Liposomal Vaccine Research Articles

Design of a Liposomal Candidate Vaccine Against Pseudomonas aeruginosa and its Evaluation in Triggering Systemic and Lung Mucosal Immunity

To design and evaluate liposomal constructs capable of inducing a potent systemic and airway humoral response to Pseudomonas aeruginosa Liposomes contained a peptide derived from P. aeruginosa pilin protein as B epitope, a peptide derived from Influenza hemagglutinin protein as Th epitope, the TLR agonist Pam3CAG or Pam2CAG as adjuvant, and a mannosylated lipid as dendritic cell targeting agent. These constructions were administered to mice intraperitoneally (i.p.) or intranasally (i.n.). Their immunogenicity was evaluated by measuring B epitope-specific immunoglobulins in the serum and the airways by ELISA. The B epitope, in its native form or after substitution of a cysteine by a serine, induced high systemic IgG titers when formulated in the presence of Pam3CAG or Pam2CAG and administered i.p.. No IgA response was observed in the airways upon injection of candidate vaccines by i.p. route, whatever the B epitope or the adjuvant. However, i.n. vaccination resulted in a significant local production of IgA. Finally, the production of IgG was more rapid when mannose was incorporated. All liposomal candidate vaccines tested induced the production of IgG and/or IgA directed against an immunogenic peptide from P. aeruginosa. Liposomal constructs could be attractive in the vaccination against P. aeruginosa.

A multicenter, open-label, phase I/II study in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated with L-BLP25: 2-year survival and safety results

3047 Background: L-BLP25 (Stimuvax; BLP25 liposomal vaccine) is an innovative cancer vaccine that incorporates the immunoadjuvant monophosphoryl lipid A and a synthetic MUC1 lipopeptide in a liposomal delivery system. Previous studies have shown that L- BLP25 has the potential to extend the survival of patients (pts) with stage IIIB locoregional NSCLC (Butts C et al., J Clin Oncol 2005;23:6674- 81). The primary objective of this study was to assess the safety of the current formulation of L-BLP25 in pts with unresectable stage IIIA or IIIB NSCLC with survival as a secondary objective. Methods: Pts with stable disease (SD) or an objective response to upfront chemoradiation received L-BLP25 + best supportive care. All pts were vaccinated according to a previously described schedule (Butts C et al., J Clin Oncol 2005;23:6674–81). Maintenance vaccinations were administered q6w until disease progression. Primary and secondary endpoints were safety and survival, respectively. Results: At September 17, 2007, 22 pts were evaluable for survival and toxicity. Of these, 1 had a complete response, 17 had a partial response and 4 had SD following chemoradiation. The 2-year survival rate was 64% (95% CI: 44–84) with a median follow-up of 2.2 years. Adverse events (AEs) occurred in all pts (16 considered L-BLP25-related). Most common (>10%) L-BLP25- related AEs besides injection site reactions were fatigue and nausea (all grade 1 or 2 except 1 case of grade 3 pneumonia). Eleven pts (50%) had an injection site reaction. Two pts discontinued L-BLP25 due to toxicity. As of September 2007, 9 pts remained on study treatment. Conclusions: The 2-year survival rate of 64% with maintenance L-BLP25 seen in this trial is similar to the 2-year survival rate recently observed in a phase IIb study of L-BLP25 in NSCLC (L-BLP25: 57%, control: 33%) (Butts C et al., J Thoracic Oncol 2007;2[Suppl. 4]:S332–33). It also compares favorably with previously reported survival for chemoradiation in stage III NSCLC. In addition, L-BLP25 was well tolerated with a similar safety profile to previous studies. A global phase III study is ongoing to further evaluate L-BLP25 in this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck Biomira, Merck Merck

Are Vaccines Making a Comeback in Non–Small-Cell Lung Cancer?

