Biological Adjuvants Research Articles

Biologic Adjuvants in Meniscus Repair: A Review of Current Translational and Clinical Evidence

Meniscus tears are common injuries in all age categories and cover a broad subset of lesions. Due to the lack of vascularization and blood clot formation, meniscus tears in the avascular zone possess poor healing potential. Preserving meniscus tissue however, is crucial to avoid early onset osteoarthritic changes in the knee joint. Meniscectomies are therefore, where possible, largely replaced by meniscus repair strategies. When tissue approximation (suturing) only is falling short for meniscal repair in the avascular zone, several types of biological augmentation can be recruited, which potentially benefits tear healing, and ultimately knee function. This review offers an overview of the current translational and clinical evidence regarding biologic augmentation methods for meniscus repair in a tear-type and location specific manner. Methods discussed include the use of mechanical stimulation with biological response ((para)meniscal rasping and trephination), bone marrow stimulation (± ACL reconstruction), external fibrin clot, platelet-rich plasma, cytokine/growth factor administration, and cell-based techniques.

Hip Preservation Techniques: The Use of Biologics to Improve Outcomes

ABSTRACT The use of biologic adjuvants in orthopedic injuries continues to expand along with the comprehension of the healing and regeneration mechanisms of tissues. Biological treatments represent a potentially attractive option for a number of hip disorders and include a variety of cell therapies and blood derived products, such as mesenchymal stem cells, bone marrow aspirate concentrate, matrix-induced autologous chondrocyte implantation, platelet rich plasma and others. Clinical studies have reported promising results and emerging basic studies have provided a clearer understanding of the underlying mechanisms of action of biologics in orthopedics. However, crucial questions remain regarding their indications, limitations, and overall efficacy. This review focuses on the current state of the use of biologics to improve outcomes in hip preservation surgery.

Biologics in trauma and orthopaedics

Use of biologic adjuvants such as platelet-derived growth factor (PDGF), bone marrow aspirate concentrate (BMAC) and other cell-derived therapies is becoming increasingly popular in trauma and orthopaedic surgery. Extensive research effort has been made in regarding biologic augmentation in order to manage tendon pathology, non-union and degenerative joint disease. We look at the various biologics gaining importance in musculoskeletal conditions and discuss the evidence base behind them. In our review article, we have defined the various biological adjuvants, their current clinical use and evaluated the evidence for treating various clinical conditions.

The immune enhancement effects of recombinant NDV expressing chicken granulocyte-macrophage colony-stimulating factor on the different avian influenza vaccine subtypes.

Avian influenza is an acute and highly contagious infectious disease that is caused by the influenza virus. Avian influenza has been widely spread all over the world, has caused property loss and has threatened human life and security. In this study, the recombinant plasmid rClone30-chGM-CSF was constructed and rescued to the recombinant virus rClone30-chGM-CSF successfully. After 8days of immunization with the recombinant virus, the titre of NDV HI (haemagglutination inhibition) antibodies in SPF chickens reached its peak. The average titre of the rClone30-chGM-CSF group reached 6 log2 and was significantly higher than the protection critical value of 4 log2 ; the titres of the rClone30 group and the blank group were 2.86 log2 and 1 log2 , respectively, indicating that the recombinant virus can effectively improve the NDV antibody titre. Then, SPF chickens were co-immunized with the recombinant virus and with three different vaccine subtypes of inactivated avian influenza. The results indicated that the SPF chickens that were immunized with the vaccine plus rClone30-chGM-CSF showed significantly higher avian influenza antibody levels than those in the single vaccine groups. Furthermore, the SPF chickens in the vaccine plus rClone30-chGM-CSF group elicited stronger CD4+ and CD8+ T-cell proliferative responses and also had upregulated transcriptional levels of interleukin-1β (IL-1β), IL-4, IL-6 and IL-17 compared with those in the single vaccine groups. This study has shown that the recombinant virus expressing chicken granulocyte-macrophage colony-stimulating factor (chGM-CSF) can be used not only as an NDV vaccine to effectively improve the titre of NDV antibodies but also as a biological adjuvant to enhance the immune effects of the avian influenza vaccine. Therefore, this recombinant virus can also be used as a biological adjuvant for other poultry vaccines.

