Prostate Cancer Vaccine Research Articles

Approval of Provenge Seen As First Step for Cancer Treatment Vaccines

Adecade in development, Dendreon’s prostate cancer vaccine, sipuleucelT (Provenge), has become the first therapeutic cancer vaccine to receive approval from the U.S. Food and Drug Administration. The FDA approved Provenge in April to treat metastatic castration (hormone)-resistant prostate cancer. In the phase III trial, known as IMPACT, patients taking Provenge had a 4.1-month median improvement in overall survival. Although 4 months is a modest increase, some view Provenge’s approval as a milestone for the entire class of immunotherapeutic cancer vaccines. “Provenge’s approval is a watershed,” said

Poxviral-Based Prostate-Specific Antigen Vaccine in Prostate Cancer

TO THE EDITOR: In the March 1, 2010, issue of Journal of Clinical Oncology, Kantoff et al reported the results of a phase II randomized trial of a poxviral-based prostate-specific antigen vaccine (PROSTVAC) in metastatic castration-resistant prostate cancer. Eighty-two patients received PROSTVAC and 40 received control vectors. The primary end point was progression-free survival, which was similar in both groups (hazard ratio, 0.884; 95% CI, 0.568 to 1.375; P .6), but overall survival (OS) favored PROSTVAC arm (25.1 v 16.6 months). The authors conclude that PROSTVAC immunotherapy is associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS. Although these data merit further exploration, we have concerns about whether both study arms are comparable. First, the difference in median age (71.6 v 79 years), percentage of lymph node involvement only (9.8% v 0%), and median survival estimated by Halabi nomogram may favor the PROSTVAC arm. Second, as Kantoff et al point out, the lack of treatment data after initial progression limits the interpretation of the survival result. PROSTVAC plus subsequent treatment improved in 3 months the survival predicted by Halabi. In the control arm, OS is reduced by 4 months as estimated by the Halabi nomogram. Half of the patients in the control arm received PROSTVAC as second-line treatment. An interesting question is whether a higher percentage of patients in the PROSTVAC arm received second-line docetaxel, obtaining a benefit in survival. Third, Kantoff et al mentioned that only docetaxel has been shown to affect survival in metastatic prostate cancer, by approximately 3 months. In the TAX 327 study, an OS of 19.2 months was reported in the every-3-weeks docetaxel arm. Nevertheless, patients included in the TAX 327 had an disfavorable prognosis when compared with the PROSTVAC study. Patients in TAX 327 were more symptomatic with a higher median prostate-specific antigen, Eastern Cooperative Oncology Group performance status of 2 was permitted, and 30% of patients had a Gleason score of 8 to 10. In a retrospective subanalysis of 110 minimally symptomatic patients, Berthold et al reported an OS of 28.4, 25.9, and 22 months for docetaxel every 3 weeks, docetaxel every week, or mitoxantrone, respectively. These differences did not reach statistical significance as a result of the small number of patients, and the results should be interpreted with caution. These data suggest than docetaxel should offer similar results to PROSTVAC in this population and should be the control arm in a phase III study. We agree with Kantoff et al that their findings are regarded as hypothesis generating, but OS data should be interpreted with caution in the absence of treatment information after progression to PROSTVAC or placebo.

Adenovirus-PSA vaccination in recurrent and castration-resistant prostate cancer: Phase II trial interim results.

