Biological Adjuvants Research Articles

Nonunion fractures, mesenchymal stem cells and bone tissue engineering.

Depending on the duration of healing process, 5-10% of bone fractures may result in either nonunion or delayed union. Because nonunions remain a clinically important problem, there is interest in the utilization of tissue engineering strategies to augment bone fracture repair. Three basic biologic elements that are required for bone regeneration include cells, extracellular matrix scaffolds and biological adjuvants for growth, differentiation and angiogenesis. Mesenchymal stem cells (MSCs) are capable to differentiate into various types of the cells including chondrocytes, myoblasts, osteoblasts, and adipocytes. Due to their potential for multilineage differentiation, MSCs are considered important contributors in bone tissue engineering research. In this review we highlight the progress in the application of biomaterials, stem cells and tissue engineering in promoting nonunion bone fracture healing. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2551-2561, 2018.

Induction of Zika specific CD8 T cell responses in the placenta after heat shock protein gp96-Ig vaccination

Abstract Heat shock protein (HSP) gp96 is a biological adjuvant that activates antigen-presenting cells and simultaneously delivers antigen specific peptides to MHC I for CD8 T cell activation. Here, we have transformed human embryonic kidney cell line (HEK-293) into powerful miniature osmotic pumps that continually secrete engineered form of gp96, gp96-Ig, along with its chaperoned antigens (ZIKV envelope immunogenic peptides) to induce ZIKV specific CD8+ cytotoxic T cell immune responses. B6 females were mated with B6 or BALB/c males and gestation day (GD) 0.5 was determined by the presence of vaginal plug. At GD 7.5 one million of irradiated 293-gp96-Ig secreting cells were injected subcutaneously (SC). Mice were followed up until the end of pregnancy (GD 19.5–21.5) or humanely euthanized 5 days after vaccination (GD 12.5). Frequency of CD8+ T cells was determent by flow cytometry, immunohistochemistry and antigen, ZIKV envelope specificity was confirmed by in vitro ZIKV peptide stimulation and by intracellular cytokine staining. We found that vaccinated mice have the same number of live-born pups as control mice without pathological changes in placenta or in fetus. This is the first finding that confirms the presence of gp96-Ig-ZIKV-induced CD8 T cells around arteries and larger blood vessels in the maternal part of the placenta, decidua. Furthermore, secreted gp96 vaccine induces very high frequency of ZIKV specific CD8 T cells in the maternal decidua (15%) without compromising placental or fetal viability. In summary, we have succeeded in generating vaccine that is expressing gp96-Ig and ZIKV envelope protein and also we confirmed that vaccination with secreted gp96-Ig-ZIKA is safe and induces CD8 T cell responses in maternal decidua.

Limited evidence for adipose-derived stem cell therapy on the treatment of osteoarthritis.

The purpose of this systematic review is to evaluate the effects of adipose derived mesenchymal stem cells (ADSCs) in the treatment of osteoarthritis (OA) in the clinical setting. A literature search was performed in the MEDLINE, EMBASE, and The Cochrane Library Database up to January 2017 for inclusion and exclusion criteria. Criteria for inclusion were clinical studies demonstrating the effects of ADSCs on OA, and written in English. The following variables were analyzed: donor site, volume of adipose tissue, preparation of ADSCs, clinical outcomes, and complication rate. Sixteen studies (knee: 14 studies, multiple joints: 1 study, ankle: 1 study) were included in this systematic review. All of the studies prepared ADSCs in the form of the stromal vascular fraction (SVF). Inconsistencies between studies were found with regards to reported clinical variability, donor sites of SVF, and reported clinical outcomes. Nine studies used either platelet-rich plasma (PRP) (7/16) or fibrin (4/16) or both PRP and Fibrin (1/16), as an adjunct at time of SVF injection. All of the studies reported an improvement in clinical outcomes with the use of SVF. Five studies reported a 90% satisfaction rate, and no study reported any complications with liposuction. Five studies reported on complications, with a 5% incidence of swelling and pain. This systematic review demonstrated that ADSCs are currently used in the form of SVF. While SVF may produce favorable clinical outcomes with minimal risk of side effects on osteoarthritis, the variability in the data and the use of biological adjuvants have confounded the effectiveness of ADSCs. This study will help surgeons understand the limitations in the literature on ADSCs. Level IV, systematic review of level IV studies.

