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Category Archive: Chemical Products
The formation of foam in aqueous processes and products—such as flume water for the transport of vegetables—can hinder or halt many industrial processing operations. Antifoams are chemicals which prevent the formation of foam, whereas defoamers control existing foam. The right antifoam must be applied properly to prevent foam formation and avoid additional problems in the production process.
The following article provides Applied Material Solution’s top tips regarding the proper use of antifoam products.
Survey the System
Before applying an antifoam to your operation, it’s important to thoroughly survey system processes to determine where and when the antifoam would serve most effectively.
- Is it an aqueous or non-aqueous system?
- What is causing the foam?
- Soap formation
- Is the foam solid stabilized?
- Get water flow diagrams and process flow diagrams when available, or draw your own. You must understand the process and what is being made. You need to know:
- Where the water came from.
- Where the water is going.
- For batch operations, what are the batch sizes? For continuous operations, what is the production rate?
- What is the pH of the system? Take note of any pH changes throughout the production process.
- Are there any chemical restrictions to the system?
- What is the temperature of the system? Take note of any temperature changes throughout the production process.
- What are the points of high and low tabulation?
- Locate the points where air may be released.
- Locate the points where air can be introduced.
- Are there any filtration membranes used in the process?
- Are there any regulatory requirements involved?
Evaluate the Point of Addition
The place and time at which antifoams should be added depends on the specifics of the process. However, as a general rule, antifoams should be applied at the point that allows for maximum dispersion through the foaming liquid and often prior to the onset of foaming. To obtain the best results, some processes may necessitate the addition of antifoam at multiple points.
Peristaltic and low-flow metering pumps are effective tools for automating the dispensing operation. Facility workers and/or vendors can set up pumps to add a predetermined concentration of antifoam/defoamer per minute, thus optimizing the performance of the foam control agent.
Test the Antifoaming Agent in Advance
Antifoams are available in multiple types of formulations of varying chemistries, each of which performs differently. When choosing a new antifoam product, it is important to understand the process and where foam poses an issue. It is critical, as previously stated, to survey the system.
While the answers to the Survey questions can help ensure the appropriate selection of the antifoam, thorough testing is also essential for determining the antifoam’s compatibility and performance within a particular application. When testing the antifoaming agent, simulate the expected operating conditions, especially the temperature, by using a medium that is similar—if not identical—to the actual foaming medium. When possible, the actual foaming medium is best.
Determine How Much Foam Is Okay
While some processing operations can handle a small amount of foam, others require complete foam elimination. In either case, the end user must determine whether a potential antifoaming agent can successfully control foam without undermining the quality of the product or process. As long as operation continues as expected, some foam in the process would just be an appearance issue, yet present no real issue or problem to the production operation.
Quality Antifoam Products from Applied Material Solutions
At Applied Material Solutions (AMS), we offer an extensive selection of antifoams and defoamers across a range of silicone and non-silicone formulations.
Our silicone antifoam products include:
- Non-aqueous silicone antifoam compounds
- Specialty silicone antifoams
- Water-based antifoam emulsions
Our non-silicone antifoam products include:
- Oil-based antifoams
- Surfactant-based and polymer-based antifoams
- Ester-based antifoams
- Water-based antifoams
AMS can assist customers with the selection of an optimal antifoam for their unique process. Once an antifoam solution is chosen, we can also help optimize the location, frequency, and antifoam dosage to ensure the best results.
For more information about our antifoaming products and services, contact us today.
Brownstock washing is a complex, dynamic process in which dirty wash water or weak black liquor (dissolved organic and inorganic material obtained from the pulp cooking process) is separated from the pulp fibers1. The organic materials are recovered for their fuel value and the inorganic material is recovered for the sodium content to regenerate NaOH.
Under-designed capital equipment can be augmented using chemical enhancements. In the case of brownstock washers, the application of defoamer is required to improve mat drainage and to control foam to enable overloaded washers to wash efficiently; this also allows pulp from the digesters to flow continuously to the bleach plant and/or the paper machine.2
Washing efficiency directly correlates to pulp cleanliness. Cleaner pulp results in better chemical recovery, lower bleaching costs, fewer deposition issues, and more consistent pulp is sent to the paper machine.
The following article provides an overview of brown stock washing deformers, outlining how they work, key benefits, and the types available.