e15070 Background: Our prior phase I adenovirus/PSA vaccine trial in patients with advanced CRPC showed the safety of this approach. We are currently conducting two phase II trials for patients with rising PSA after local therapy and for patients with CRPC and small amount of disease bulk to determine toxicity, immune response, and outcomes. Methods: In Protocol #1 men with rising PSA after local therapy and negative bone scan and CT are randomized to vaccine alone at days 0, 30, and 60 or vaccine 14 days after the initiation of androgen deprivation therapy (ADT). In Protocol #2 men with CRPC and negative bone scan (or positive bone scan with slow PSADT and PSA < 10) receive the vaccine using the same 3 injections schedule. Each injection consists of 10E8 pfu of the Ad/PSA vaccine suspended in a collagen matrix. Results: To date 20 patients have been enrolled in both protocols and have been followed a median of 10.5 months. The median age is 70 years, and median enrollment PSA levels are 1.45 ng/mL in Protocol #1 and 8.70 ng/mL in Protocol #2. Median duration of follow-up at this time is 10.5 months. Preliminary results show that 77% of the patients in both protocols demonstrated anti-PSA T cell responses (by Ellispot) above preinjection levels and 72% of patients demonstrated an increase in PSA doubling time (100% of patients in protocol # 1 and 62% of patients in protocol # 2). No grade 3 or 4 toxicities have been seen to date. Progression-free and overall survival data is premature at this time, with one patient deceased from disease progression in the CRPC trial to date. Conclusions: Early results from the first fifteen patients demonstrate the induction of anti-PSA T cells responses in a high percentage of the vaccinated patients and increase in PSADT in more than half of the patients. No serious vaccine-related toxicities have been identified. No significant financial relationships to disclose.

812. Bacterial Vector Mediated Vaccination for Prostate Cancer

812. Bacterial Vector Mediated Vaccination for Prostate Cancer

Abstract 4750: Clinical and Immune Data From an Ongoing Phase II Trial of an Adenovirus/PSA Vaccine for Prostate Cancer

Abstract Introduction and Objectives: Our Phase I adenovirus/PSA vaccine trial has proved that this vaccine is safe. We are conducting a Phase II clinical trial with two separate protocols for patients with recurrent or hormone refractory prostate cancer assessing toxicity, immune responses, and changes in PSA levels. Methods: In Protocol #1 men with recurrent prostate cancer following definitive initial treatment for their disease were placed in one of two arms: Arm A; men receive the vaccine alone at days 0, 30, and 60; Arm B; men receive the vaccine 14 days after the initiation of androgen deprivation therapy (ADT). In Protocol #2 men with hormone refractory disease receive the vaccine alone using the same 3 injection schedule. Each injection consists of 108 pfu of the Ad/PSA vaccine suspended in a collagen matrix. All patients return at regular intervals for physical, chemical, radiologic, and immunologic evaluations. Results: To date fifteen patients have been enrolled and have been followed a median of 10.5 months. The patients have a median age of 70 years, and median enrollment PSA levels of 1.67 ng/ml in Protocol #1 and 8.70 ng/ml in Protocol #2. In our preliminary results at this early stage of the trial, seventy seven percent of the patients in both protocols demonstrated anti-PSA T cell responses above preinjection levels. Sixty four percent of the patients demonstrated an increase in PSA doubling time (PSADT). Conclusions: In an attempt to follow up on the success of our Phase I clinical trial of the Ad/PSA vaccine we have initiated a Phase II trial to investigate the therapeutic efficacy of the vaccine in men with recurrent prostate cancer, either following definitive therapy prior to other treatments or hormone refractory. Early results from the first fifteen patients demonstrate the induction of anti-PSA T cells responses in a high percentage of the vaccinated patients and increase in PSADT in more than half of the patients. No serious vaccine-related toxicities have been identified in the patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4750.

Abstract LB-80: Correlation of serum cytokines with clinical responses in patients treated with BPX-101, a novel dendritic cell vaccine for metastatic castration resistant prostate cancer (mCRPC)