OX40 triggering concomitant to IL12-engineered cell vaccine hampers the immunoprevention of HER2/neu-driven mammary carcinogenesis

ABSTRACTThis study evaluated the effects of combining an OX40 agonistic antibody (aOX40) with a cell vaccine targeting HER2/neu, called “Triplex”. Such HER2/neu cell vaccine included two biological adjuvants (interleukin 12 (IL12) and allogeneic histocompatibility antigens) and was previously found able to prevent autochthonous HER2/neu-driven mammary carcinogenesis. Timing of aOX40 administration, concomitantly or after cell vaccination, gave opposite results. Unexpectedly, vaccine efficacy was hampered by concomitant OX40 triggering. Such decreased immunoprevention was likely due to a reduced induction of anti-HER2/neu antibodies and to a higher level of Treg activation. On the contrary, aOX40 administration after the completion of vaccination slightly but significantly increased immunopreventive vaccine efficacy, and led to increased production of GM-CSF and IL10. In conclusion, OX40 triggering can either impair or ameliorate immunoprevention of HER2/neu-driven mammary carcinogenesis depending on the schedule of aOX40 administration.

Principles of Nonunion Management: State of the Art.

A substantial proportion of fractures can present with nonunion, and the management of nonunion continues to present a challenge for orthopaedic surgeons. A variety of biological, mechanical, patient, and injury factors can contribute to the occurrence of nonunion, and often the cause of nonunion may be multifactorial. Successful management often requires assessment and treatment of more than one of these factors. This article reviews common factors that may contribute to nonunion including infection, impaired biology, and metabolic disorders. In addition, new and evolving strategies for diagnosing the cause and effectively treating nonunion including the diagnosis of infection, metabolic workup, bone grafting, cell-based therapies, and biological adjuvants are reviewed and discussed.

The Role of Biologic Therapy in Rotator Cuff Tears and Repairs.

The purpose of this review was to establish the foundation of the major biologic adjuvants to rotator cuff repairs and review recent scientific findings. Platelet-rich plasma (PRP) overall has no significant impact on functional outcomes and repair integrity, but may be more advantageous in small to medium tears. Further studies should focus on leukocyte-rich versus poor preparations and the use of PRP in patients that are high risk for repair failure. Biologic and synthetic patches or augments provide mechanical stability for large and massive rotator cuff tears and decrease re-tear rates. Mesenchymal stem cells have demonstrated improved healing rates without an impact on outcomes. Cytokines and growth factors show promise in animal models, but require human trials to further evaluate. In massive or revision repairs, allograft or synthetic patch augmentation should be considered. Platelet-rich plasma may have benefit in smaller tears. Further studies are needed to evaluate the value of mesenchymal stem cells and various cytologic chemical signals.

Use of Platelet-Rich Plasma Immediately After an Injury Did Not Improve Ligament Healing, and Increasing Platelet Concentrations Was Detrimental in an In Vivo Animal Model

Background: Limited information in basic science and clinical trials exists to determine if ligament healing may be accelerated with the use of biological adjuvants, such as platelet-rich plasma (PRP). However, there has been widespread acceptance of PRP for use in clinical practice, despite an inadequate understanding of its biological mechanism of action. Purpose: To determine whether a single dose of PRP could accelerate ligament healing and correspondingly improve histological characteristics and biomechanical properties when injected immediately postoperatively into the injured medial collateral ligament (MCL) of New Zealand White rabbits. Study Design: Controlled laboratory study. Methods: Eighty skeletally mature New Zealand White rabbits (160 knees) were used. The MCL was torn midbody to simulate a grade 3 tear. After an acute injury of the MCL, the administration of autologous PRP at 3 different platelet concentrations (0 million/uL, platelet-poor plasma [PPP]; 0.6 million/uL, 2 times the baseline [2× PRP]; and 1.2 million/uL, 4 times the baseline [4× PRP]) was performed and compared with a saline injection control in the contralateral knee. Histological analysis and a biomechanical endpoint characterization were utilized to assess ligamentous healing and compare it to a sham surgery group. Results: The PPP (P = .001) and 4× PRP (P = .002) groups had a significantly lower collagen subscore than the sham surgery group. No other differences were observed among the treatment groups, including the vascularity subscore and overall ligament tissue maturity index score. Compared with saline-injected contralateral knees, the maximum load for PPP and 2× PRP was not significantly different (P = .788 and .325, respectively). The maximum load and stiffness for knees treated with 4× PRP were significantly less than for the saline-treated contralateral knees (P = .006 and .001, respectively). Conclusion: One single dose of PPP or 2× PRP at the time of injury did not improve ligament healing. In addition, 4× PRP negatively affected ligament strength and histological characteristics at 6 weeks after the injury. Clinical Relevance: The current practice of treating knee ligament injuries with PRP may not improve healing at low doses of PRP. The decreased mechanical properties and histological appearance of the torn MCL suggest that high doses of PRP decrease the quality of repair tissue. Further in vivo studies are necessary to determine the dosing and timing of PRP administration after a ligament injury before the widespread use of PRP to treat ligament injuries is recommended.