Vascular Supply and Bone Marrow Concentrate for the Improvement of Allograft in Bone Defects: A Comparative In Vivo Study

BackgroundSurgical repair of critical-sized bone defects still remains a big challenge in orthopedic surgery. Biological enhancement, such as growth factors or cells, can stimulate a better outcome in bone regeneration driven by well-established treatments such as allogenic bone graft. However, despite the surgical options available, correct healing can be slowed down or compromised by insufficient vascular supply to the injured site. Materials and methodsIn this pilot study, critical size bone defects in rabbit radius were treated with allograft bone, in combination with vascular bundle and autologous bone marrow concentrate seeded onto a commercial collagen scaffold. Microtomographical, histological and immunohistochemical assessments were performed to evaluate allograft integration and bone regeneration. ResultsResults showed that the surgical deviation of vascular bundle in the bone graft, regardless from the addition of bone marrow concentrate, promote the onset of healing process at short experimental times (8 wk) in comparison with the other groups, enhancing graft integration. ConclusionThe surgical procedure tested stimulates bone healing at early times, preserving native bone architecture, and can be easily combined with biological adjuvant.

Laser adjuvant for vaccination.

The use of an immunologic adjuvant to augment the immune response is essential for modern vaccines which are relatively ineffective on their own. In the past decade, researchers have been consistently reporting that skin treatment with a physical parameter, namely laser light, augments the immune response to vaccine and functions as an immunologic adjuvant. This "laser adjuvant" has numerous advantages over the conventional chemical or biological agents; it is free from cold chain storage, hypodermic needles, biohazardous sharp waste, irreversible formulation with vaccine antigen, undesirable biodistribution in vital organs, or unknown long-term toxicity. Since vaccine formulations are given to healthy populations, these characteristics render the "laser adjuvant" significant advantages for clinical use and open a new developmental path for a safe and effective vaccine. In addition, laser technology has been used in the clinic for more than three decades and is therefore technically matured and has been proved to be safe. Currently, four classes of laser adjuvant have been reported; ultrashort pulsed, non-pulsed, non-ablative fractional, and ablative fractional lasers. Since each class of the laser adjuvant shows a distinct mechanism of action, a proper choice is necessary to craft an effective vaccine formulation toward a desired clinical benefit for a clinical vaccine to maximize protection. In addition, data also suggest that further improvement in the efficacy is possible when a laser adjuvant is combined with chemical or biological adjuvant(s). To realize these goals, further efforts to uncover the molecular mechanisms of action of the laser adjuvants is warranted. This review provides a summary and comments of the recent updates in the laser adjuvant technology.

ADJUVANT AND OTHER EFFECTS OF BCG VACCINE AND ITS INFLUENCE ON THE EPIDEMIOLOGY OF NEW CORONAVIRUS DISEASE COVID-19

The live BCG vaccine, causing a complex response of both innate and cellular as well as humoral adaptive immunity, is a biological adjuvant. It serves as a trigger for a "trained" immune system response, characterized by the activation of monocytes, macrophages, natural killer cells, and lymphoid elements of inborn populations, all contribute to the early activation of non-antigen-specific protective programmes of the body fight against a number of viral, fungal, protozoan infections and neoplastic clones. One of the infections, altered by BCG vaccination, may be COVID-19. The pathogenesis of the development of acute interstitial pneumonia/respiratory distress syndrome caused by COVID-19 is characterized by the triggering of excessive systemic action of inflammatory mediators, in particular, cytokines, due to violation of the focal inflammatory barriers. Gamma-interferon, produced by lymphocytes after BCG vaccination, modulates the activity of a number of interleukins, which in turn may attenuate course of COVID-19 by reducing the activity of IL-12 and IL-18 -dependent reactions. There is an antigenic cross-reaction between the peptides from causative agents of mycobacterioses and SARS-CoV2 because of their proteins' homology. Unlike many adjuvants, BCG decreases the incidence of lymphoid malignancies and its effect on various autoimmunopathies is different, not necessarily harmful. The peculiar character of BCG vaccination effect may be related to its very early impact on immature immune system and symbiotic character of host-BCG interactions. Geo-epidemiological data on the relationship between the historical practice of using BCG vaccination in different countries and the current incidence of new coronavirus infection and mortality from it are presented. Historically, the medical and social reasons for the different national policies of health authorities regarding the use of the BCG vaccine are considered.