Abstract Background: We report interim clinical and immune monitoring results for the low dose cohort of patients enrolled in an ongoing Phase I/IIa clinical trial of BPX-101, a novel, autologous dendritic cell (DC) vaccine for mCRPC based on AP1903-inducible, iCD40-expressing DCs. Methods: Men with progressive mCRPC were enrolled in a 3+3 dose escalation Phase I/IIa trial evaluating BPX-101 and AP1903. BPX-101 is produced from a single leukapheresis procedure by elutriation, differentiation of monocytes into DCs, transduction with Ad5f35-inducible human (ih)-CD40, antigen loading with a form of Prostate Specific Membrane Antigen (PSMA), and pre-activation with lipopolysaccharide and activating agent, AP1903. BPX-101 was administered intradermally every 2 weeks for 6 doses. AP1903 (0.4 mg/kg) was infused 24 hours after each BPX-101 dose. Blood samples were collected weekly, cryopreserved and batched for immune monitoring assays after completion of the first 12-weeks of therapy. IL-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IL-12, GMCSF, TNFα, IFNγ, IP-10, MCP-1, MIP-1α, MIP-1ß, and RANTES levels were evaluated, using a LINCOplex Immunoassay Panel. Results: Of six subjects enrolled to date, three patients enrolled in the low dose cohort (4 × 106 cells) have completed at least 12 weeks of therapy (median 23, range 22-27), and all remain on study with objective stable disease. No unexpected drug-related adverse events have been observed in any patient to date. Changes in levels of MCP-1, MIP-1α, MIP- 1ß, and RANTES tracked closely for all three low dose-cohort subjects. In one subject who experienced a 46% PSA decline after 8 weeks and a 20% measurable metastatic disease reduction per RECIST 1.1 after 12 weeks of therapy, MCP-1 levels spiked 17.5-, 17.2-, 4.2- and 6.8-fold over baseline levels one week after vaccinations #1, 2, 3 and 5 respectively, and returned to within 8-30% of baseline levels the following week. In this same patient, IFNγ and GM-CSF levels followed a similar pattern; GM-CSF spiked from undetectable baseline levels to 22.0, 16.2, 9.9, and 11.7 pg/ml one week after vaccinations #1, 2, 3 and 5 respectively, and returned to undetectable levels the following week. In a second patient, who experienced a 6% PSA decline after 12 weeks of therapy, GM-CSF levels spiked from undetectable levels to 63.2 pg/mL at week 5, returning to undetectable levels over the next 7 weeks. Serum IL-6 levels for the low dose cohort fell from a mean of 9.3 pg/mL at baseline (med 5.2, range 4-18.8), to a mean of 1.6 pg/mL (med 1.2, range 1.0-2.6) at 6 weeks and a mean of 0.6 pg/mL (med 0.09, range 0-1.8) at 12 weeks. Conclusions: In two of three subjects completing 12 weeks of therapy at the lowest dose, dramatic spikes in serum inflammatory cytokine levels correlated with PSA declines in both and measurable disease decline in one. Serum IL-6 levels, which may have prognostic value in patients with mCRPC, fell significantly (65-99%) in all three subjects. By the end of March, 2010, three patients in the mid-dose cohort (12.5 × 106 cells) will have completed 12 weeks of therapy, and enrollment of up to six patients in the high dose cohort (25 × 106 cells) will have begun. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-80.

Abstract 2934: Increased type-2 T cell rates and coincidence of Th17 spikes with autoimmune events and PSA declines upon combined prostate GVAX and anti-CTLA4 immunotherapy

Abstract The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic, hormone-refractory prostate cancer (mHRPC). All patients received a 500 million cell priming dose of GVAX on day 1 followed by bi-weekly intradermal treatments of 300 million cells over a 24-week period. Ipilimumab was administered every 4 wks from day 1 during the same period. Initially, 12 patients were enrolled in cohorts of 3 and each cohort was assigned an escalating dose of Ipilimumab at 0.3, 1, 3 or 5 mg/kg. 16 additional patients were enrolled in the expansion cohort of 3 mg/kg Ipilimumab. Results showed that the GVAX and Ipilimumab combination was active in mHRPC patients. PSA declines of more than 50% (Partial Response, PR) were observed in 5 of 22 patients in the 3-5 mg/kg Ipilimumab doses, and were associated with Autoimmune Breakthrough Events (ABE), including Grade 2 or 3 hypophysitis and Grade 3 alveolitis. PSA stabilizations (Stable Disease, SD) were observed in 1/3 pts in lower (0.3 and 1 mg/kg), and in 7 of 22 in the higher (3-5 mg/kg) dose levels. In this study, cytokine profiles of peripheral blood-derived T cells were determined ex vivo and after in vitro stimulation with PMA and ionomycin by intracellular staining for IL-2, −4, −5, −10, TNF-α, IFN-γ and IL-17A. Of these cytokines, only IL-4 was detectable ex vivo in CD4+ and CD8+ T cells; post-treatment increases were detectable in the higher (3-5 mg/kg) but not in the lower (0.3-1 mg/kg) Ipilimumab dose levels. After PMA/ionomycin stimulation, no consistent changes were observed in the frequencies of IFN-γ, IL-2 and TNF-α-producing type-1 T cells compared to pre-treatment values. In contrast, significantly increased rates of IL-4 and IL-5 producing CD4+ and CD8+ T cells were found upon treatment (visit 1 versus visit 5) at higher (3-5 mg/kg) Ipilimumab dose levels. Overall these data clearly demonstrate a shift in favor of a Type-2 cytokine profile due to the GVAX/Ipilimumab administration. The frequencies of IL-17A producing CD4+ T (Th17) cells increased over the course of treatment in 5 of 18 patients. Of note, in 3 (PR) out of 5 of these patients this increase of the Th17 subset coincided with onset of hypophysitis and/or adrenal insufficiencies, as well as the onset of PSA decline. The two patients with increased Th17 rates without these pituitary or adrenal-related ABE showed SD. In summary, our results show that combined GVAX/Ipilimumab administration gives rise to Type-2/Th17 cytokine profiles in mHRPC patients, but that only increases in Th17 show a relation to ABE and PSA responses. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2934.