Adjuvant Biological Therapies in Chronic Leg Ulcers

Current biological treatments for non-healing wounds aim to address the common deviations in healing mechanisms, mainly inflammation, inadequate angiogenesis and reduced synthesis of extracellular matrix. In this context, regenerative medicine strategies, i.e., platelet rich plasmas and mesenchymal stromal cell products, may form part of adjuvant interventions in an integral patient management. We synthesized the clinical experience on ulcer management using these two categories of biological adjuvants. The results of ten controlled trials that are included in this systematic review favor the use of mesenchymal stromal cell based-adjuvants for impaired wound healing, but the number and quality of studies is moderate-low and are complicated by the diversity of biological products. Regarding platelet-derived products, 18 controlled studies investigated their efficacy in chronic wounds in the lower limb, but the heterogeneity of products and protocols hinders clinically meaningful quantitative synthesis. Most patients were diabetic, emphasizing an unmet medical need in this condition. Overall, there is not sufficient evidence to inform routine care, and further clinical research is necessary to realize the full potential of adjuvant regenerative medicine strategies in the management of chronic leg ulcers.

The Subchondral Bone Is Affected by Bone Marrow Stimulation: A Systematic Review of Preclinical Animal Studies.

Despite the mechanical and biological roles of subchondral bone (SCB) in articular cartilage health, there remains no consensus on the postoperative morphological status of SCB following bone marrow stimulation (BMS). The purpose of this systematic review was to clarify the morphology of SCB following BMS in preclinical, translational animal models. The MEDLINE and EMBASE databases were systematically reviewed using specific search terms on April 19, 2016 based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The morphology of the SCB was assessed using of microcomputed tomography (bone density) and histology (microscopic architecture). Seventeen animal studies with 520 chondral lesions were included. The morphology of SCB did not recover following BMS. Compared with untreated chondral defects, BMS resulted in superior morphology of superficial SCB and cartilage but inferior morphology (specifically bone density, P < 0.05) of the deep SCB. Overall, the use of biological adjuvants during BMS resulted in the superior postoperative morphology of SCB. Alterations in the SCB following BMS were confirmed. Biologics adjuvants may improve the postoperative morphology of both SCB and articular cartilage. Refinements of BMS techniques should incorporate consideration of SCB damage and restoration. Investigations to optimize BMS techniques incorporating both minimally invasive approaches and biologically augmented platforms are further warranted.

Heat shock protein gp96-Ig vaccine induces antigen specific CD8 T cell response in the placenta

Abstract The placenta acts as a barrier against infections, due to multiple unique structural, cellular, and immune properties. The detrimental effects of congenital viruses, including Zika virus (ZIKV), on pregnancy and fetal outcomes occur in part because of impaired placental function and profound pathological changes have been observed infected placentas. Our hypothesis is that induction of appropriate vaccine-induced immune responses in the placenta are key to successful prevention of congenital viruses’ infections in developing fetus. The main goal of our study is to developed novel heat shock protein (HSP) based vaccine approach that will induce antigen-specific responses in the placenta and will lead to the prevention of the pathogen transmission to the fetus. HSP gp96 is a biological adjuvant that activates antigen-presenting cells and simultaneously delivers antigen specific peptides to MHC I for CD8 T cell activation. B6 females were mated with B6 mice and gestation day (GD) 0.5 was determined by the presence of vaginal plug. At GD 5.5, 0.5 million of OT1-gfp cells were injected in the tail vein. Two days after, 2.5 million 3T3-gp96-OVA-Ig or 3T3-gp96-Ig cells were injected subcutaneously (SC). Five days later, pregnant uteri were collected and placental and decidual single cells suspension was obtained. Frequency of OT1-gfp cells was determent by flow cytometry. We found that secreted gp96 vaccine delivered by SC route induces very high frequency of antigen specific CD8 T cells in the placenta (15%) and decidua (10%) without compromising placental or fetal viability. Our findings are highly supportive of development of novel gp96-Ig vaccine as unique systemic and placenta-homing, antigen-specific CD8 CTL vaccine strategy.