Histological and Biomechanical Evaluation of Biologic Adjuvants in a Murine Tendon Bone Healing Model

Histological and Biomechanical Evaluation of Biologic Adjuvants in a Murine Tendon Bone Healing Model

Histological and Biomechanical Evaluation of Biologic Adjuvants in a Murine Tendon Bone Healing Model

Histological and Biomechanical Evaluation of Biologic Adjuvants in a Murine Tendon Bone Healing Model

A DNA Vaccine Expressing Fusion Protein E2-NT(gp96) Induces Hepatitis C Virus Cross-Neutralizing Antibody in BALB/c Mice

Background: Development of an effective prophylactic vaccine is the optimal long-term goal for the eventual control of HCV infection. An effective HCV vaccine should be able to elicit neutralizing antibodies (NAbs). Glycoprotein E2 of HCV is the major target for NAbs. Methods: In this study, we designed and constructed a DNA vaccine (pcDNA-E2-NT(gp96)) encoding a fusion protein composed of HCV E2 ectodomain (genotype 1a) and N-terminal domain of gp96 as a biological adjuvant. Two possible forms of a fusion protein, namely E2-NT(gp96) and NT(gp96)-E2, were made and subjected to in silico modeling and analysis. After the selection of the best form and confirmation its expression capacity in COS-7 cells, recombinant pcDNA-E2-NT(gp96) plasmid was generated by cloning of target genes into pcDNA3.1(+) plasmid. Constructed DNA vaccine immunogenicity was evaluated in BALB/c mice by measurement specific antibodies by ELISA and their neutralization capacity by neutralization assay. Results: In silico modeling and analysis showed that the E2-NT(gp96) structure was more valid than NT(gp96)-E2. Docking result revealed that the selected fusion protein had a high tendency for interaction with the main receptor (CD81) of HCV. GFP expression in COS-7 cells confirmed the E2-NT(gp96) expression capacity. Restriction enzyme digestion and sequencing results confirmed the integrity of the constructed plasmid. ELISA results showed that the pcDNA-E2-NT(gp96) induced high titers of specific antibodies in immunized mice. The sera of immunized mice cross-neutralized JFH1/HCVcc genotype 2a by 55% relative to pre-immune sera. Conclusions: Total results showed that the generated DNA vaccine induced potent immune responses in immunized mice. Therefore, our findings are sufficiently encouraging to propose the pcDNA-E2-NT(gp96) as a promising vaccine candidate for HCV infection.

33. Comparison of bone morphogenetic protein and allogeneic stem cells in lateral interbody lumbar fusion

BACKGROUND CONTEXT Lateral interbody fusion (LLIF) is often performed with biologic adjuvants to promote fusion. Commercially available bone allograft containing allogeneic stem cells (ASC) and bone morphogenetic protein-2 (BMP) are designed to promote fusion while avoiding the morbidity of iliac crest autograft; however, no study to date has directly compared the two in LLIF. The ASC studied is Osteocel Pro (NuVasive, Inc). PURPOSE This non-industry funded study compares fusion rate, complications, and costs between LLIF with BMP and ASC. STUDY DESIGN/SETTING Single center retrospective comparative study. PATIENT SAMPLE Patients with 1-3 lumbar levels treated with LLIF. OUTCOME MEASURES Outcomes measures are fusion at 1 year postoperative, complication rates, length of stay, and costs. METHODS A retrospective chart review was conducted to identify patients treated with LLIF and ASC or BMP from February 2012 through September 2017. Patients were included who had from 1-3 lumbar levels treated with LLIF and at least 1 year of radiographic follow up. Interbody fusion was assessed on lumbar X-ray images using a validated scale. RESULTS A total of 94 patients were included representing 162 levels fused. Of these, 74 patients and 133 levels were treated with BMP; 20 patients and 29 levels were treated with ASC. Comparing patients treated with BMP or ASC, there were no differences in age [61.6 vs 60.4, p=0.7], BMI [29.8 vs 28.3, p=0.3], gender [60.8% vs 55.0% female], smoking status [12.2% vs 10.0%, p=1], diabetes [28.4% vs 15.0%, p=0.2], Charleston Comorbidity Index [4.3 vs 3.5, p=0.2], revision status [47.3% vs 45.0%, p=0.9], intraoperative complications [4.1% vs 5.0%, p=1], postoperative complications [37.8% vs 30.0%, p=0.5], or blood loss [881 vs 528ml, p=0.2]. More levels were fused in the BMP group (1.8 vs 1.45, p=0.04) and the BMP group tended toward a longer length of stay [4.8 vs 3.8 days, p=0.06]. There was a nonsignificant trend toward a higher fusion rate with BMP vs ASC[98.5% vs 93.1%, p=0.1]. The average amount of rhBMP used per level was 2.0 cc compared to 5.9 cc of ASC. There was no difference in the cost of the BMP per level compared with ASC [4.45% vs 4.80%, p=0.33], but the BMP group tended toward a higher cost of total care [103.5% vs 87.6%, p=0.1]. CONCLUSIONS ASC and BMP are both acceptable adjuvants in LLIF that demonstrate comparable fusion rates at 1 year with comparable cost in the setting of similar groups of patients. The radiographic fusion rate seen in our study compares to previous reports in the literature using ASC. Cost considerations are becoming ever more cogent in spine surgery; the results of this study can inform decision making regarding which biologic adjuvant to use in lumbar interbody fusion. FDA DEVICE/DRUG STATUS Osteocel (Approved for this indication), rhBMP (Infuse) (Not approved for this indication)