How Do Brown Stock Washing Defoamers Work?
Brownstock washing defoamers have two purposes. First is to control the foam and prevent vats from overflowing onto the floor causing loss of product (the pulp) and housekeeping issues, while providing drainage on the washers which provides cleaner pulp and improves washing efficiency.
Second is to recover valuable spent liquor. The black liquor is recovered for the fuel value and to regenerate NaOH by recovering sodium from the washing process.
The foam level in the vat is not an indication of how well the defoamer is performing. If the foam is not spilling over on to the floor it is then purely cosmetic. The real indication of the defoamer’s performance is how well the foam is being released from the fiber. When the foam is released from the fiber it allows drainage.
It is important to understand the defoamer must have a positive Entry Coefficient and a positive Spreading Coefficient. These are expressed in the following equations:
(Entry Coefficient) E = γw/a + γw/o – γo/a
Where γ is the surface tension or interfacial tension in dynes/cm2
(Spreading Coefficient) S = γw/a – γw/o – γo/a
Where “w” is water, “o” is oil, and “a” is air
The equations briefly explained:
The Entry Coefficient is equal to the surface tension of the black liquor + the interfacial tension between liquor and oil (i.e. the defoamer), minus the surface tension of the oil. This allows the defoamer droplet to enter the monolayer at the air/water interface.
The same is true for the Spreading Coefficient: black liquor – the interfacial tension between liquor and oil, minus the surface tension of the oil. This causes the defoamer droplet to spread along the air/water interface forming a defoamer “lens.”
Hydrophobic particles within the defoamer facilitate the entering of the oil droplet into the surfactant monolayer at the air/water interface. With a positive Entry Coefficient, the defoamer droplet enters the surfactant monolayer at the air/water interface. Once the droplet is there, the positive Spreading Coefficient allows the defoamer droplet to spread across the monolayer forming a lens. The shape of the lens is altered by the movements in the foam. Stress occurs until the lens breaks and the foam lamella ruptures. This results in foam control throughout the pulp mill.
On fiber, larger and larger bubbles are formed until the buoyancy of the bubble overcomes its adherence to the fiber and floats away from the fiber. The foam on the fiber causes an apparent increase in the fiber’s size. As the foam is removed from the fiber the apparent fiber size decreases creating a shorter path for the water to travel through the mat. The shorter path for the water results in improved drainage.
It should be noted, when using defoamers in brown stock washing operations, it is important to understand that the defoamer must perform a balancing act, where the defoamer is sufficiently compatible in the black liquor to not cause deposition, yet incompatible (insoluble) enough to perform efficiently on the washer. A defoamer is never soluble in the medium it is defoaming.
Benefits of Brown Stock Washing Defoamers
A good defoamer program should facilitate production of the pulp, and add economic value to the pulp mill process by addressing the following:
- Housekeeping issues
- Increased chemical recovery
- Reduced energy costs
- Lower bleaching costs
- The reduction of the environmental impact of the mill
- Fewer safety hazards
- Increased production rates
- Increased quality of the end product
- Lower reject rates3
Types of Defoamers for Brown Stock Washing Operations
Brown stock washing defoamers come in a variety of formulas and strengths to suit the needs of different pulp and paper processes. The types available include:
- Oil-based defoamers
- Water-extended, oil-based defoamers
- Concentrated or water-based silicone defoamers
- Polymer-based defoamers
Oil-based and water-extended oil-based defoamers are less common than they were 15 to 20 years ago. They are used primarily in mills where silicone and/or silicates are not allowed.
Brown Stock Washing Defoamer Solutions From AMS
Brown stock washing defoamers are essential to both product and process quality. As a leading manufacturer and supplier of foam control products, Applied Materials Solutions has an extensive range of products suitable for use in these pulping applications. Our product offerings include:
- Water-based silicone defoamers: (e.g. TRANS-2994 and TRANS-2931)
- Oil-based defoamers: (e.g. TRANS-7285 and TRANS-7115)
For additional information about our brown stock washing defoamers and other product solutions, contact us today.
Brownstock washing – A review of the literature, TAPPI Journal January 2014, Ricardo B. Santos and Peter W. Hart; page 9
Brownstock Washing – Practices and Fundamentals. TAPPI Press, Peter Hart and Michael Brown, Chapter 15, page 545
Brownstock Washing – Practices and Fundamentals. TAPPI Press, Peter Hart and Michael Brown, Chapter 15, page 562
Applied Material Solutions (AMS) is a Wisconsin-based company that manufactures high-quality hydrophobic treated silica products, including both precipitated and fumed varieties. By leveraging our unique range of manufacturing capabilities, our expert team produces a wide range of silica products for use in a diverse set of industries.
The following blog post provides an overview of hydrophobic treated silica products, outlining the chemical properties, applications, and solutions available from AMS.