For decades we have investigated immune-based therapies in other types of cancer, namely melanoma, prostate, renal cell, nonHodgkin’s lymphoma, bladder cancer, and renal cell carcinoma. However, lung cancer has historically not been considered to be an immunogenic group of tumors. Therefore, the foundation of any lung cancer immunotherapy must rest on a solid rationale for activating and directing the immune system to recognize subtle differences between cancer cells and normal cells. The article by Neninger Vinageras et al focuses on the successes of therapies targeting epidermal growth factor receptor to identify one such difference. The results support a unique strategy involving both immune activation and targeted therapy. The investigators constructed a conjugated vaccine product involving a yeast-derived human recombinant epidermal growth factor (EGF) protein and an Escherichia coli– derived P64K Neisseria meningitides protein. Within 4 weeks of completion of frontline platinum-based chemotherapy advanced non–small-cell lung cancer (NSCLC), patients (50 stage IIIB; 30 stage IV) were randomly assigned to receive vaccine or supportive care. Results demonstrated significant correlation of survival in the vaccinated patients (n 40) to two surrogate parameters: induction of anti EGF antibodies (immune effect) and reduction in serum EGF concentration (targeted effect). Results also suggested overall survival advantage in vaccine-treated patients compared with controls at 60 years or younger. Historically, there have been several hypotheses to explain potential lack of anticancer immune activity in NSCLC. These include ineffective priming of tumor-specific T cells, lack of high-avidity of primed tumor-specific T cells, and physical or functional disabling of primed tumor-specific T cells by the primary host and or tumorrelated mechanism. For example, in NSCLC a high proportion of the tumor-infiltrating lymphocytes are immunosuppressive T regulatory cells (CD4 CD25 ) that secrete transforming growth factor(TFG) and express a high level of cytotoxic T-lymphocyte antigen4. These cells have been shown to impede immune activation by facilitating T-cell tolerance to tumor associated antigens rather than cross-priming CD8 T cells resulting in the nonproliferation of killer T cells that recognize the tumor without attacking it. Elevated levels of interleukin (IL)-10 and TFGare found in patients with NSCLC. Animal models have shown immune suppression is mediated by these cytokines serving as a defense for malignant T cells against the body’s immune system. Other vaccines in NSCLC have focused on methods of enhancing tumor antigen recognition. Most notable approaches already involved in phase III investigation in NSCLC include Belagenpumatucel-L, L-BLP 25, and MAGE-3 vaccines. Belagenpumatucel-L is a nonviral gene-based allogeneic vaccine that incorporates the TFG2 antisense gene into a cocktail of four different NSCLC cell lines. A recent randomized phase II trial involving 75 patients was recently completed. A dose-related survival advantage to belagenpumatucel-L was demonstrated. Furthermore, patients who achieved stable disease or better with vaccination had increased production of relevant immunostimulatory cytokines (interferon; IL-6; IL-4) and positive clinical outcomes were correlated with development of human leukocyte antigen antibody response as well as T-lymphocyte activation. The L-BLP 25 liposome vaccine consists of a lipoprotein that is slightly larger that one tandem-repeat of the MUC1 backbone and an immunoadjuvant, monophosphoral lipid-A contained in a liposomal formulation. Trials of the L-BLP-25 vaccine in stage III and IV NSCLC patients demonstrated safety of the vaccine but did not demonstrate a statistically significant survival benefit. However, a subset of patients (n 75) with IIIB disease demonstrated a trend towards improved survival (P . 09). MAGE-3 is aberrantly expressed in a wide variety of tumors, including NSCLC. Several CD8 T-cell epitopes of MAGE-3 have been identified in vitro. Based on these findings, synthetic peptides corresponding to these epitopes have been introduced into clinical vaccination studies. A recent randomized phase II trial was conducted involving 182 stage IB or II NSCLC MAGE-A3 positive patients (122 vaccine and 60 placebo). Results demonstrated a trend towards improved survival in the stage II patients receiving the vaccine compared with placebo. Within the next two years it is likely that the phase III trials involving belagenpumatucel-L, MAGE-3 vaccine and L-BLP 25 will be completed. Other vaccines in NSCLC demonstrating evidence of activity in phase I/II trials include GVAX, B7.1, EP2101, L523S and telomerase GV1001. It is hoped that over the next few years our knowledge of the immune system’s role against cancer will further improve and our clinical experience with the use of various vaccines involving different stages of disease in NSCLC will enable a “toolbox” of these nontoxic therapeutics to be expanded into the management of NCSLC.

