Prostate Cancer Vaccine Research Articles

Overall survival (OS) analysis of a phase II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer (mCRPC)

5013 Background: Therapeutic poxviral vaccines for prostate cancer are safe with preliminary evidence of clinical benefit in phase I/II studies. PROSTVAC-VF (PV) comprises 2 recombinant viral vectors (Vaccinia and Fowlpox), each encoding transgenes for prostate specific antigen (PSA) and 3 immune costimulatory molecules (B7.1, ICAM-1, and LFA3: TRICOM). PV is administered subcutaneously in a heterologous prime-boost regimen with concurrent low-dose GM-CSF. Methods: 122 patients (pts) were treated in a multi-center, double-blind, RCT of a vaccination series. Pts were randomized 2:1 to PV + GM-CSF vs. placebo empty vector + control saline injections (C). Vaccinia-based vector was used for priming followed by 6 planned Fowlpox-based vector boosts. The trial completed enrollment in July 2005. Eligible pts had metastatic disease, a rising PSA despite castrate testosterone levels, and a Gleason score of ≤7. Pts with a history of prior chemotherapy use, visceral metastasis, or narcotic use were excluded. The 1º endpoint was progression free survival (PFS), with progression defined as 2 new lesions on bone scan or RECIST-defined progression. Vaccination was discontinued after progression. Results: 82 pts received PV and 40 received C. Pt characteristics were similar (means): age (72PV/76C), PSA (134PV/188C), Alk-Phos (142PV/159C), LDH (207PV/218C), Hgb (13PV/13C), and number bone metastatic sites (5.3PV/6.5C). Mean number of vaccinations was 5.4 PV and 5.3 C. PFS was similar in the 2 groups (p = 0.56). However, at 3 years post study, PV patients had a better overall survival than C patients (25 alive, 30%, PV, versus 7 alive, 17%, C) and a longer median survival (24.5 months PV, versus 16 months C); estimated hazard ratio 0.6 (95% CI 0.4–0.9); stratified log rank p = 0.016. Conclusions: In a RCT, PV immunotherapy was associated with an 8.5 month improvement in median OS in men with mCRPC. These data provide evidence of prolonged anti-tumor activity, but need to be confirmed in a larger phase III study. [Table: see text]

Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization

Androgen ablation (AA) causes apoptosis of normal and neoplastic prostate cells. It is a standard treatment for advanced prostate cancer. Androgen ablation-mediated immunological effects include bone marrow hyperplasia, thymic regeneration, T and B cell lymphopoeisis and restoration of age-related peripheral T cell dysfunction. Androgens also regulate the transcription of several cytokines. Dendritic cells (DC) are the most potent antigen presenting cells that can activate antigen-specific naïve T cells. Despite myriad clinical trials involving DC-based prostate cancer immunotherapies, the effects of AA on DC function remain largely uncharacterized. Therefore, we investigated the effects of AA on DC and whether it could improve the efficacy of prostate cancer immunotherapy. Cytokine expression changes due to AA were quantified by multiplex ELISA. Flow cytometry was used to assess AA-mediated effects on DC maturation and expression of costimulatory markers. Mixed leukocyte reactions and cell-mediated lysis assays elucidated the role of androgens in DC function. The effect of AA on the efficacy of vaccination against a prostate tumor-associated antigen was tested using Elispot assays. Androgen ablation increased dendritic cell maturation and costimulatory marker expression, but had no effect on DC costimulatory function. However, DC isolated from castrated mice increased the expression of key cytokines by antigen-experienced T cells while decreasing their expression in naïve cells. Finally, androgen ablation improved immune responses to vaccination only when applied after immunization. Androgen ablation causes differential effects of DC on primary and secondary T cell responses, thus augmenting vaccine immunogenicity only when applied after immunization.

Recent Advances in Cancer Immunotherapy with an Emphasis on Vaccines

Recent Advances in Cancer Immunotherapy with an Emphasis on Vaccines was the first meeting organized by the European Society of Cancer Immunology and Immunotherapy and Progress in Vaccine against Cancer, in collaboration with the Institute of Biological Research and Biotechnology of the National Hellenic Research Foundation, in a joint effort towards the setting up of a new generation of cancer vaccines. The main topics of the meeting included: the role of the tumor microenvironment in protecting the tumor from immune attack; differences in immunotherapy outcome in hematological malignancies versus solid tumors; rationale of multi-epitope vaccines; Treg cell elimination/inactivation, tumor stroma destruction, angiogenesis inhibition and the potentiality of ‘preventive’ vaccination in breast, colon, prostate and ovarian cancer in the early stages and during the ‘wait-and-see’ period. The ninth Progress in Vaccines against Cancer meeting will be held in Sofia, Bulgaria, 8–10 October 2009, at the Hilton Hotel.

