Towards clinical TCR gene therapy: tumor models and receptors

During the past few decades great progress has been made in the field of cancer immune therapy. There has been increased understanding on strategies tumors use to induce immune tolerance and evade immune responses, which enabled the design of clinical immune therapy trials. Two recent approaches that either oppose or circumvent immune tolerance towards tumors have successfully been tested in phase I clinical trials. First, immune tolerance can be opposed by monoclonal antibodies that block T cell inhibitory molecules. For example, Ipilimumab and MDX-1106 block Cytotoxic T-Lymphocyte Antigen- 4 (CTLA-4) and Programmed Death-1 (PD-1) receptor, respectively, and administration of these antibodies resulted in anti-tumor activities in patients with metastatic melanoma and renal cell carcinoma. In fact, the combination of Ipilimumab and Dacarbazine (DTIC, currently the standard first-line treatment for melanoma) increased the response rates by three-fold. These results have encouraged further testing of dosing and combinations of these immune modulating reagents. Second, immune tolerance can be circumvented by adoptive transfer of autologous and ex-vivo expanded tumor infiltrating lymphocytes (TILs). TIL therapy preceded by non-myeloablative lymphodepletion resulted in objective response rates in about 50% of advanced metastatic melanoma patients in two different medical centers, suggesting, but not yet proving anti-melanoma activity. Equally interesting were the complete responses observed in TIL therapy that ranged between 10 and 22% and seem higher than those observed for other treatments of melanoma (see Table 1). Recently, a simpler and faster method was developed to generate ‘young’ TILs that harbor characteristics associated with improved T cell persistence and in vivo survival. This young TIL culture protocol yields bulk T cells, omits the extensive in vitro testing of tumor reactivity, enriches for CD8+ T cells and depletes suppressive T cells (Treg cells). Next to TILs, adoptive transfer of tumor specific T cell clones generated from autologous peripheral T cells resulted in objective responses in 8 out of 10 metastatic melanoma patients. Notably, Butler and colleagues ‘educated’ peripheral T cells using artificial antigen-presenting cells loaded with HLA-A2-restricted tumor antigens. This protocol yielded tumor-specific T cells that are clinically long-lived and effective in melanoma patients. Collectively, the above-mentioned studies show the potential of immune therapy and especially the successes of adoptive therapy with tumor-specific T cells

The role of coinfections in HIV epidemic trajectory and positive prevention: a systematic review and meta-analysis.

OBJECTIVES: Recurrent or persistent coinfections may increase HIV viral load and, consequently, risk of HIV transmission, thus increasing HIV incidence. We evaluated the association between malaria, herpes simplex virus type 2 (HSV-2) and tuberculosis (TB) coinfections and their treatment on HIV viral load. DESIGN: Systematic review and meta-analysis of the association of malaria, HSV-2 and TB coinfections and their treatment with HIV viral load. METHODS: PubMed and Embase databases were searched to 10 February 2010 for studies in adults that reported HIV plasma and/or genital viral load by coinfection status or treatment. Meta-analyses were conducted using random-effects models. RESULTS: Forty-five eligible articles were identified (six malaria, 20 HSV-2 and 19 TB). There was strong evidence of increased HIV viral load with acute malaria [0.67 log(10) copies/ml, 95% confidence interval (CI) 0.15-1.19] and decreased viral load following treatment (-0.37 log(10) copies/ml, 95% CI -0.70 to -0.04). Similarly, HSV-2 infection was associated with increased HIV viral load (0.18 log(10) copies/ml, 95% CI 0.01-0.34), which decreased with HSV suppressive therapy (-0.28 log(10) copies/ml, 95% CI -0.36 to -0.19). Active TB was associated with increased HIV viral load (0.40 log(10) copies/ml, 95% CI 0.13-0.67), but there was no association between TB treatment and viral load reduction (log(10) copies/ml -0.02, 95% CI -0.19 to 0.15). CONCLUSION: Coinfections may increase HIV viral load in populations where they are prevalent, thereby facilitating HIV transmission. These effects may be reversed with treatment. However, to limit HIV trajectory and optimize positive prevention for HIV-infected individuals pre-antiretroviral therapy, we must better understand the mechanisms responsible for augmented viral load and the magnitude of viral load reduction required, and retune treatment regimens accordingly

An in vitro model of murine middle ear epithelium.

Otitis media (OM) or middle ear inflammation is the most common pediatric disease and leads to significant morbidity. Although understanding of underlying disease mechanisms is hampered by complex pathophysiology it is clear that epithelial abnormalities underpin the disease. There is currently a lack of a well characterised in vitro model of the middle ear (ME) epithelium that replicates the complex cellular composition of the middle ear. Here we report the development of a novel in vitro model of mouse middle ear epithelial cells (mMECs) at air liquid interface (ALI) that recapitulates the characteristics of the native murine ME epithelium. We demonstrate that mMECs undergo differentiation into the varied cell populations seen within the native middle ear. Proteomic analysis confirmed that the cultures secrete a multitude of innate defence proteins from their apical surface. We could show that the mMECs supported the growth of the otopathogen, NTHi, suggesting that the model can be succesfully utilised to study host pathogen interactions in the middle ear. Overall, our mMEC culture system can help better understand the cell biology of the middle ear and improve our understanding of the pathophysiology of OM. The model also has the potential to serve as a platform for validation of treatments designed to reverse aspects of epithelial remodelling underpinning OM development

