4||–||Safety/efficacy||NCT01688492||Recruiting|
|Iplimumab||I/II||66||CTLA-4||–||Safety/efficacy||NCT00323882||Active, not recruiting|
|Ipilimumab plus sargamostim||I||36||CTLA-4||–||Safety||NCT00064129||Active, not recruiting|
|Ipilimumab||III||600||CTLA-4||Placebo||OS||NCT01057810||Active, not recruiting|
|Ipilimumab||II|| ||CTLA-4||Ipilimumab plus docetaxel||Safety/efficacy||NCT00050596||Completed|
|Radiotherapy plus placebo||III||800||CTLA-4||Radiotherapy plus placebo||OS||NCT00861614||Active, not recruiting|
|Ipilimumab plus PROSTVAC||I||30|| ||–||Safety||NCT00113984||Completed|
|PROSTVAC|| || || || || || || |
|PROSTVAC plus docetaxel/prednisone||II||144||PSA||Docetaxel/prednisone||OS||NCT01145508||Active, not recruiting|
|PROSTVAC plus GM-CSF||III||1200||PSA||PROSTVAC plus placebo or placebo plus placebo||OS||NCT01322490||Recruiting|
|Sipuleucel T|| || || || || || || |
|Sipuleucel-T plus abiraterone||II||60||APC8015||–||Safety/efficacy||NCT01487863||Recruting|
|Sipuleucel-T plus Indoximod||II||50||APC8015||Sipuleucel T plus placebo||Safety/efficacy||NCT01560923||Recruting|
|Sipuleucel-T||II||80||APC8015||–||Immune responses||NCT00901342||Active, not recruiting|
|Sipuleucel-T plus DNA vaccine||II||30||APC8015||Sipuleucel-T||Efficacy||NCT01706458||Recruting|
|Sipuleucel-T (differing antigen concentrations)||II||120||APC8015||Sipuleucel-T||Safety/efficacy||NCT00715078||Active, not recruiting|
|Sipuleucel-T plus low-dose cyclophosphamide ± anti PD-1 monoclonal antibodies||II||57|| ||Sipuleucel-T||Safety||NCT01420965||Recruting|
|GVAX|| || || || || || || |
|GVAX plus ipilimumab||I||28||CTLA-4||–||Efficacy||NCT01510288||Terminated|