Targeted therapy for advanced prostate cancer: Looking through new lenses

Prostate cancer is the most common noncutaneous malignancy in men and also the third leading cause of death due to cancer in males. The conventional initial therapy for localized advanced or metastatic disease is hormone or androgen deprivation therapy. Although hormone-based therapies generally result in rapid responses, the disease then progresses to a phase when they fail to control the malignancy despite castrate testosterone levels. Some patients with castration-resistant prostate cancer continue to respond to secondary hormonal manipulations, and docetaxel-based chemotherapy improves median survival to about 18 months. Prostate cancer is termed hormone-refractory when it no longer responds to hormonal therapy. Currently, other therapeutic options, such as radical prostatectomy, radiation therapy or cryotherapy offer improvement in survival mostly in early stages. New therapy approaches based on a deeper understanding of especially metastatic prostate cancer are of vital importance. Here we discuss up-to-date clinical trials of agents with novel targets and present paradigms in prostate cancer vaccine therapy, metastasis suppressor genes, and some provocative findings on combination therapies of cytotoxic agents, which might provide a platform for developing effective treatment for advanced prostate cancer.

Targeted therapy for advanced prostate cancer: Looking through new lenses

Prostate cancer is the most common noncutaneous malignancy in men and also the third leading cause of death due to cancer in males. The conventional initial therapy for localized advanced or metastatic disease is hormone or androgen deprivation therapy. Although hormone-based therapies generally result in rapid responses, the disease then progresses to a phase when they fail to control the malignancy despite castrate testosterone levels. Some patients with castration-resistant prostate cancer continue to respond to secondary hormonal manipulations, and docetaxel-based chemotherapy improves median survival to about 18 months. Prostate cancer is termed hormone-refractory when it no longer responds to hormonal therapy. Currently, other therapeutic options, such as radical prostatectomy, radiation therapy or cryotherapy offer improvement in survival mostly in early stages. New therapy approaches based on a deeper understanding of especially metastatic prostate cancer are of vital importance. Here we discuss up-to-date clinical trials of agents with novel targets and present paradigms in prostate cancer vaccine therapy, metastasis suppressor genes, and some provocative findings on combination therapies of cytotoxic agents, which might provide a platform for developing effective treatment for advanced prostate cancer.

Dendritic-Cell Vaccination for Prostate Cancer

Vaccination with tumor antigen-loaded dendritic cells has been one of the most frequently applied immunotherapeutic strategies in prostate cancer. Immunological effects have been observed in a majority of patients, while clinical effects have been modest and transient. Advances in the understanding of the interplay between cancer and the immune system have generated new concepts in tumor immunology and immunotherapy that might aid in the improvement of vaccine effectiveness. The combination of immunotherapy with conventional treatment modalities and targeting of immunosuppressive mechanisms has demonstrated improved immunological and clinical results that warrant further investigation.

PTEN Knockout Prostate Cancer as a Model for Experimental Immunotherapy

Testing immunotherapeutic strategies for prostate cancer has been impeded by the lack of relevant tumor models in immunocompetent animals. This opportunity is now provided by the recent development of prostate specific PTEN knockout mice, which show spontaneous development of true adenocarcinoma arising from prostate epithelium and more faithfully recapitulate the human disease than any previous model. We investigated the feasibility of using tumor cells derived from this model to test tumor vaccination and adoptive immunotherapeutic strategies for prostate cancer. PTEN-CaP8 adenocarcinoma cells derived from the biallelic PTEN knockout prostate cancer model were used to vaccinate nontumor bearing litter mates. Tumor specific effector cells were generated from splenocytes of vaccinated mice by mixed lymphocyte-tumor reactions, and antiproliferative effects and cytokine generation were examined in vitro. The effect of vaccination or adoptive immunotherapy on luciferase marked PTEN-CaP8 subcutaneous tumors was monitored by tumor volumetric measurements and noninvasive bioluminescence imaging. Vaccination of litter mate mice with irradiated PTEN-CaP8 cells showed a significant prophylactic effect against the subsequent tumor challenge. Effector cells harvested from vaccinated litter mates showed significant interferon-gamma secretion upon co-incubation with PTEN-CaP8 target cells and they were capable of efficient target cell growth inhibition in vitro. Intratumor adoptive transfer of effector cells resulted in significant growth inhibition of preestablished prostate tumors in vivo. The PTEN knockout model serves as a highly useful model in which to investigate tumor cell vaccination and adoptive immunotherapeutic strategies in the context of true adenocarcinoma of the prostate. This model should accelerate efforts to develop effective immunotherapies for human prostate cancer.