Induction of Cytotoxic T-Lymphocytes and Antitumor Activity by a Liposomal Lipopeptide Vaccine

We have previously described a simple yet effective liposome-based therapeutic vaccine, DOTAP/E7, which contains only two molecules, the cationic lipid DOTAP and a peptide antigen derived from the E7 oncoprotein of human papillomavirus (HPV) type 16. In the current report, we have improved the vaccine formulation by incorporation of E7-lipopeptide instead of the water-soluble native E7 peptide into the DOTAP liposome. The lipopeptide consists of an N-terminal alpha- or -palmitoyl lysine connected to the E7 peptide via a dipeptide Ser-Ser linker. The DOTAP/E7-lipopeptide vaccine exhibited an enhanced functional antigen-specific CD8 (+) T lymphocyte response in vivo compared to the previous DOTAP/E7 formulation. More importantly, the cytotoxic T cells induced by the DOTAP/E7-lipopeptide vaccine could efficiently eliminate an existing HPV positive TC-1 tumor. The antitumor activity of lipopeptide formulated in DOTAP liposome was more than twice as potent as that of native E7, likely owing to the increased peptide entrapment efficiency in the liposomal complex. Our results also showed that it is essential to have the dipeptide spacer sequence between E7 peptide and the attached fatty acid to achieve a full immune response. Overall, the improved DOTAP/E7-lipopeptide vaccine described herein showed a significantly enhanced therapeutic effect for the treatment of a cervical cancer model.

BLP-25 liposomal vaccine: a promising potential therapy in nonsmall-cell lung cancer

Despite marginal improvements in survival gained from multimodality treatment, long-term survival rates remain low for lung cancer, which remains the leading cause of cancer-related mortality in North America. BLP25 liposomal (L-BLP25) vaccine (Stimuvax™) is a promising liposomal vaccine designed to generate an immune response against MUC1, a glycoprotein expressed on the cell surface of many normal epithelial tissues and over or aberrantly expressed on many carcinoma cells, including non-small-cell lung cancer (NSCLC). MUC1 is potentially a good target for immunotherapy, as evidenced by preclinical data and in Phase I and II clinical trials demonstrating the potential early activity of L-BLP25 with minimal toxicity in NSCLC. A Phase III randomized, placebo-controlled trial of L-BLP25 is currently being conducted in stage III NSCLC patients.

Induction of Cytotoxic T-Lymphocytes and Antitumor Activity by a Liposomal Lipopeptide Vaccine

Induction of Cytotoxic T-Lymphocytes and Antitumor Activity by a Liposomal Lipopeptide Vaccine

L-BLP25: a MUC1-targeted peptide vaccine therapy in prostate cancer

Renewed interest in cancer vaccine strategies has occurred with the identification of tumour-associated antigens and a further understanding of the immunoregulatory pathways involved in cancer development and progression. MUC1 is a mucinous glycoprotein that is overexpressed and aberrantly glycosylated in many human malignancies, including prostate cancer. BLP25 is a synthetic, liposomal cancer vaccine that targets the extracellular tandem repeat sequences of the MUC1 tumour-associated antigen. Preclinical L-BLP25 studies have shown the induction of a cell-mediated response and subsequent Phase I and II studies have established the vaccine dose, schedule and excellent safety profile. A Phase II study in advanced non-small cell lung cancer demonstrated a strong survival trend in favour of L-BLP25 in a subgroup of patients with locoregional stage IIIB disease. L-BLP25 also shows promise in prostate cancer. A pilot Phase II study in hormone naive patients with prostate-specific antigen failure after radical prostatectomy demonstrated a prolongation of prostate-specific antigen doubling time with little morbidity. These encouraging results suggest the potential of L-BLP25 in the management of cancer.