Abstract A009: Forty-three week follow-up of a phase 1a clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients

Abstract While progress has occurred in both cellular and immune checkpoint therapy, the benefit of therapeutic cancer vaccines has been difficult to demonstrate. Prostate cancer may be an exception with the modest activity of Sipuleucel T. We have developed a potentially low cost and easy to administer therapeutic vaccine with the combination of tumor antigen (PSA) and biologic adjuvants (IL2 and GM-CSF). This study is a phase 1a clinical trial of a PSA/IL-2/GM-CSF vaccine in biochemically recurrent hormone-naïve and hormone-independent prostate cancer patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of serious adverse events (SAEs) and dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations (“induction vaccination”). Twenty patients enrolled and nineteen patients completed all six intradermal injections (one patient received 5 vaccines, missed week 11 vaccine) of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11 and 15. None of the patients vaccinated in the phase 1a portion had an SAE or DLAE with the most common AE relating to grade 1 injection site reactions. Fifteen of the 18 patients who received vaccines had immune responses to PSA as demonstrated in a lymphocyte blastogenesis assay by week 31. Interestingly, after vaccination 14 of 20 patients had an increase in the doubling time of their serum PSA, suggesting a slowing of the growth of the prostate cancer. Five of 20 patients have progressed (3 PSA progression and 2 radiologic progression) at 43 weeks’ follow-up. Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle McKinney, Jessica Wang-Rodriguez. Forty-three week follow-up of a phase 1a clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A009.

Biologic Adjuvants for the Management of Osteochondral Lesions of the Talus.

Surgical techniques for the management of recalcitrant osteochondral lesions of the talus have improved; however, the poor healing potential of cartilage may impede long-term outcomes. Repair (microfracture) or replacement (osteochondral transplants) is the standard of care. Reparative strategies lead to production of fibrocartilage, which, compared with the native type II articular cartilage, has decreased mechanical and wear properties. The success of osteochondral transplants may be hindered by poor integration between grafts and host that results in peripheral cell death and cyst formation. These challenges have led to the investigation of biologic adjuvants to augment treatment. In vitro and in vivo models have demonstrated promise for cartilage regeneration by decreasing inflammatory damage and increasing the amount of type II articular cartilage. Further research is needed to investigate optimal formulations and time points of administration. In addition, clinical trials are needed to investigate the long-term effects of augmentation.

The composite biological adjuvants enhance immune response of porcine circovirus type2 vaccine

The porcine circovirus (PCV) is one of the most economically important infection diseases of pigs. Granulocyte–macrophage colony-stimulating factor (GM-CSF) or Flic as an immune adjuvant has been shown to enhance the immunogenicity of vaccines in previous study. However, the composite biological adjuvants stimulate more effective immunological response. In this study, the porcine GM-CSF (pGM-CSF) and FliC protein were expressed by pSUMO in E.coli Rosetta (DE3) and purified by Ni-NTA Sepharose, respectively. The immunogenicity of PCV vaccine with pGM-CSF and FliC was firstly evaluated to identify the immunoenhancement in mice. The results indicated that mice immunized with vaccine + pGM-CSF + FliC enhanced immune responses ability significantly and quickly. Then, the immune response level of PCV vaccine with pGM-CSF and FliC was assessed in piglets. The results indicated that pigs immunized with vaccine + pGM-CSF + FliC showed significantly higher PCV antibody level than those immunized with vaccine and single adjuvant or vaccine alone. Furthermore, pigs in the vaccine + pGM-CSF + FliC group elicited stronger CD4+ and CD8 + T cells proliferative responses than those in all other groups and showed the effectively up-regulated transcriptional level of IL-1, IL-8 and IL-17 stimulating the immune system. We demonstrated that GM-CSF and FliC as composite biological adjuvants of the vaccine showed a stronger immune response and it is promising application for vaccines to against PCV.