An investigational prostate cancer vaccine [Prostvac]* has demonstrated an "encouraging" improvement in survival

An investigational prostate cancer vaccine [Prostvac]* has demonstrated an "encouraging" improvement in survival

High Intensity Focused Ultrasound (HIFU)-enhanced Autologous in situ Vaccination for Prostate Cancer

High Intensity Focused Ultrasound (HIFU)-enhanced Autologous in situ Vaccination for Prostate Cancer

Melatonin as an adjuvant to therapeutic prostate cancer vaccines

Melatonin as an adjuvant to therapeutic prostate cancer vaccines

Initial treatment with prostate cancer vaccines, rather than hormonal therapy, prior to use of the combination may improve survival

Initial treatment with prostate cancer vaccines, rather than hormonal therapy, prior to use of the combination may improve survival

A prostate cancer vaccine comprising whole cells secreting IL-7, effective against subcutaneous challenge, requires local GM-CSF for intra-prostatic efficacy.

A panel of cytokine-secreting RM-9 prostate cancer cells were tested as whole cell vaccines to determine their capacity to evoke an anti-prostate cancer immune response. In our model, vaccines secreting mGM-CSF or mIL-7 resulted in the highest increase in circulating T lymphocytes after vaccination, prolonged survival and, in a proportion of animals, tumor-free survival. Anti-tumor effects were more evident after a subcutaneous RM-9 challenge than after an intraprostatic challenge. However, when the RM-9/mGM-CSF cell line was used as intraprostatic tumor challenge, protection after RM-9/mIL-7 vaccination was restored.

Paradigm Shifts in Cancer Vaccine Therapy

Cancer vaccines constitute a unique therapeutic modality in that they initiate a dynamic process involving the host's immune response. Consequently, (a) repeated doses (vaccinations) over months may be required before patient clinical benefit is observed and (b) there most likely will be a "dynamic balance" between the induction and maintenance of host immune response elements to the vaccinations vs. host/tumor factors that have the potential to diminish those responses. Thus "patient response" in the form of disease stabilization and prolonged survival may be more appropriate to monitor than strictly adhering to "tumor response" in the form of Response Criteria In Solid Tumors (RECIST) criteria. This can be manifested in the form of enhanced patient benefit to subsequent therapies following vaccine therapy. This article will review these phenomena unique to cancer vaccines with emphasis on prostate cancer vaccines as a prototype for vaccine therapy. The unique features of this modality require the consideration of paradigm shifts both in the way cancer vaccine clinical trials are designed and in the way patient benefit is evaluated.

Therapeutic vaccines for prostate cancer: what have we learned?

Several characteristics of prostate cancer make it an attractive target for immunotherapy. The majority of tumors are relatively indolent, allowing for sufficient time to generate an immune response prior to disease progression. In addition, given the relatively few cytotoxic therapies of proven benefit, a large number of patients with advanced prostate cancer have had limited or no prior chemotherapy that can decrease the ability to mount an immune response. In recent years, numerous preclinical and clinical studies have investigated a variety of approaches to prostate cancer immunotherapy, including the use of vaccines consisting of whole tumor cells, antigen-presenting cells (APCs) and poxvirus-based vaccines. These trials are not only providing initial evidence of clinical efficacy, they are highlighting the importance of end points and patient selection in clinical trial design. This editorial reviews a few promising vaccines for prostate cancer and how clinical trials of these agents alone inform us about immunotherapy clinical trial design for metastatic castrate-resistant prostate cancer (CRPC).

