Immunomodulatory therapies include the treatment with cytokines and monoclonal an-tibodies. Cytokines are small molecules that are secreted to control the immune response.
They can be administered intratumorally or systemically as well as a monotherapy or in combination with another therapy. Clinical trials have been performed to investigate the efficacy of interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in an adjuvant treatment setting. IL-2, one of the most-potent anti-tumor cytokines, was administered in a phase I cinical trial intratumorally using a IL-2 encod-ing DNA.116 The therapy led to a stimulation of the immune system and to a decrease of PSA level in >50 % of patients which could be measured until day 14 after IL-2 in-jection. GM-CSF controls the proliferation and differentiation of myeloid cells and can trigger macrophages and dendritic cells to facilitate anti-tumor action.103 Several stud-ies proofed the efficacy of GM-CSF administration in PCa tumor therapy. In one study patients were treated with subcutaneous injections of GM-CSF resulting in a decline of PSA levels in almost all patients.117 In a phase II cinical trial 24 % of treated patients were disease free for a median of more than five years.118 The overall benefit of GM-CSF administration has to be further investigated.119
Monoclonal antibodies (mAbs) are the second immunomodulating therapy option. They are concerned with the so called immune checkpoint blockade. Two prominent check-point controls, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1), are the aim of recent investigations to evaluate the efficacy
of mAbs in cancer immunotherapy. Especially, CTLA4 has drawn attention in the treat-ment of prostate cancer. In principle, CTLA4 inhibits T-cell activation by antagonizing the co-stimulatory molecule CD28.120–122 It has been suggested that CTLA4 binds with higher affintiy to B7.1 and B7.2 than CD28 thus it dampens the activation of T-cells and is able to facilitate inhibitory signals to T-cells.123–128 It is thought that CTLA4 functions through the inhibtion of helper T cells and the induction of regulatory T cells.121, 129, 130
In 2011 ipilimumab, the monoclonal IgG1 antibody for CTLA4, was FDA approved for the treatment of melanoma. Positive results on the PSA level in patients with hormone-refractory PCa were reveiced with low doses of ipilimumab.131 In total, ten anti-CTLA4 clinical trials were conducted or are still ongoing for the treatment of prostate cancer, whether alone or in combination with cytokines or other conventional therapies.115 Sev-eral issues have to be investigated in the future. Firstly, the proper dose for a mono- or combination therapy has to be determined. Another issue is the time point of treatment for prostate cancer with ipilimumab. An early stage treatment might be more beneficial for the overall survival of patients.115
In the past, it was believed that HER-2/neu, an oncoprotein which is involved in the pro-liferation and differentiation of epithelial cells, could be targeted in advanced PCa. But the clinical trials that were performed showed no convincing results.132–134 Finally, the prostate-specific membrane antigen (PSMA) which is highly expressed in high-grade PCa, was the target of studies using a PSMA-specific monoclonal antibody coupled to radioisotopes for the targeted killing of prostate cancer cells. As the clinical trials showed no significant outcome,135, 136 it was suggested to treat PCa in an earlier stage thus leading to a better anti-tumor response.
Antigen-targeted immunotherapies are thought to induce an immune response against an antigen that is specific for a certain tumor. In case of PCa targeted immunotherapies against PSA, prostatic acid phosphatase (PAP), PSMA and against whole-tumor cell lysates have been investigated.
Sipuleucel-T is a dendritic cell-based immunotherapy that defines the treatment with autologous peripheral blood mononuclear cells which are cultured and pulsed with a
fusion protein consisting of PAP and GM-CSFex vivo. Finally, the cells are re-injected into the patients. It is believed that the monocytes differentiate into professional antigen presenting cells and stimulate PAP-specific CD4+and CD8+T-cells. The T-cells are acti-vated and mediate an anti-tumor response. In 2010, Sipuleucel-T was approved by the FDA. Several clinical trials of phase III were conducted and revealed that the median survival benefit was over four months. PSA responses were not observed, but PAP-specific T-cells responses could be measured (73 % versus 12.1 %).137–139 Other dendritic cell-based immunotherapies feature the co-culturing with peptides, tumor lysates or with messenger RNA.103
Recombinant viral vectors are an attractive therapy option for the treatment of PCa.
They have the advantage of being easily generated and of carrying large amounts of highly immunogenic genetic material. Poxviruses, i.e. vaccinia virus, were widely used in the eradication of small pox.140 Once the poxvirus is injected, it infects epithelial cells resulting in the apoptosis of some of these cells. Apoptotic bodies are taken up by professional antigen presenting cells which will present antigens to CD4+and CD8+ T-cells that derived from the virus. It is also possible that APCs are directly infected with poxviruses thus priming an immune response. But using poxviruses as an immunother-apy features also a disadvantage. Due to fact that the strong antibody response against viral proteins which can outcompete an immune response against the encoded antigens, a homologous prime-boost regimens will be rather ineffective.141 ProstVac-VF is a re-combinant viral vector immunotherapy that tries to circumvent this disadvantage. In a heterologous prime-boost regimen a PSA-expressing vaccinia virus is used during the prime and a PSA-expressing fowlpox virus is injected in the boost immunization.142, 143 To date, seven randomized phase II trials were performed of which three trials were conducted as a combination therapy (for an overview, see144). The results obtained from these trials were indifferent. A decline in PSA levels were infrequent through out all studies. An antibody response could not be detected, but an increase in vaccine-specific T-cells was seen in all trials. One double-blinded, randomized phase II study showed promising results. In this Prost-Vac-VF study a median survival benefit of 8.5 months
could be observed.145
It is also possible to use prostate tumor lysates as a so called whole cell-based vaccine for the treatment of PCa. The major advantages of tumor lysates are that allogenetic cancer cell lines can be expanded in large amounts thus reducing the therapy costs. GVAX is a whole cell-based vaccine consisting of two allogeneic prostate cancer cells lines (LNCaP and PC-3) that are adenoviraly transfected with GM-CSF and after irradiation injected into the patient.146 GM-CSF should promote the differentiation of APCs thus triggering the activation of T-cells. Two GVAX studies (VITAL-1 and VITAL-2) were conducted and both were terminated prematurely. The primary goal of both trials was an improvement in survival. VITAL-1 was terminated, as a preliminary analysis showed that the chance of reaching the primary goal was less than 30 %.144, 147 Also VITAL-2 was terminated early, as an increase in deaths was observed in the doxetacel/GVAX group.144, 148 As a benefit of the GVAX therapy could not be observed, the future development of GVAX is unclear.
As the prostate expresses tissue specific antigens, i.e. PSMA and PSA, peptides from these proteins can be identified and used in peptide-based vaccines. The advantage of this vaccine type is the low production costs. The use of overlapping peptides that are recognized by the patient’s T-cells allows to include multiple CTL epitopes. One phase II clinical trial was conducted using peptides derived from PSA, PSMA, PAP and other epithelial tumor antigens.149 An increase in IgG and CTL responses could be observed, but only 21 % of patients showed a decrease in PSA levels of>50 %.