Clinical subtypes and prognosis in breast cancer according to parity: a nationwide study in Korean Breast Cancer Society.

We explored the association between parity and the risk of developing a specific subtype of breast cancer. We also assessed the association between parity and prognosis according to subtypes. A total of 158,189 patients were enrolled in the Korean Breast Cancer Society Registry database between 1996 and 2015 in Korea. The database provided information on sex, age, number of parity, surgical method, stage, histological findings, presence of biologic markers, adjuvant therapy, and date and cause of death. The patients with higher parity showed a higher ratio of triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2) subtypes. In univariate analysis, women with TNBC who had more than three children had a worse prognosis compared to other groups (HR 1.83; 95% CI 1.34-2.49; P < 0.001). This association was also observed in women younger than 50years (HR 1.63; 95% CI 1.07-2.48; P = 0.021). In multivariate analysis stratified by subtypes, women who had more than three children were associated with a worse prognosis in TNBC in the total population (HR 1.53; 95% CI 1.11-2.12; P = 0.011). This association was also observed in patients younger than 50years of age (HR 1.53; 95% CI 1.09-2.61; P = 0.017). Women who had more than three children were more likely to develop hormone receptor-negative (HR-) subtypes. Women who had more than three children were associated with worse prognosis in patients younger than 50years of age and in patients with TNBC.

Evaluating the Current Literature on Treatments Containing Adipose-Derived Stem Cells for Osteoarthritis: a Progress Update.

Recent studies have investigated the effect of treatments containing adipose-derived mesenchymal stem cells (ADMSCs) on human osteoarthritis. These have mostly used biologic adjuvants which may influence results. Thus, the purpose of this systematic review is to evaluate the current literature on these treatments when used in isolation. Five studies in this review used cultured ADMSCs, while four studies used stromal vascular fraction and three used micro-fragmented adipose tissue to deliver ADMSCs. No studies reported serious treatment-related adverse effects and all reported improvements in clinical measures for at least one dose. This was not necessarily reflected in imaging evaluations nor were improvements always maintained. Current low-level evidence is limited due to variability in study methodology but indicates that treatments containing ADMSCs, when used in isolation, are safe and have the potential to reduce pain and improve function. Randomized controlled trials are now needed.

Abstract A45: Preliminary results of a phase 1 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”). The patients will receive intradermal injections of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11 and 15. Enrollment of the twenty patients in the Phase 1a has been completed. To date, 14 patients in the Phase 1a portion of the trial have received all 6 vaccines. Twelve of the 15 patients who have received vaccines have increased immune responses to PSA in a lymphocyte blastogenesis assay by week 19. After 6 vaccines, 9 of 14 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 33 months. None of the patients vaccinated in the Phase 1a portion have had a DLAE. Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle McKinney, Weg Ongkeko, Kyoko Sakamoto, Jessica Wang-Rodriguez. Preliminary results of a phase 1 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 AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A45.

Select Biomarkers on the Day of Anterior Cruciate Ligament Reconstruction Predict Poor Patient-Reported Outcomes at 2-Year Follow-Up: A Pilot Study.