Sipuleucel-T: A Vaccine for Metastatic, Asymptomatic, Androgen-Independent Prostate Cancer

To review the design, efficacy, safety, dosing, therapeutic, and pharmacoeconomic considerations of sipuleucel-T, an investigational, autologous, dendritic, cell-based prostate cancer vaccine. English-language literature searches of MEDLINE (1966-September 2007) and the Cochrane Database (2007, Issue 3) were performed using the terms sipuleucel-T, APC8015, and prostate cancer vaccine. Other data sources were identified from bibliographies of selected articles and from press releases. All published articles or abstracts on human studies of sipuleucel-T for androgen-independent prostate cancer (AIPC) were reviewed for inclusion. Manufacturer Web sites, Food and Drug Administration (FDA) documents, and the clinical trials registry were used to obtain information regarding ongoing clinical trials. AIPC is an incurable disease with a median survival rate of 18-20 months. Docetaxel-based chemotherapy is currently the only FDA-approved treatment for AIPC with a survival benefit (2.4 mo). Sipuleucel-T is a novel active cellular immunotherapy under investigation for the treatment of metastatic, asymptomatic AIPC. In clinical trials, the primary endpoint of time to disease progression was not met; however, an underpowered analysis of data suggests that sipuleucel-T prolongs survival by a median of 4.5 months compared with placebo. Sipuleucel-T has been relatively well tolerated, although a possible increased risk of cerebrovascular events may exist. In May 2007, the FDA did not approve the biologics license application for sipuleucel-T since the primary endpoint of the Phase 3 trials was not met. However, its approval will be reconsidered by the FDA once interim survival results from an ongoing Phase 3 trial, IMPACT, are determined. These data are anticipated to be released in the fourth quarter of 2008. Metastatic AIPC is an incurable disease that currently has limited treatment options. Approval of sipuleucel-T hinges on results from the IMPACT trial. If improved survival is shown, sipuleucel-T may become the first approved active cellular immunotherapy for treating metastatic, asymptomatic AIPC.

Prostate Cancer Vaccines

Standard systemic treatment of prostate cancer today is comprised of antihormonal and cytostatic agents. Vaccine therapy of prostate cancer is principally attractive because of the presence of tumor-associated antigens such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), and others. Most prostate cancer vaccine trials have demonstrated some activation of the immune system, limited clinical success, and few adverse effects.One strategy to overcome the problem of limited clinical success of vaccine therapies in prostate cancer could be strict patient selection. The clinical course of patients with prostate cancer (even in those with PSA relapse following surgery or radiotherapy with curative intention, or those with metastatic disease) can vary significantly. In patients with organ-confined prostate cancer, the most promising immunotherapeutic approach would be an adjuvant therapy following surgery or radiotherapy. Patients with PSA relapse following surgery or radiotherapy could also benefit from immunotherapy because tumor burden is usually low. However, most patients in prostate cancer vaccine trials had metastatic hormone-refractory prostate cancer (HRPC). High tumor burden correlates with immune escape phenomena. Nevertheless, 2 years ago, it was demonstrated, for the first time, that a tumor vaccine can prolong survival compared with placebo in patients with HRPC. This was demonstrated with the vaccine sipuleucel-T (APC-8015; Provenge), a mixture of cells obtained from the patient's peripheral blood by leukapheresis followed by density centrifugation and exposition. The Biologics License Application for this vaccine was denied by the US FDA in mid 2007, however, because the trial had failed to reach the primary endpoint (prolongation of time to tumor progression). Nevertheless, clinical trials with sipuleucel-T are ongoing, and the approach still looks promising. Another interesting approach is a vaccine made from whole tumor cells: GVAX. This vaccine is presently being studied in phase III trials against, and in combination with, docetaxel. The results from these trials will become available in the near future. Besides the precise definition of the disease status of patients with prostate cancer, combinations of vaccine therapy with radiotherapy, chemotherapy, and/or hormonal therapy are approaches that look promising and deserve further investigation.

Cancer immunotherapy based on recombinant Salmonella enterica serovar Typhimurium aroA strains secreting prostate-specific antigen and cholera toxin subunit B

Prostate cancer is the most common malignant tumor in men and is normally associated with increased serum levels of prostate-specific antigen (PSA). Therefore, PSA is one potential target for a prostate cancer vaccine. In this study we analyzed the functionality of new bacterial PSA vaccines, expressed and secreted via the hemolysin (HlyA) secretion system of Escherichia coli, the prototype of Type I secretion systems (T1SS) using an attenuated Salmonella enterica serovar Typhimurium aroA strain as carrier. The data demonstrate that a bacterial live vaccine encompassing T1SS in combination with cholera toxin subunit B can be successfully used for delivery of PSA to induce cytotoxic CD8+ T-cell responses resulting in an efficient prevention of tumor growth in mice.