Chemical Properties of Hydrophobic Treated Silica
In addition to its hydrophobic—i.e., water-repelling—properties, treated silica demonstrates several characteristics that make it well-suited for use in a wide range of applications. As an ingredient in other materials and products, it offers the following benefits:
- Foam control. It serves as a key active ingredient in many foam control products, such as antifoaming agents, defoamers, and deaerators.
- Powder free flow encouragement. It facilitates the free flow of powdered substances that have a tendency to “cake” or clump together. It also enhances their storage stability.
- Processing improvements. The utilization of treated silica allows for optimal processability, hydrophobicity control, thickening, thixotropy, rheology control, and suspension and stability behavior. For example, motionless particles can be restored to their original level of viscosity with a minimum expenditure of energy.
- Adsorbent qualities. It can adsorb compounds in gaseous, liquid, or solid states and act as a carrier that allows for the conversion of liquids and pastes into powders.
- Anti-blocking, anti-sagging, anti-setting, and anti-setoff attributes. An example of an application in which these qualities are critical is in anti-setoff spray powder, which industry professionals use to maintain an air gap between printed sheets of paper to prevent ink bleed-through.
- Mechanical improvements. It can improve tensile strength, elongation at break, and tear resistance and help minimize the effect of temperature on mechanical properties.
- When used in materials, such as polymers, it reinforces both strength and structure.
- Pigment stabilization and dispersion. It can prevent or delay the sedimentation of solids in liquid systems, as well as disperse sediments that have already settled, break down solid particles, and stop such particles from recombining.
- Print definition enhancements. The resolution and print quality of toners can be significantly improved through the use of hydrophobic treated silica.
- Thermal insulation. Amorphous silicon dioxide is a highly non-conductive material, making it an excellent choice for thermal insulation applications.
Common Applications of Hydrophobic Treated Silica
Hydrophobic treated silica finds application in a variety of materials and products. Some of its most common uses include:
- Defoamers and antifoams
- Fire extinguishers
- Silicone rubber
- Silicone sealants
- Paints and coatings
- Polyester resins
- Inks and toners
Hydrophobic Treated Silica Solutions From AMS
At AMS, we manufacture treated silica products for a myriad of customer applications. Armed with years of silica treatment manufacturing experience and a modern manufacturing facility, our team can produce an array of products across a wide range of particle sizes, hydrophobicity levels, and surface areas to suit our customers’ needs.
From development to production to testing and regulation, AMS strives to meet the requirements outlined by our customers and to provide the highest level of quality, accuracy, and performance. In doing so, we aim to minimize customer investment—both in regard to time and money—and maximize customer satisfaction.
For additional information about our treated silica solutions, contact us today.
Corn oil plays a central role in maintaining the profitability of today’s fuel ethanol facilities. Corn oil demulsifiers serve to improve oil release during the mechanical extraction process, resulting in significantly increased corn oil yields. Those improved yields translate to higher profits.
Corn oil demulsifiers also cut down on solids present in corn oil and create cleaner, higher-quality oil. Decreased levels of system deposition also translate to less downtime spent maintaining or cleaning said systems.
How They Work
Corn oil demulsifiers aim to break the emulsion between the water and oil components of the corn oil. When demulsifying agents are dosed, they begin to interfere with the stability of the emulsion. This causes oil droplets to shift around and join together into larger droplets. These larger droplets of corn oil are much easier to separate and capture through the centrifugation process.
Extraction aids like corn oil demulsifiers can also improve the release of corn oil during centrifugation. Their benefits extend beyond the initial dosing period, as well. Demulsifiers modify surface chemistry within the syrup and allow oil to be released more easily, which means that it takes less centrifugal energy to separate the oil from the surface. The result of this process is increased corn oil production and notably cleaner corn oil.
Benefits of Demulsifiers
Corn oil demulsifiers confer a wide array of advantages and AMS’s additives normally result in the following improvements:
- Decreased demulsifier feed rates
- Reduced demulsifier costs
- Higher corn oil yields
- Superior corn oil quality
- Reduced presence of solids in produced oil
- Improved profit margins
- Effectiveness in a broad range of operating conditions
Applied Material Solutions
At Applied Material Solutions, we produce an array of corn oil separation aids and demulsifiers. We also regularly customize our products to align with the individual needs of each plant’s conditions. Our customizable product line includes:
- AMulSion COD-A
- AMulSion COD-G
- AMulSion COD-J
For more information about our selection of corn oil demulsifiers or capabilities, please don’t hesitate to contact our team today to learn how AMS can help improve your corn oil production.