Abstract 5588: T cell activation in relation to clinical responsiveness in patients with metastatic hormone-refractory prostate cancer receiving combined Prostate GVAX and anti-CTLA4 immunotherapy

Abstract The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic, hormone-refractory prostate cancer (mHRPC). Patients received a 500 million cell GVAX priming dose on day 1 followed by 12 bi-weekly intradermal administrations of 300 million cells, while Ipilimumab was administered every 4 wks from day 1 for a total of 6 times. Initially, 12 patients were enrolled in cohorts of 3 and each cohort was assigned an escalating dose of Ipilimumab at 0.3, 1, 3 or 5 mg/kg. 16 additional patients were enrolled in the expansion cohort of 3 mg/kg Ipilimumab. Results showed that the GVAX and Ipilimumab combination was clinically active in mHRPC patients. PSA declines of more than 50% (Partial Response, PR) were observed in 5 of 22 patients in the 3-5 mg/kg Ipilimumab doses and PSA stabilizations (Stable Disease, SD) were observed in 1/3 pts in lower (0.3 and 1 mg/kg), and in 7/22 in the higher (3-5 mg/kg) dose levels. Phenotypic and functional (anti-tumor) effector T cell activation was monitored to identify changes that might predict or correlate with clinical efficacy. Most notably, pronounced and significant increases in frequencies of activated and effector CD4+ and CD8+ T cells were observed by HLA-DR and ICOS expression upon administration of high (3 and 5 mg/kg) but not of low (0.3 and 1 mg/kg) Ipilimumab doses. We also observed a significant increase of CTLA4 and PD-1 expression on CD4+ T cells compared to pre-treatment values in the 3 mg/kg Ipilimumab-administered patients. The latter might be indicative of the induction of concomitant negative feedback signaling. As an indiciation of Tumor-Associated Antigen (TAA) specific responsiveness we tested HLA-Tetramer (Tm) reactivity to NY-ESO and PSMA in HLA-A2 or -A3 positive patients. For NY-ESO, GVAX/Ipi-induced increased seroreactivity (by Western Blot or ELISA) was observed in 6/28 patients. Of these 6 patients, three could be tested for Tm reactivity and in two (1SD, 1 Progressive Disease, PD) increased NY-ESO157 rates were found concomitant with increasing serum Ab levels, whereas no Tm reactivity was detected in 8 patients without seroconversions. Whereas PSMA seroconversions were observed in a total of 12/28 patients (and of note, in 4/5 PR), no Tm positivity at any time was found in a total of 15 patients tested. Further functional Treg and CTL analyses are ongoing. So far, only early HLA-DR upregulation on CD4+ or CD8+ T cells (visit 1 versus visit 3) showed any value for response prediction, since it was observed to significant levels in patients with PR or SD, but not in patients with PD. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5588.