Background The majority of patients develop posttraumatic osteoarthritis within 15 years of anterior cruciate ligament (ACL) injury. Inflammatory and chondrodegenerative biomarkers have been associated with both pain and the progression of osteoarthritis; however, it remains unclear if preoperative biomarkers differ for patients with inferior postoperative outcomes. Hypothesis/Purpose The purpose of this pilot study was to compare biomarkers collected on the day of ACL reconstruction between patients with “good” or “poor” 2-year postoperative outcomes. We hypothesized that inflammatory cytokines and chondrodegenerative biomarker concentrations would be significantly greater in patients with poorer outcomes. Study Design Prospective cohort design. Methods 22 patients (9 females, 13 males; age = 19.5 ± 4.1 years; BMI = 24.1 ± 3.6 kg/m2) previously enrolled in a randomized trial evaluating early anti-inflammatory treatment after ACL injury. Biomarkers of chondrodegeneration and inflammation were assessed from synovial fluid (sf) samples collected on the day of ACL reconstruction. Participants completed Knee Injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) questionnaires two years following surgery. Patients were then categorized based on whether their KOOS Quality of Life (QOL) score surpassed the Patient Acceptable Symptom State (PASS) threshold of 62.5 points or the IKDC PASS threshold of 75.9 points. Results Patients that failed to reach the QOL PASS threshold after surgery (n = 6, 27%) had significantly greater sf interleukin-1 alpha (IL-1α; p = 0.004), IL-1 receptor antagonist (IL-1ra; p = 0.03), and matrix metalloproteinase-9 (MMP-9; p = 0.01) concentrations on the day of surgery. Patients that failed to reach the IKDC PASS threshold (n = 9, 41%) had significantly greater sf IL-1α (p = 0.02). Conclusion These pilot data suggest that initial biochemical changes after injury may be an indicator of poor outcomes that are not mitigated by surgical stabilization alone. Biological adjuvant treatment in addition to ACL reconstruction may be beneficial; however, these data should be used for hypothesis generation and more definitive randomized clinical trials are necessary.

Abstract CT061: Interim results of a phase Ia clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients

Abstract While progress has occurred in both cellular and immune checkpoint therapy, the benefit of therapeutic cancer vaccines has been difficult to demonstrate. Prostate cancer may be an exception with the modest activity of sipuleucel-T. We have developed a potentially lower cost and easy to administer therapeutic vaccine with the combination of tumor antigen (PSA) and biologic adjuvants (IL-2 and GM-CSF). This study is a Phase 1a clinical trial of a PSA/IL-2/GM-CSF vaccine in 20 biochemically recurrent hormone-naïve and hormone-independent prostate cancer patients. Major inclusion criteria include adenocarcinoma of the prostate, rising serum PSA and no measurable disease. Phase 1a examines the rate of serious adverse events (SAEs) and dose limiting adverse events (DLAEs) in an initial course of 6 vaccinations (“induction vaccination”). Twenty patients enrolled and nineteen patients completed all six intradermal injections (one patient received 5 vaccines, missed week 11 vaccine) of the PSA/IL-2/GM-CSF vaccine at weeks 1, 2, 3, 7, 11 and 15. None of the patients vaccinated in the Phase 1a portion had a SAE or DLAE with the most common AE relating to grade 1 injection site reactions. Fifteen of the 18 patients who received vaccines had immune responses to PSA as demonstrated in a lymphocyte blastogenesis assay by week 31. Interestingly, after vaccination 14 of 20 patients had an increase in the doubling time of their serum PSA, suggesting a slowing of the growth of the prostate cancer. Four of 20 patients have progressed (3 PSA progression and 1 radiological progression) at 31 weeks follow-up. Citation Format: Jonathan F. Head, Gregory A. Daniels, Michelle A. McKinney, Weg M. Ongkeko, Kyoko Sakamoto, Jessica Wang-Rodriguez. Interim results of a phase Ia clinical trial of a PSA, IL-2, GM-CSF containing prostate cancer therapeutic vaccine in PSA defined biochemical recurrent prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT061.

Characterization and in vitro expression studies of a potential xenogeneic DNA vaccine against canine mammary tumours

Matrix metalloproteinases-7 (MMP-7) which is expressed in a wide variety of malignant cells has been seen tobe extensively up-regulated in mammary carcinomas. MMP-7 can promote cancer invasion and angiogenesis through proteolytic cleavage of extracellular matrix and basement membrane proteins. This property of MMP-7 makes it a promising target in the context of immunotherapy. Further, to enhance DNA-based immunization, a cytokine gene can be employed as an adjuvant. Interleukin-18 (IL-18) is a Th1-type cytokine that has been demonstrated as a potential biological adjuvant in murine tumour models. The present study was undertaken to clone murine MMP-7 (mMMP-7) and IL-18 genes in pVIVO2.mcs eukaryotic expression vector and to characterize their expression by immunofluorescence and Western blotting. This double gene construct now may be used as a potential xenogeneic DNA vaccine against canine tumour model.