Semiconductor diode laser device adjuvanting intradermal vaccine

A brief exposure of skin to a low-power, non-tissue damaging laser light has been demonstrated to augment immune responses to intradermal vaccination. Both preclinical and clinical studies show that this approach is simple, effective, safe and well tolerated compared to standard chemical or biological adjuvants. Until now, these laser exposures have been performed using a diode-pumped solid-state laser (DPSSL) devices, which are expensive and require labor-intensive maintenance and special training. Development of an inexpensive, easy-to-use and small device would form an important step in translating this technology toward clinical application.Here we report that we have established a handheld, near-infrared (NIR) laser device using semiconductor diodes emitting either 1061, 1258, or 1301nm light that costs less than $4000, and that this device replicates the adjuvant effect of a DPSSL system in a mouse model of influenza vaccination. Our results also indicate that a broader range of NIR laser wavelengths possess the ability to enhance vaccine immune responses, allowing engineering options for the device design.This small, low-cost device establishes the feasibility of using a laser adjuvant approach for mass-vaccination programs in a clinical setting, opens the door for broader testing of this technology with a variety of vaccines and forms the foundation for development of devices ready for use in the clinic.

Current trends in orthobiologics and shoulder surgery

Shoulder pathology is of growing concern for the aging population, people who pursue an active lifestyle, and manual laborers. Rotator cuff disease and osteoarthritis represent the two most common disorders leading to shoulder pain, disability, and degeneration. The use of biologic adjuvants in the treatment of these conditions has shown promise. Platelet concentrates, scaffolds, and hyaluronic acid continue to be studied extensively to better understand the mechanism of action, clinical indications, and favored mode of application to be of greatest benefit to the pathologic shoulder. This review presents the most current literature update on the use of biologics to treat patients with shoulder disease.

Abstract B009: Phase I clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer vaccine in PSA defined biochemical recurrent prostate cancer patients

Abstract Immunotherapy for cancer has had two main approaches that have led to clinical applications. The first is stimulating immune responses to tumor cells with cytokines or cellular immunotherapy and the second is blocking tumor immune evasion and the associated inhibition of T-cell activation with antibodies to the CTLA-4 receptor, PD-1 receptor or PD-L1. We have taken a different approach and have developed therapeutic cancer vaccines that are a combination of tumor antigens (proteins overexpressed by tumors) with biological adjuvants (the cytokines IL-2 and GM-CSF). This study is a Phase 1a/1b clinical trial of a PSA/IL-2/GM-CSF vaccine in recurrent prostate cancer in hormone-naïve and hormone-independent patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations (“induction vaccination”). Twenty patients will receive intradermal injections of the PSA/IL-2/GM-CSF vaccine at weeks 0, 1, 2, 6, 10 and 14. To date, twelve patients in the Phase 1a portion of the trial have received all 6 vaccines. Eight of the 11 patients who have received all 6 vaccines had increased immune responses to PSA in a lymphocyte blastogenesis assay by week 19. Six of 10 of the patients had an increase in the doubling time of their serum PSA, suggesting a slowing of the progression of the cancer. Median follow up after the first vaccine is 23 months (range: 4-32 months). None of the patients vaccinated in the Phase 1a portion have had a DLAE and enrollment continues in the Phase 1a. Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle McKinney, Weg Ongkeko, Kyoko Sakamoto, Jessica Wang-Rodriguez. Phase I clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer vaccine in PSA defined biochemical recurrent prostate cancer patients [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B009.

Área de espalhamento de gotas de soluções com inseticida biológico e adjuvantes em folhas de mandioca

This project aim to evaluate the efficiency of spreading droplets in solutions with biological insecticide and adjuvants in leaves of different varieties of cassava. The experimental design was entirely randomized in a factorial 3x7, with four replications. It was performed three solutions with biological insecticide, with and without adjuvants: Bacillus thuringiensis (500 g ha-1, Dipel WP® - 32.0 g Kg-1), B. thuringiensis (500 g ha-1) + glicerine (0.5% v v-1, Hygrogem® byproduct from the soybean biodiesel) and B. thuringiensis + mineral oil (0.5% v v-1, Nimbus®) and were evaluated in seven varieties of cassava (Baianinha, Cascuda, Fecula Branca, IAC 118, OlhoJunto, Peru and IPR-Uniao). The spreading of droplets of the solutions was evaluated on adaxial and abaxial leaf surfaces of the varieties. Only the treatment B. thuringiensis+mineral oil caused surface tension reduction of the drops in about 34.43% and 33.74% in relation to the others treatments B. thuringiensis and B. thuringiensis + glicerina, respectively. The treatment B. thuringiensis + mineral oil caused the greater spreading of the droplets on the adaxial surface of the leaf than the others treatments. The treatment B. thuringiensis + mineral oil caused greater spreading of the droplets in the abaxial surface of the leaf to the varieties Cascuda and Olho Junto. It was concluded that the spreading of the drops of solutions with biological inseticide in leaf surfaces of cassava varieties was dependent of adjuvant added to solution.