Time-course study of injection site inflammatory reactions following intraperitoneal injection of Atlantic cod ( Gadus morhua L.) with oil-adjuvanted vaccines

The inflammatory response of Atlantic cod ( Gadus morhua L.) following vaccination with oil-based vaccines has not been previously characterized in any detail. In this study, groups of Atlantic cod were intraperitoneally injected with commercial oil-adjuvanted vaccines ALPHA JECT 3000 (AJ 3000) and AJ 6-2. A water-based vaccine ALPHA MARINE™ Vibrio (AVM), an experimental liposome vaccine and physiological saline (placebo) were also included for comparison. Histopathological changes at the injection sites were evaluated semi-quantitatively at 1, 2, 4, 8, 12, 16, 20 and 25 weeks post-vaccination (p.v.), parallel with the examination of vaccine antigen retention. Gross intra-abdominal lesions were only examined at 12 and 25 weeks. The results show that the onset of inflammation in all vaccinated groups was rapid to develop, with intense cellular infiltrations predominated by mononuclear cells especially in groups injected by oil-based vaccines. Inflammation induced by AVM and liposome vaccines resolved within 12 weeks. In contrast, oil-adjuvanted vaccines produced mild, persistent but ultimately decreasing reactions. Persistent antigens were observed in oil-based and liposome vaccines. The results show that the cod inflammatory response is similar to other bony fish species. The findings also suggest that cod has an efficient innate immune system that is able to rapidly remove or sequester antigens from the injection site leading to the down-regulation of inflammation. Oil-adjuvanted vaccines appear to be well-tolerated by this species and show promise as a possible approach for disease control.

Regulation of airway eosinophil and neutrophil infiltration by α-galactosylceramide in a mouse model for respiratory syncytial virus (RSV) vaccine-augmented disease

Respiratory syncytial virus (RSV) is a leading cause of respiratory disease among infants, the elderly and immunocompromised adults. In this study, we assessed the effects of α-galactosylceramide, a known immunoregulatory lipid, on liposomal RSV vaccine-induced responses in BALB/c mice subsequently challenged with RSV. Liposomes containing a recombinant fragment of the RSV G protein were prepared with and without α-galactosylceramide and used to immunize mice by the intranasal route. The inclusion of α-galactosylceramide in the liposomal formulation caused a dramatic reduction in bronchoalveolar lavage neutrophils, but also an increase in eosinophils, following subsequent RSV challenge. The reduction in neutrophils was specific to mice receiving α-galactosylceramide-containing liposomes and was not reproduced in mice administered liposomes containing another α-galactosyl lipid, α-galactosylphosphatidylglyceroylalkylamine. Lung IL-13 mRNA levels were particularly elevated in mice administered α-galactosylceramide-containing liposomes followed by RSV challenge. This study demonstrates a striking ability of α-galactosylceramide to modulate the cellular airway infiltrate in mice immunized with liposomal RSV vaccine followed by RSV challenge.

Oral vaccination with liposome-encapsulated recombinant fusion peptide of urease B epitope and cholera toxin B subunit affords prophylactic and therapeutic effects against H. pylori infection in BALB/c mice

A new fusion peptide CtUBE of cholera toxin B subunit and Helicobacter pylori urease B subunit epitope was expressed in Escherichia coli. With this fusion peptide, an oral liposome vaccine against H. pylori infection was prepared and evaluated in BALB/c mice. Based on the results of urease tests, quantitation of culturable bacteria colonies in mice stomachs and histological identification of gastritis, the mice were protected significantly after intragastric vaccination with this CtUBE liposome vaccine, which increased the content levels of specific anti-urease serum IgG and mucosal IgA for both prophylactic and therapeutic vaccination protocols. These results showed that the fusion peptide CtUBE retained immunogenicity and could be used as antigen in the development of an oral vaccine against H. pylori infection.