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JAMES Bond fans will need to deploy his famous three digit code number to open a specially designed bottle of the spy's favourite champagne released to coincide with hi latest film Skyfall.
French fizz producer Bollinger, James Bond's preferred bubbles since 1956 in print and the early 1970s on film, has launched one of its best champagnes in a high tech box shaped like the secret agent's favoured Walther PPK gun silencer for the latest top-rating movie Skyfall.
But you'll have to remember Bond's famed triple digit code number to open a combination lock on the package before unmasking the bottle inside, a Bollinger La Grande Annee 2002 high-end vintage champagne.
The wine is considered by the producer one of its best in the past decade.
The complete special edition package costs $288.
The design of the gun-related packaging was not expected to cause a backlash by anti-alcohol lobbyists, Bollinger export director Guy de Rivoire said.
"We consider it to be more about elegance and fun," Mr de Rivoire said.
"We know it will attract a male audience, and there are a lot of female Bond fanatics who are keen champagne drinkers too," he said.
The 007 presentation box is available at specialist wine shops including David Jones, Vintage Cellars and Dan Murphys.
Originally published as Crack Bond's Bollinger champers code

domain: news


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It’s hard to say when my obsession with Diet Dr. Pepper started. It was probably back when the slogan was something like “Tastes more like regular Dr. Pepper.”
But I’m not a big fan of the taste of regular DP. Nope, I love the diet stuff. Seriously! It’s way better tasting with none of the calories. Score!
There’s something so wonderful about the the carbination and the sweet flavor. It’s like having a dessert, only you drink it! I can’t go more than a couple days without one. (Course that’s probably because of the caffeine.)
If you haven’t tried a Diet DP lately, I highly recommend you do.
Who needs coffee when there’s a DDP around until next time? -LJ

domain: food


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Docuworld Film Festival
The world of documentaries!
Because great documentaries change the way we see the world, we dedicate ourselves to exposing documentaries from every corner of the earth, giving a voice to the voiceless.
Take a break from your daily routine and come experience something totally different. Docuworld Film Festival is so much more than just an ordinary Festival.