Abstract B20: Immune vs. clinical response monitoring in patients with metastatic hormone-refractory prostate cancer receiving combined prostate GVAX and anti-CTLA4 immunotherapy

Abstract The effects of a GM-CSF-secreting allogeneic prostate cancer vaccine (Prostate GVAX) and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with metastatic, hormone-refractory prostate cancer (mHRPC). Patients received a 500 million cell GVAX priming dose on day 1 followed by 12 bi-weekly intradermal administrations of 300 million cells, while Ipilimumab was administered every 4 wks from day 1 for a total of 6 times. Initially, 12 patients were enrolled in cohorts of 3 and each cohort was assigned an escalating dose of Ipilimumab at 0.3, 1, 3 or 5 mg/kg. 16 additional patients were enrolled in the expansion cohort of 3 mg/kg Ipilimumab. Results showed that the GVAX and Ipilimumab combination was clinically active in mHRPC patients. PSA declines of more than 50% (Partial Response, PR) were observed in 5 of 22 patients in the 3–5 mg/kg Ipilimumab dose cohorts, and were associated with Autoimmune Breakthrough Events (ABE), including Grade 2 or 3 hypophysitis and Grade 3 alveolitis. PSA stabilizations (Stable Disease, SD) were observed in 1/3 patients in lower (0.3 and 1 mg/kg), and in 7 of 22 in the higher (3–5 mg/kg) dose levels. Moreover, regressing bone and lymph node metastases were observed in 2/5 PR patients. Immune response monitoring was performed to identify changes that might predict or correlate with clinical efficacy. Most notably, pronounced and significant increases in frequencies of activated and effector CD4+ and CD8+ T cells were observed by HLA-DR and ICOS expression upon administration of high (3 and 5 mg/kg) Ipilimumab doses; a relation to clinical behaviour was only observed for HLA-DR with earlier and more pronounced increases in patients with PR or SD. As an indication of tumor-specific responsiveness HLA-Tetramer (Tm) and seroreactivity to NY-ESO and PSMA were tested. For NY-ESO, therapy-induced increased seroreactivity (by Western Blot or ELISA) was observed in 6/28 patients. Of these 6 patients, three could be tested for Tm reactivity and in two (1SD, 1 Progressive Disease, PD) increased NY-ESO157 rates were found concomitant with increasing serum Ab levels, whereas no Tm reactivity was detected in 8 patients without seroconversions. PSMA seroconversions were observed in a total of 12/28 patients (and, of note, in 4/5 PR), but no Tm positivity at any time was found in a total of 15 patients tested. In the 3–5 mg/kg dose levels (n=22), PSMA seroconversion was associated with increased overall survival (P=0.062). In addition, combined GVAX/Ipilimumab administration was found to induce Type-2/Th17 profiles, as determined ex vivo by intracellular staining of peripheral T cells. Significantly increased levels of IL-4 in both CD4+ and CD8+ T cells were observed in patients with PR or SD (P&amp;lt;0.05), but not in patients with PD, while Th17 spikes in 3/5 patients coincided with ABE and PSA responses. In summary, our analyses so far reveal a relationship between clinical efficacy, PSMA seroconversion, and generalized T cell activation accompanied by Th2 and Th17 skewing. Together these data point to a mechanism of action whereby combined Prostate GVAX and anti-CTLA4 immunotherapy can induce both Th2/humoral and Th17/cell-mediated immune responses, resulting in tumor destruction and collateral autoimmunity. Supported by the Prostate Cancer Foundation and the Dutch Cancer Society (KWF-VU 2006-3697) Citation Information: Clin Cancer Res 2010;16(7 Suppl):B20

Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer

Therapeutic prostate-specific antigen (PSA) -targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study. In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections. Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061. PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study.

Combining low-dose cyclophosphamide with GM-CSF–secreting prostate cancer immunotherapy enhances antitumor immune effects