B1-01: A multi-centre phase IIB randomized controlled study of BLP25 liposome vaccine (L-BLP25 or Stimuvax) for active specific immunotherapy of non-small cell lung cancer (NSCLC): updated survival analysis

B1-01: A multi-centre phase IIB randomized controlled study of BLP25 liposome vaccine (L-BLP25 or Stimuvax) for active specific immunotherapy of non-small cell lung cancer (NSCLC): updated survival analysis

A multi-centre, open-label study to assess the safety of Stimuvax (BLP25 liposome vaccine or L-BLP25) in non-small cell lung cancer (NSCLC) patients (pts) with unresectable stage III disease

3075 Background: L-BLP25 is an innovative cancer vaccine that incorporates a synthetic MUC1 lipopeptide in a liposomal delivery system. L-BLP25 is expected to elicit an immune response to cancer cells that express MUC1. Previous clinical studies have demonstrated that L-BLP25 has the potential to extend survival of pts with stage IIIB locoregional NSCLC (Butts C et al., JCO 2005; 23:6674–6681). The present ph I-II study was designed to assess the safety of the current formulation of L-BLP25 using a monophosphoryl lipid A in pts with unresectable stage IIIA and stage IIIB NSCLC. Methods: Pts with stable disease or an objective response to upfront radical therapy with chemoradiation for unresectable stage III NSCLC, plus ECOG 0–1 were eligible. All pts were vaccinated according to a previously described schedule (1). Maintenance immunizations were administered every 6-wks until disease progression. Primary and secondary endpoints were safety and survival respectively. Results: Twenty-two pts were recruited at 7 sites in Canada. 16 pts were evaluated for this interim safety analysis (8 stage IIIA, 8 stage IIIB, median age; 57, ECOG 0 56%, concurrent chemotherapy; 93.8%). Thirteen pts had a partial response and 3 had stable disease following chemoradiation. Thirteen pts experienced an adverse event (AE) during the first 4 vaccinations of which 7 pts had a L-BLP25 related adverse event. Grade 1/2 AEs related to L-BLP25 ≥10% included fatigue, dyspnea, insomnia, anorexia, headache, diarrhea, paresthesia, abdominal pain, influenza-like illness, urinary tract infection and peripheral neuropathy. No pts discontinued L-BLP25 due to an AE and no grade 3/4 AEs related to L-BLP25 were reported. Six pts (37.5%) had an injection site reaction. As of September 2006, 10 pts were still on study treatment. Conclusions: This formulation of L-BLP25 was well tolerated and the side effect profile was similar to that seen in previous studies (1). A controlled global multi-center phase III trial is underway to further evaluate L-BLP25 in this patient population. No significant financial relationships to disclose.

Liposomal vaccines with conformation-specific amyloid peptide antigens define immune response and efficacy in APP transgenic mice

We investigated the therapeutic effects of two different versions of Abeta(1-15 (16)) liposome-based vaccines. Inoculation of APP-V717IxPS-1 (APPxPS-1) double-transgenic mice with tetra-palmitoylated amyloid 1-15 peptide (palmAbeta(1-15)), or with amyloid 1-16 peptide (PEG-Abeta(1-16)) linked to a polyethyleneglycol spacer at each end, and embedded within a liposome membrane, elicited fast immune responses with identical binding epitopes. PalmAbeta(1-15) liposomal vaccine elicited an immune response that restored the memory defect of the mice, whereas that of PEG-Abeta(1-16) had no such effect. Immunoglobulins that were generated were predominantly of the IgG class with palmAbeta(1-15), whereas those elicited by PEG-Abeta(1-16) were primarily of the IgM class. The IgG subclasses of the antibodies generated by both vaccines were mostly IgG2b indicating noninflammatory Th2 isotype. CD and NMR revealed predominantly beta-sheet conformation of palmAbeta(1-15) and random coil of PEG-Abeta(1-16). We conclude that the association with liposomes induced a variation of the immunogenic structures and thereby different immunogenicities. This finding supports the hypothesis that Alzheimer's disease is a "conformational" disease, implying that antibodies against amyloid sequences in the beta-sheet conformation are preferred as potential therapeutic agents.

