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

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

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

TCR Gene Transfer: MAGE-C2/HLA-A2 and MAGE-A3/HLA-DP4 Epitopes as Melanoma-Specific Immune Targets

Adoptive therapy with TCR gene-engineered T cells provides an attractive and feasible treatment option for cancer patients. Further development of TCR gene therapy requires the implementation of T-cell target epitopes that prevent “on-target” reactivity towards healthy tissues and at the same time direct a clinically effective response towards tumor tissues. Candidate epitopes that meet these criteria are MAGE-C2336-344/HLA-A2 (MC2/A2) and MAGE-A3243-258/HLA-DP4 (MA3/DP4). We molecularly characterized TCRαβ genes of an MC2/A2-specific CD8 and MA3/DP4-specific CD4 T-cell clone derived from melanoma patients who responded clinically to MAGE vaccination. We identified MC2/A2 and MA3/DP4-specific TCR-Vα3/Vβ28 and TCR-Vα38/Vβ2 chains and validated these TCRs in vitro upon gene transfer into primary human T cells. The MC2 and MA3 TCR were surface-expressed and mediated CD8 T-cell functions towards melanoma cell lines and CD4 T-cell functions towards dendritic cells, respectively. We intend to start testing these MAGE-specific TCRs in phase I clinical trial

Pre-operative Evaluation of Eustachian Tube Function Using a Modified Pressure Equilibration Test is Predictive of Good Postoperative Hearing and Middle Ear Aeration in Type 1 Tympanoplasty Patients

ObjectivesThe Eustachian tube (ET) plays an important role in maintaining a normally aerated middle ear. Inflammation in middle ear disease is related to ET dysfunction, and postoperative restoration of middle ear integrity and hearing are closely related to ET function in chronic ear disease patients. After successful tympanoplasty, restoration of a well-aerated middle ear with good ET function can permit better compliance of the tympanic membrane. In this study, we evaluated the predictive validity of preoperative ET function measurements.MethodsWe reviewed 137 patients who underwent type 1 tympanoplasty. All patients had non-cholesteatomatous chronic otitis media and received canal wall-up-type tympanomastoidectomies. Patients were categorized into four groups according to preoperative ET function measurements using a modified pressure inflation-deflation equilibration test. Group I patients had residual pressures less than 10 daPa, and Group IV patients showed no pressure change (poor results). Groups II and III were intermediate. Hearing levels were determined using pure tone averages at four frequencies. Postoperative tympanography was performed to determine middle ear aeration.ResultsThe preoperative air bone (AB) gap was 29.6±7.0 dB, and the postoperative gap was 16.5±5.7 dB; thus, there was significant overall improvement. In all groups, hearing was significantly better after surgery, but the worst postoperative hearing level was seen in Group IV patients. Type B tympanograms were more frequently recorded in Group IV patients than they were in Group I or II patients. Postoperative AB gaps were 9.2±3.8 dB in patients with type A tympanograms, 13.4±2.1 dB in those with type As, 24.1±2.5 dB in those with type C, and 18.5±2.8 dB in those with type B.ConclusionET function measured with a modified pressure equilibration test using an inflation-deflation manometric method is a good indicator of an aerated middle ear and is predictive of improved postoperative hearing

Nurses’ Contacts and Potential for Infectious Disease Transmission

These data can help predict staff availability and provide information for pandemic preparedness planning