Prostate GVAX® is an allogeneic cell-based prostate cancer vaccine engineered to secrete GM-CSF. The release of GM-CSF by this immunotherapy serves to recruit dendritic cells, which then present tumor antigens to T cells, thus initiating antitumor immune responses. However, preclinical data show that, when used alone, cell-based immunotherapy is generally unable to break specific T-cell tolerance in tumor-bearing hosts. The study by Wada and colleagues employed an autochthonous prostate cancer mouse model to demonstrate that low-dose cyclophosphamide given prior to a cell-based GM-CSF–secreting vaccine (T-GVAX) abrogated immune tolerance, augmented prostatic CD8+ T-cell infiltration, mediated depletion of regulatory T cells (Tregs), and increased expression of dendritic cell maturation markers. In addition, this combination decreased the wet weight of mouse prostate glands, lowered histological tumor scores, and increased the density of apoptotic bodies. These findings add to existing data from other preclinical models showing enhancement of antitumor immunity when cyclophosphamide is administered in sequence with GM-CSF–secreting immunotherapy for the treatment of breast and pancreatic cancers. These studies provide a rationale for designing clinical trials that combine low-dose cyclophosphamide with GM-CSF–secreting cell-based immunotherapy in patients with prostate and other cancers.

Multidimensional glycan arrays for enhanced antibody profiling.

Carbohydrate-binding antibodies play a critical role in basic and clinical research. Monoclonal antibodies that bind glycans are used to measure carbohydrate expression, and serum antibodies to glycans can be important elements of the immune response to pathogens and vaccines. Carbohydrate antigen arrays, or glycan arrays, have emerged as powerful tools for the high-throughput analysis of carbohydrate-protein interactions. Our group has focused on the development and application of neoglycoprotein arrays, a unique array format wherein carbohydrates are covalently attached to a carrier protein prior to immobilization on the surface. The neoglycoprotein format permits variations of glycan structure, glycan density, and neoglycoprotein density on a single array. The focus of this study was on the effects of neoglycoprotein density on antibody binding. First, we evaluated binding of five monoclonal antibodies (81FR2.2, HE-195, HE-193, B480, and Z2A) to the blood group A antigen and found that neoglycoprotein density had a substantial effect on recognition. Next, we profiled serum antibodies in 15 healthy individuals and showed that inclusion of multiple neoglycoprotein densities helps distinguish different subpopulations of antibodies. Finally, we evaluated immune responses induced by a prostate cancer vaccine and showed that variations in neoglycoprotein density enable one to detect antibody responses that could not be detected otherwise. Neoglycoprotein density is a useful element of diversity for evaluating antibody recognition and, when combined with variations in glycan structure and glycan density, provides multidimensional glycan arrays with enhanced performance for monoclonal antibody development, biomarker discovery, and vaccine optimization.

The application of exosomes as a nanoscale cancer vaccine

Cancer is a leading cause of death globally, and it is predicted and projected to continue rising as life expectancy increases. Although patient survival rates for some forms of cancers are high due to clinical advances in treatment protocols, the search for effective cancer vaccines remains the ultimate Rosetta Stone in oncology. Cervarix®, Gardasil®, and hepatitis B vaccines are currently employed in preventing certain forms of viral cancers. However, they are, strictly speaking, not ‘true’ cancer vaccines as they are prophylactic rather than therapeutic, are only effective against the oncogenic viruses, and do not kill the actual cancer cells. On April 2010, a new prostate cancer vaccine Provenge® (sipuleucel-T) was approved by the US FDA, and it is the first approved therapeutic vaccine that utilizes antigen-presenting cell technology involving dendritic cells in cancer immunotherapy. Recent evidence suggests that the use of nanoscale particles like exosomes in immunotherapy could form a viable basis for the development of novel cancer vaccines, via antigen-presenting cell technology, to prime the immune system to recognize and kill cancer cells. Coupled with nanotechnology, engineered exosomes are emerging as new and novel avenues for cancer vaccine development. Here, we review the current knowledge pertaining to exosome technology in immunotherapy and also seek to address the challenges and future directions associated with it, in hopes of bringing this exciting application a step closer toward an effective clinical reality.

Current Perspectives in Prostate Cancer Vaccines

The use of vaccines as a potential therapeutic modality for the treatment of cancer has been extensively studied. Recent advances include identification and characterization of tumor-associated antigens, novel vaccine delivery systems, and the combination of vaccines with immune stimulants and other therapeutic modalities. Immunotherapy as a modality for treatment of prostate cancer has received significant attention. There are several characteristics of prostate cancer that make it an ideal target for immunotherapy. Prostate cancer's relative indolence allows sufficient time to generate immune responses, which may take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal vital tissue. This review focuses on promising new vaccines and novel perspectives in the treatment of prostate cancer.