Biologic Treatments for Sports Injuries II Think Tank-Current Concepts, Future Research, and Barriers to Advancement, Part 2: Rotator Cuff.

Rotator cuff tears are common and result in considerable morbidity. Tears within the tendon substance or at its insertion into the humeral head represent a considerable clinical challenge because of the hostile local environment that precludes healing. Tears often progress without intervention, and current surgical treatments are inadequate. Although surgical implants, instrumentation, and techniques have improved, healing rates have not improved, and a high failure rate remains for large and massive rotator cuff tears. The use of biologic adjuvants that contribute to a regenerative microenvironment have great potential for improving healing rates and function after surgery. This article presents a review of current and emerging biologic approaches to augment rotator cuff tendon and muscle regeneration focusing on the scientific rationale, preclinical, and clinical evidence for efficacy, areas for future research, and current barriers to advancement and implementation.

Abstract A048: Phase 1 clinical trial of a therapeutic prostate cancer vaccine containing PSA/IL-2/GM-CSF in PSA defined biochemical recurrent prostate cancer patients

Abstract Immunotherapy for cancer has had two main approaches that have lead to clinical applications. The first is stimulating immune responses to tumor cells with cytokines or cellular immunotherapy and the second is blocking tumor immune evasion and the associated inhibition of T-cell activation with antibodies to the CTLA-4 receptor, PD-1 receptor or PD-L1. We have taken a different approach and have developed therapeutic cancer vaccines that are a combination of tumor antigens (whole cells or proteins) with biological adjuvants (the cytokines IL-2 and GM-CSF). This study is a Phase 1a/1b clinical trial of a PSA/IL-2/GM-CSF vaccine in recurrent prostate cancer in hormone-naïve and hormone-independent patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations (“induction vaccination”). The Phase 1b examines the rate of DLAEs with a continued course of an additional 6 vaccinations (“maintenance vaccine”). All patients will receive intradermal injections of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11, and 15. In an additional 28 patients the six maintenance vaccines will alternate IL-2 and the complete vaccine (PSA/IL-2/GM-CSF) at weeks 23, 27, 31, 35, 39 and 43. To date, twelve of twenty patients in the Phase 1a portion of the trial have received at least one vaccine injection and ten patients have received all 6 vaccines. Seven of the ten patients that have received 3 vaccines had increased responses to PSA in a lymphocyte blastogenesis assay and five of the nine patients had an increase in their response after 6 vaccines. None of the patients vaccinated in the Phase 1a portion have had a DLAE and enrollment continues in the Phase 1a. Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle McKinney, Weg Ongkeko, Jessica Wang-Rodriguez, Kyoko Sakamoto, Robert L. Elliott. Phase 1 clinical trial of a therapeutic prostate cancer vaccine containing PSA/IL-2/GM-CSF in PSA defined biochemical recurrent prostate cancer patients. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A048.

In Silico Analysis of HA2/Mx Chimera Peptide for Developing an Adjuvanted Vaccine to Induce Immune Responses Against Influenza Viruses.

The direct transmission of avian influenza viruses to human and increasing drug resisted strains posing new threats for public health. Therefore, development of efficient vaccines is needed to generate protective and persistent immunity to the viruses. Three motifs of Mx protein sequence in human, mouse and poultry located in interferon induced (GTP ase) domain were candidate as biologic adjuvant for enhancing the immune responses against influenza virus. Chimera proteins composed with the conserved HA2 subunit of influenza virus and the Mx motifs named HA2/Mx were modeled and evaluated by in silico analysis includes bioinformatics algorithms in order to explore biological characteristics of these peptides. Amongst the predicted models, HA2/Mx1 peptide showed the better results following protein structures prediction, antigenic epitopes determination and model quality evaluation. Comparative homology modeling was performed with Swiss Model and the model was validated using ProSA. Epitope predictions revealed the construct could induce both B and T cell epitopes that expect a high immune response. Taken together, these data indicate that the HA2/Mx1 chimera peptide can be potentiated for developing an adjuvant-fused influenza vaccine capable of stimulating effective immune response.