Preliminary evaluation of oligomannose-coated liposome vaccines against lethal protozoan infections in mice

Preliminary evaluation of oligomannose-coated liposome vaccines against lethal protozoan infections in mice

Monophosphoryl lipid A analogues with varying 3-O-substitution: synthesis and potent adjuvant activity

Structurally defined immunostimulatory adjuvants play important roles in the development of new generation vaccines. Here described are the syntheses of three monophosphoryl lipid A analogues ( 1– 3) with different substitution at 3-O-position of the reducing sugar and their potent immunostimulatory adjuvant activity. The syntheses involve the preparation of glycosylation acceptors benzyl 3,4-di- O-benzyl-2-deoxy-2-[( R)-3-tetradecanoyloxytetradecanamido]-β- d-glucopyranoside ( 16) and benzyl 3- O-allyl-4- O-benzyl-2-deoxy-2-[( R)-3-tetradecanoyloxytetradecanamido]-β- d-glucopyranoside ( 17). The glycosylation reactions between the donor 4,6-di- O-benzylidene-2-deoxy-2-(2′,2′,2′-trichloroethoxycarbonylamino)-α- d-glucopyranosyl trichloroacetimidate ( 21) and acceptors 16 and 17 provide the desired β-(1→6)-linked disaccharides 22 and 23, respectively. Selective reductive ring opening of the 4,6-di- O-benzylidene group, installation of a phosphate group to the 4′-hydroxyl group, and the final global debenzylation produce the designed monophosphoryl lipid A analogues 1– 3. All three synthetic analogues induce antigen specific T-cell proliferation and interferon-gamma (IFN-γ) production in ex vivo experiments with a totally synthetic liposomal vaccine system. The immunostimulatory potency of compound 1– 3 is in the same order of magnitude as that of the detoxified natural lipid A product isolated from Salmonella minnesota R595 (R595 lipid A). The substituent at the 3-O-position of the reducing sugar does not have much effect on the adjuvant activity of monophosphoryl lipid A analogues. The preliminary lethal toxicity study indicates that the 3-O-acylated hepta-acyl monophosphoryl lipid A may not be more toxic than its 3-O-deacylated hexa-acyl analogue.

One Step Membrane Incorporation of Viral Antigens as a Vaccine Candidate Against HIV

Liposomes can been used as potential immunoadjuvants, because they have the ability to elicit both a cellular mediated immune response and a humoral immune response. Studies have shown liposomes to be effective immunopotentiators in hepatitis A and influenza vaccines. For all these purposes, liposomes can be prepared by different methods. After disperging suitable membrane lipids in an aqueous phase and spontaneous formation of multilamellar large vesicles (MLV), mechanical procedures such as ultrasonication, homogenization by a French press or by other high pressure devices and, or extrusion through polycarbonate membranes with defined pore sizes lead to a reduction in size and number of lamellae of the vesicles. A second group of preparation procedures uses suitable detergents, e.g., bile salts or alkylglycosides. A third group of procedures starts with dissolving the lipids in an organic solvent and mixing it with an aqueous phase. The concentration of the organic solvent is then reduced by suitable procedures.Here we present a new technique for the preparation of liposomes with associated membrane proteins, where lipid vesicles are formed immediately after injection into a micellar protein solution. The model membrane protein used for these studies is a truncated recombinant gp41 produced in E. coli. This viral membrane antigen is a possible candidate protein for the establishment of HIV-vaccines.The data presented here, show an efficient and reproducible one step membrane protein encapsulation procedure into liposomes in a closed and sterile containment. We examined encapsulation efficiency, membrane protein conformation and immunogenicity of this possible liposomal vaccine candidate, which can be produced in GMP-compliant quality with the described technique.