Prioritization strategies for pandemic influenza vaccine in 27 countries of the European Union and the Global Health Security Action Group: a review

Background: Although there is rapid progress in vaccine research regarding influenza pandemic vaccines it is expected that pandemic influenza vaccine production can only start once the pandemic virus has been recognized. Therefore, pandemic vaccine capacity will be limited at least during the first phase of an influenza pandemic, requiring vaccine prioritization strategies. WHO recommends developing preliminary priorities for pandemic vaccine use. The goal of this review is to provide a thorough overview of pandemic vaccine prioritization concepts in the 27 European Union (EU) member states and the four non-EU countries of the Global Health Security Action Group. Methods: Between September and December 2006 data was collected for each country through two data sources: (i) the national influenza pandemic plan; (ii) contacting key persons involved in pandemic planning by email and/or phone and/or fax Results: Twenty-six (84%) countries had established at least one vaccine priority group. Most common reported vaccine priority groups were health care workers (HCW) (100%), essential service providers (ESP) (92%) and high risk individuals (HRI) (92%). Ranking of at least one vaccine priority group was done by 17 (65%) of 26 countries. Fifteen (88%) of these 17 countries including a ranking strategy, decided that HCW with close contact to influenza patients should be vaccinated first; in most countries followed and/or ranked equally by ESP and subsequently HRI. Rationales for prioritization were provided by 22 (85%) of 26 countries that established vaccine priority groups. There was large variation in the phrasing and level of detailed specification of rationales. Seven (32%) of 22 countries providing rationales clearly associated each vaccine priority group with the specific rationale. Ten (32% of the 31 countries studied) countries have consulted and involved ethical experts to guide decisions related to vaccine prioritization. Conclusion: In the majority of the countries the establishment of vaccine priority groups, ranking and underlying rationales are in line with WHO recommendations. In most public plans the criteria by which prioritized groups are identified are not easily recognizable. Clarity however, may be necessary to assure public acceptability of the prioritization. Ethical experts, results of modelling exercises could play an increasing role in the future decision making process

The Bandim TBscore – reliability, further development, and evaluation of potential uses

Background: The tuberculosis (TB) case detection rate has stagnated at 60% due to disorganized case finding and insensitivity of sputum smear microscopy. Of the identified TB cases, 4% die while being treated, monitored with tools that insufficiently predict failure/mortality. Objective: To explore the TBscore, a recently proposed clinical severity measure for pulmonary TB (PTB) patients, and to refine, validate, and investigate its place in case finding. Design: The TBscore's inter-observer agreement was assessed and compared to the Karnofsky Performance Score (KPS) (paper I). The TBscore's variables underlying constructs were assessed, sorting out unrelated items, proposing a more easily assessable TBscoreII, which was validated internally and externally (paper II). Finally, TBscore and TBscoreII's place in PTB-screening was examined in paper III. Results: The inter-observer variability when grading PTB patients into severity classes was moderate for both TBscore (κ W=0.52, 95% CI 0.46–0.56) and KPS (κ W=0.49, 95% CI 0.33–0.65). KPS was influenced by HIV status, whereas TBscore was unaffected by it. In paper II, proposed TBscoreII was validated internally, in Guinea-Bissau, and externally, in Ethiopia. In both settings, a failure to bring down the score by ≥25% from baseline to 2 months of treatment predicted subsequent failure (p=0.007). Finally, in paper III, TBscore and TBscoreII were assessed in health-care-seeking adults and found to be higher in PTB-diagnosed patients, 4.9 (95% CI 4.6–5.2) and 3.9 (95% CI 3.8–4.0), respectively, versus patients not diagnosed with PTB, 3.0 (95% CI 2.7–3.2) and 2.4 (95% CI 2.3–2.5), respectively. Had we referred only patients with cough >2 weeks to sputum smear, we would have missed 32.1% of the smear confirmed cases in our cohort. A TBscoreII>=2 missed 8.6%. Conclusions: TBscore and TBscoreII are useful monitoring tools for PTB patients on treatment, as they could fill the void which currently exists in risk grading of patients. They may also have a role in PTB screening; however, this requires our findings to be repeated elsewhere

Automatic Outbreak Detection Algorithm versus Electronic Reporting System

To determine efficacy of automatic outbreak detection algorithms (AODAs), we analyzed 3,582 AODA signals and 4,427 reports of outbreaks caused by Campylobacter spp. or norovirus during 2005–2006 in Germany. Local health departments reported local outbreaks with higher sensitivity and positive predictive value than did AODAs

Timeliness of Surveillance during Outbreak of Shiga Toxin–producing Escherichia coli Infection, Germany, 2011

In the context of a large outbreak of Shiga toxin–producing Escherichia coli O104:H4 in Germany, we quantified the timeliness of the German surveillance system for hemolytic uremic syndrome and Shiga toxin–producing E. coli notifiable diseases during 2003–2011. Although reporting occurred faster than required by law, potential for improvement exists at all levels of the information chain