The flagellin D2/D3 domain induces TLR5- and inflammasome- independent antibody responses (INM2P.357)

Abstract The detailed understanding of the molecular mechanisms underlying the biological activity adjuvants is critical for rational design of more effective vaccines. Bacterial flagellin, a potent immunogen, is being developed as a new adjuvant and platform for human vaccines. We have demonstrated that the conserved D0 and D1 domains of flagellin promote antibody responses through activation of their respective innate immune receptors, but are not required for Salmonella flagellin (FliC) induced antibody responses. We hypothesized that additional flagellin domains also influence specific aspects of flagellin-induced B cell responses. Mice were immunized with a mixture of FliC mutants proteins and ovalbumin, and sera were collected for quantification of anti-flagellin and anti-ovalbumin specific antibody responses. The results from our studies demonstrate that the D2/D3 domain of the FliC is also required for flagellin-induced primary antibody responses and robust secondary responses. D2/D3 domain is capable of inducing antibody responses independent of TLR5 and the inflammasome. Our data indicate the flagellin D2/D3 domain synergizes with the TLR5 (D1) and inflammasome (D0) activating domains to induce potent antibody responses, and that the D2/D3 domain also functions as an adjuvant to promote antibody responses against co-administered antigens. Future studies will elucidate the contribution of the FliC D2/D3 domain to B cell responses and its utility in vaccines.

Biologic adjuvants and bone: current use in orthopedic surgery.

Normal bone healing is a complex process that eventually restores original structure and function to the site of trauma. However, clinical circumstances such as nonunion, critical-sized defects, systemic bone disease, and fusion procedures have stimulated a search for ways to enhance this normal healing process. Biologics are an important part of this search and many, including bone marrow aspirate concentrate, demineralized bone matrix, platelet-rich plasma, bone morphogenic proteins, and platelet-derived growth factor, are currently in clinical use. Many others, including mesenchymal stem cells, parathyroid hormone, and Nel-like molecule-1 (NELL-1) will likely be in use in the future depending on the results of preclinical and clinical trials.

Abstract 2892: Vaccination with a therapeutic cancer vaccine containing prostate specific antigen and the biological adjuvants IL-2 and GM-CSF results in reduced serum PSA in prostate cancer patients

Abstract In 1997 we initiated a phase I/II clinical trial of a therapeutic prostate cancer vaccine. We have enrolled 12 biopsy confirmed prostate cancer patients in this study and 11 finished the initial course of 6 intradermal vaccinations containing prostate specific antigen (50 μg) and biological adjuvants (IL-2, 20,000 units, and GM-CSF, 16.7 μg) at 0, 1, 2, 6, 10 and 14 weeks. During this study the prostate cancer patients received no other concurrent therapy (surgery, hormone, radiation, radioactive seeds, chemotherapy). One of the 12 patient's PSA rose from 7.6 to 13.7 after the fourth vaccination and he (patient #8) withdrew from the study to seek other therapy. In the remaining 11 prostate cancer patients serum PSA concentrations were determined before initiating vaccination and 3-4 weeks after the 6th vaccination. There was a decrease in the PSA levels in 8 of 12 of the prostate cancer patients after 6 vaccinations. One of the patients (patient #3), whose PSA had dropped from 6.8 to 6.4 and had previously received radiotherapy (the only patient previously treated), elected to withdraw from the study and underwent radical prostatectomy. Nine of the original 12 patients have received monthly 3 intradermal IL-2 injections (11 million units) alternated with 3 further vaccinations for the 6 months following the initial vaccinations, and 8 patients have been followed from 18 to 92 months. The mean PSA values for the 8 patients still being followed without additional therapy were 5.8 initially, decreasing to 4.1 after 6 vaccines, 3.7 after 12 vaccines and is 4.7 after a mean follow-up of 49 months (median follow-up of 45.5 months). These promising results have led to the creation of the U.S. Navy Cancer Vaccine Program with a Phase I clinical trial at the Veterans Administration Medical Center San Diego/UCSD Medical School. Citation Format: Jonathan F. Head, Robert L. Elliott. Vaccination with a therapeutic cancer vaccine containing prostate specific antigen and the biological adjuvants IL-2 and GM-CSF results in reduced serum PSA in prostate cancer patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2892. doi:10.1158/1538-7445.AM2014-2892