Lyophilisation and sterilisation of liposomal vaccines to produce stable and sterile products

The advantages of liposomes as delivery systems for peptide, protein and DNA vaccines is well-recognised, unfortunately their application has been stinted by their instability during storage and their limited shelf-life. Further, sterilisation of these systems has been problematic, with degradation of the liposomes being reported after sterilisation using the various techniques available. Work form our laboratory has investigated techniques that can be applied to particulate liposomal vaccines such that they can be prepared in a freeze-dried and sterile format. In this article, we describe techniques for the lyophilisation, cryoprotection and sterilisation of liposomal vaccines. Applying these methods allows for the retention of both the chemical integrity of the lipids and the key physico-chemical characteristics of the liposomes (e.g., particle size, zeta potential, and dynamic viscosity), thus supporting the enhanced transition of liposomal vaccines from the bench to the clinic.

Liposomal vaccines—targeting the delivery of antigen

Vaccines that can prime the adaptive immune system for a quick and effective response against a pathogen or tumor cells, require the generation of antigen (Ag)-specific memory T and B cells. The unique ability of dendritic cells (DCs) to activate naïve T cells, implies a key role for DCs in this process. The generation of tumor-specific CD8 + cytotoxic T cells (CTLs) is dependent on both T cell stimulation with Ag (peptide–MHC-complexes) and costimulation. Interestingly, tumor cells that lack expression of T cell costimulatory molecules become highly immunogenic when transfected to express such molecules on their surface. Adoptive immunotherapy with Ag-pulsed DCs also is a strategy showing promise as a treatment for cancer. The use of such cell-based vaccines, however, is cumbersome and expensive to use clinically, and/or may carry risks due to genetic manipulations. Liposomes are particulate vesicular lipid structures that can incorporate Ag, immunomodulatory factors and targeting molecules, and hence can serve as potent vaccines. Similarly, Ag-containing plasma membrane vesicles (PMV) derived from tumor cells can be modified to incorporate a T cell costimulatory molecule to provide both TCR stimulation, and costimulation. PMVs also can be modified to contain IFN-γ and molecules for targeting DCs, permitting delivery of both Ag and a DC maturation signal for initiating an effective immune response. Our results show that use of such agents as vaccines can induce potent anti-tumor immune responses and immunotherapeutic effects in tumor models, and provide a strategy for the development of effective vaccines and immunotherapies for cancer and infectious diseases.

Comparative Immunological Response of Commercial Oil Based and Liposomal Vaccines of Avian Influenza H7

Comparative Immunological Response of Commercial Oil Based and Liposomal Vaccines of Avian Influenza H7

A Pilot Study of the Liposomal MUC1 Vaccine BLP25 in Prostate Specific Antigen Failures After Radical Prostatectomy

Men with biochemical failure after radical prostatectomy have few therapeutic options other than androgen deprivation therapy. Targeted therapies in this group are appropriate because the optimal timing of the initiation of hormonal therapy in this patient population is unknown. A single institution pilot trial was performed using BLP25 liposome vaccine in hormone naïve patients with prostate specific antigen failure after radical prostatectomy to determine if prostate specific antigen progression could be halted. Men with biochemical failure after radical prostatectomy were enrolled. Primary end points were efficacy and safety of the MUC1 BLP25 liposomal vaccine. Changes in prostate specific antigen doubling time were also evaluated. Patients received a single intravenous dose of cyclophosphamide, followed by vaccinations with BLP25 liposome vaccine for up to 1 year. Prostate specific antigen was measured at baseline and during treatment, and prostate specific antigen doubling time was calculated for these intervals. A total of 16 patients with a median age of 60 years were enrolled. All patients received cyclophosphamide and 15 of 16 completed the primary treatment period. Ten patients completed the maintenance period. After the 8-week primary treatment period 8 of 16 patients had stable or decreased prostate specific antigen. At the last on-study prostate specific antigen measurement 1 patient maintained stable prostate specific antigen but all others had progression. However, 6 of the 16 patients had greater than 50% prolongation of prostate specific antigen doubling time compared to pre-study prostate specific antigen doubling time. BLP25 liposome vaccine shows promise for prolonging prostate specific antigen doubling time in hormone naïve men with biochemical failure after prostatectomy and little morbidity. This could potentially translate into the deferral of hormonal therapy. Further testing in this population of patients is warranted.