Phase I Clinical Trial of an Adenovirus/Prostate-Specific Antigen Vaccine for Prostate Cancer: Safety and Immunologic Results

We performed a phase I clinical trial of adenovirus/prostate-specific antigen (PSA) vaccine in men with measurable metastatic hormone-refractory disease. Men with measurable metastatic disease received one vaccine injection. Toxicity, immune responses, changes in PSA doubling times, and patient survival were assessed. Thirty-two patients with hormone-refractory metastatic prostate cancer were treated with a single s.c. vaccine injection at one of three dose levels, either as an aqueous solution or suspended in a Gelfoam matrix. All patients returned for physical and clinical chemistry examinations at regular intervals up to 12 months after injections. The vaccine was deemed safe at all doses in both administration forms. There were no serious vaccine-related adverse events; the most prevalent were localized erythema/ecchymoses and cold/flu-like symptoms. Anti-PSA antibodies were produced by 34% of patients and anti-PSA T-cell responses were produced by 68%. PSA doubling time was increased in 48%, whereas 55% survived longer than predicted by the Halabi nomogram. The adenovirus/PSA vaccine was proven safe with no serious vaccine-related adverse events. The majority of vaccinated patients produced anti-PSA T-cell responses and over half survived longer than predicted by nomogram. Although the latter data are only derived from a small number of patients in this phase I trial, they are encouraging enough to pursue further studies.

Therapeutic vaccines in metastatic castration-resistant prostate cancer: principles in clinical trial design

Although docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer in 2004, additional therapies are still required. Prostate cancer is often slow-growing and expresses many tumor-associated antigens, making it a feasible target for immunotherapy. Several therapeutic cancer vaccines have been developed for prostate cancer, including antigen-presenting-cell-based, vector-based, and whole tumor cell vaccines. Initial trials demonstrated that vaccine approaches have limited toxicity. Clinical trials of targeted biologic therapies have demonstrated that patient selection is vital, and there is preliminary evidence that clinical parameters can be used to encompass metastatic prostate cancer patients who will more probably respond to vaccine treatment. In addition to appropriate patient selection, a successful clinical trial must have an appropriate primary endpoint as well. Three randomized, ‘placebo’-controlled studies in metastatic castration-resistant prostate cancer have suggested a clinically significant survival advantage in spite of a lack of improvement in time to progression, implying that overall survival is the ideal endpoint for such trials. Careful examination of data from completed immunotherapy clinical trials in prostate cancer has identified appropriate patient populations and endpoints. Those principles need to be applied to future trial design to properly evaluate prostate cancer vaccines.

Adoptive immunotherapy with CTL induced by PSA-pulsed dendritic cell vaccine for prostate cancer in mice

Objective:To observe the anti-tumor effect of adoptive immunotherapy with CTL induced by PSA-pulsed dendritic cell vaccine against prostate cancer in mice.Methods:Nude mice were s.c.inoculated with LNCaP tumor cells to establish prostate cancer model.CTL induced in vitro by different peptide-pulsed dendritic cells(Non-DC,Ova-DC,Lys-DC and PSA-DC) were used for adoptive immunotherapy of experiment nude model through vena caudalis on d 15 and d 22 after inoculation.The survival of nude mice and the sizes of tumors were observed with d 50 after the initial treatment as the endpoint.Results:The tumor sizes in Non-DC,Ova-DC,Lys-DC and PSA-DC groups on d 30 and d 50 after adoptive immunotherapy were significantly larger than that at d 15 after inoculation(P0.01).The tumors sizes in Lys-DC and PSA-DC groups were significantly smaller than those in the Non-DC and Ova-DC groups(P0.01).The survival periods of animals in Lys-DC and PSA-DC groups were significantly longer than those in the Non-DC and Ova-DC groups(P0.01).Conclusion:Adoptive immunotherapy with CTL induced by DC-based PSA vaccine can inhibit the growth of prostate cancer LNCaP cells in nude mice and increase the survival of the animals.