Enhanced Treatment Effect of Irradiation When Combined With a Tissue Vaccine for Prostate Cancer

Enhanced Treatment Effect of Irradiation When Combined With a Tissue Vaccine for Prostate Cancer

A novel murine model of allogeneic vaccination against prostate cancer.

Prostate cancer continues to be a major cause of death in men. Surgical and medical treatments of the disease have improved, but metastasic disease remains a significant clinical problem. Novel therapies such as whole cell vaccination offer the potential of treating disease by stimulating the immune system. To study the efficacy of a whole cell vaccine in prostate cancer two strains of mice were used: C57BL/6 (H-2Kb) and C3H/HeJ (H-2K(k)) in combination with four different cell lines. Thus, a model was constructed of allogeneic and syngeneic vaccine, as well as a challenge tumour for each strain. Two novel cell lines were developed during this study. Firstly, the non tumourigeneic PMC-1 was derived from a normal mouse prostate and immortalized with HPV16. Secondly, the tumourigeneic PMC-1 C6ras1p1 was transformed with human ras gene which formed tumours in both SCID and C3H/HeJ mice. Protection, and the nature of the immune response to syngeneic and allogeneic vaccine, in males and females was examined in both strains. Vaccination with both syngeneic and allogeneic irradiated whole cell vaccines induced protection from syngeneic challenge in females. However, no protection was observed when allogeneic vaccine was given to male mice. This correlated with the immune response. Two types of cellular immune responses were generated in females. A NK-mediated response was observed in C57BL/6 mice, whilst C3H/HeJ mice developed a CTL response. Little or no cellular immune response was observed in males. The cytokine profile in C3H/HeJ females was a mixture of Th1 and Th2 whilst a mainly Th1 profile was observed in C57BL/6 mice. Male mice showed a diminished cytokine secretion compared to females which was further depressed after challenge. The difference in immunity was largely as expected, since tolerance to prostate antigens should not normally develop in female mice. However, this makes this model particularly relevant clinically since it directly mimics the human situation and thus may accelerate the development of whole cell vaccines for clinical use.

Clinical Safety of a Viral Vector Based Prostate Cancer Vaccine Strategy

The primary objective of this phase I study was to evaluate the clinical safety of a vaccine using recombinant vaccinia virus (prime) and recombinant fowlpox virus (boost) in combination with granulocyte-macrophage colony-stimulating factor in patients with prostate cancer. The vaccines contained transgenes for prostate specific antigen, a triad of co-stimulatory molecules and a tumor antigen whose amino acid sequence had been modified to enhance its immunogenicity. Secondary end points were immunological and clinical responses, changes in prostate specific antigen velocity, and the kinetics of vaccinia virus clearance from the vaccination site, serum, peripheral blood mononuclear cells, urine and saliva. The 15 patients enrolled in this study had metastatic prostate cancer. Patients were given recombinant fowlpox-prostate specific antigen/triad of co-stimulatory molecules alone or recombinant vaccinia-prostate specific antigen/triad of co-stimulatory molecules followed by recombinant fowlpox-prostate specific antigen/triad of co-stimulatory molecules on a prime and boost schedule with or without recombinant-granulocyte-macrophage colony-stimulating factor protein or recombinant fowlpox-granulocyte-macrophage colony-stimulating factor vector. Prostate specific antigen specific immune responses were measured using an enzyme-linked immunosorbent spot assay for interferon-gamma production. Polymerase chain reaction for vaccinia DNA and a plaque assay for live virus were also used. Some grade 2 toxicity was seen in patients who received a higher dose of recombinant fowlpox-granulocyte-macrophage colony-stimulating factor but no toxicity exceeded grade 2. Viable vaccinia was detected after vaccination at the site swab of 1 of 4 patients analyzed. Prostate specific antigen specific immune responses were seen in 4 of 6 patients who were HLA-A2+ and decreases in serum prostate specific antigen velocity were observed in 9 of 15. Based on the safety and preliminary immunogenicity results of this trial we recommend initiating a randomized, phase II study of prostate specific antigen/triad of co-stimulatory molecules vaccines in patients with less advanced prostate cancer.