Prostvac-VF: a vector-based vaccine targeting PSA in prostate cancer

Prostvac is a prostate cancer vaccine regimen consisting of a recombinant vaccinia vector as a primary vaccination, followed by multiple booster vaccinations employing a recombinant fowlpox vector. Both vectors contain the transgenes for prostate-specific antigen (PSA) and multiple T-cell co-stimulatory molecules (TRICOM). The PSA-TRICOM vaccines infect antigen-presenting cells (APCs) and generate proteins that are expressed on the surface of the APCs in an immune context. The interaction of these APCs with T cells initiates a targeted immune response and T cell-mediated tumor cell destruction. Preliminary clinical trials have indicated negligible toxicity, and Phase II trials have suggested a survival benefit after treatment with Prostvac, especially in patients with indolent disease characteristics. Preclinical and clinical data indicate that radiation, hormonal therapy, and chemotherapy may be combined with Prostvac to enhance the vaccine's efficacy. Additional strategies are in development to further enhance the clinical benefits of Prostvac, and a Phase III trial is being planned in metastatic castration-resistant prostate cancer.

176 Vector-based Vaccines for Cancer Therapy

Our program has been involved in the design and development of recombinant vector based vaccines for the therapy of human carcinomas. Emphasis has been based on the development of a pox virus-based regimen, i.e., recombinant vaccinia prime vaccination followed by multiple booster vaccinations with recombinant fowlpox vectors. Clinical trials have demonstrated that one can administer multiple boosts of recombinant fowlpox without host neutralizing activity. Vaccines have now been developed which contain transgenes for three human T-cell costimulatory molecules (TRICOM) and transgenes for either PSA for prostate cancer vaccines, or CEA-MUC-1 for use in the therapy of most carcinomas. These vaccines have demonstrated evidence of antigen-specific T-cell responses, the initiation of antigen cascade, objective clinical responses, drops in serum markers, delays in time to progression, and most importantly, evidence of increase in patient survival. In two separate clinical trials, evidence of increased survival has been observed in prostate cancer patients with hormone refractory disease and with metastatic disease, respectively. Preclinical studies have clearly demonstrated that vaccine-induced T-cell immunity can act synergistically with radiation therapy, and certain chemotherapeutic agents by altering the phenotype of tumor cells to make them more susceptible to T-cell-mediated attack. Evidence is also emerging that the dynamic process of T-cell-mediated immunity initiated by vaccine therapy can have a positive influence on subsequent therapies.

A phase II trial of an adenovirus/PSA vaccine for prostate cancer

3065 Background: Our phase I adenovirus/PSA vaccine trial has proven the vaccine is safe. We are conducting a phase II clinical trial with two separate protocols for patients with recurrent or hormone-refractory prostate cancer assessing toxicity, immune responses, and change in PSA levels. Methods: In Protocol 1 men with recurrent prostate cancer after definitive initial treatment were randomized to arm A (vaccine injection alone at days 0, 30, and 60) or arm B (vaccine injection 14 days after initiation of androgen deprivation therapy). In Protocol 2 men with hormone-refractory disease receive the vaccine alone at days 0, 30, and 60. Each injection consists of 108 pfu of Ad/PSA vaccine suspended in a collagen matrix. All patients return at regular intervals for physical, chemical, radiologic, and immunologic evaluations. Twenty-five patients will be enrolled in arms A and B in Protocol 1 and 32 in Protocol 2. Results: To date 10 patients have completed 3 monthly injections and have been followed a median of 5 months. Median patient age is 70 years (range 61–84), and median enrollment PSA levels are 0.79 ng/ml (range 0.24–3.93) in Protocol 1 and 5.47 ng/ml (range 0.29–11.17) in Protocol 2. Preliminary results show 86% in both protocols demonstrating anti-PSA T cell responses above preinjection levels. 25% have stable serum PSA levels, 50% have decreased levels, and 25% have increased levels. 11% have stable serum prostatic acid phosphatase (PAP) levels, 56% have decreased levels, and 33% have increased levels. Conclusions: These early results from the first few months of this phase II trial demonstrate the induction of anti-PSA T-cell responses in a high percentage of the vaccinated patients and stabilization or declines in serum PSA and PAP levels. No serious vaccine-related toxicities have been identified. No significant financial relationships to disclose.