domain: artistic


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DENVER, CO – July 16, 2021 Everside Health Group, Inc. ("Everside") today announced that it has filed a registration statement on Form S-1 with the U.S. Securities and Exchange Commission (“SEC”) relating to a proposed initial public offering of its common stock. The number of shares to be offered and the price range for the proposed offering have not yet been determined. Everside intends to list its common stock on the New York Stock Exchange under the symbol "EVSD."
Morgan Stanley, J.P. Morgan, Goldman Sachs & Co. LLC, BofA Securities, and William Blair will act as book-running managers for the proposed offering.
The proposed offering will be made only by means of a prospectus. Copies of the preliminary prospectus, when available, may be obtained from:
Morgan Stanley & Co. LLC, Attn: Prospectus Department, 180 Varick Street, 2nd Floor, New York, NY 10014, or by email at email@example.com;
J.P. Morgan Securities LLC, c/o Broadridge Financial Solutions, 1155 Long Island Avenue, Edgewood, NY 11717, by telephone at 866-803-9204 or by email at firstname.lastname@example.org;
Goldman Sachs & Co. LLC, Attn: Prospectus Department, 200 West Street, New York, NY 10282, by telephone at (866) 471-2526 or by email at email@example.com;
BofA Securities, NC1-004-03-43, 200 North College Street, 3rd floor, Charlotte, NC 28255-0001, Attn: Prospectus Department, or by email at firstname.lastname@example.org; or
William Blair & Company, L.L.C., Attn: Prospectus Department, 150 North Riverside Plaza, Chicago, IL 60606, by telephone at (800) 621-0687 or by email at email@example.com.
A registration statement relating to these securities has been filed with the SEC but has not yet become effective. These securities may not be sold, nor may offers to buy be accepted, prior to the time the registration statement becomes effective. This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction.
About Everside Health Everside Health, formerly Paladina Health, Activate Healthcare and Healthstat, is one of the largest direct primary care providers in the U.S., operating 340+ health clinics in 33 states located at or near the facilities of its employer, union and other benefit sponsor clients. Everside's patient-focused, care-obsessed, technology-driven healthcare delivery model aligns incentives to benefit the patient, the physician and the benefit provider, all while reducing the total cost of care. Patients receive convenient, low- or no-cost access to physicians and 24/7 virtual care, reducing the need for costly ER use. Everside Health is based in Denver, Colorado.

domain: economics


President Muhammadu Buhari has vowed that Mazi Nnamdi Kanu, the leader of the Indigenous People of Biafra, IPOB, will never be released.
In a recent interview with Channels, Buhari stated that he would not interfere with the courts.
Remember that some Igbo leaders met with President to demand Kanu’s unconditional release.
Buhari said that it was a difficult decision to make, but that he would consider it.
When asked if KANU would be released, Mr. President responded, “We cannot free Nnamdi Kanu.” It does not have a political solution. His case will be heard by the courts. One of the promises I made to myself was that I would never interfere with the judiciary’s work. I’ve given him a chance to present his case.
Kanu has made a mockery of us. He was given incorrect information and made nasty statements about us. He needs to accept accountability for his conduct.
It’s worth remembering that Kanu, the leader of the Indigenous People of Biafra (IPOB), is facing treason charges from the federal government.


COMMENT | Corporal David Edmund, 29, and Lance Corporal Moses Logers, 25, were discovered missing on July 19 while on duty on Pulau Perak.
Edmund and Logers were both attached to the Fourth Battalion of the Royal Ranger Regiment (4RRD) based at the Bukit Cowder Camp.
According to a report, the absence of the two Sarawakian soldiers was detected late evening on July 19 when the placement chief made a parade of night checks.
On July 29, Defence Minister Mohamad Sabu (photo) said efforts to find the members of the armed forces by the three military branches were halted on July 26, as no new leads were discovered.
That was the last official statement from the minister. Almost three weeks into the disappearance, there has been no further update from the Defence Ministry...


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Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer
Journal for ImmunoTherapy of Cancer volume 7, Article number: 38 (2019)
Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses.
We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61).
Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions.
The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors.
ClinicalTrials.gov identifier: NCT01915524.
Active immunotherapy targeting selected tumor associated antigens (TAAs) aims to improve outcomes by producing antigen-specific cellular and/or humoral immune responses , with the aim of controlling tumor growth and prolonging survival. However, several phase III trials using this approach in patients with early-, as well as late-stage non-small cell lung cancer (NSCLC) did not reach their primary endpoint [2, 3]. To date, these immunotherapeutic approaches have mostly targeted single antigens, whereby immune escape of tumor cell populations not expressing a single target antigen may have posed a stumbling block. Insufficient immunogenicity of cancer vaccine formulations, not able to break tolerance towards tumor/self-antigens and other immune escape mechanisms, such as activation of inhibitory immune checkpoints  may have contributed to these disappointing results. The success of checkpoint blocking antibodies in the treatment of NSCLC offers a new way to overcome immune escape and holds promise to increase the efficacy of antigen-specific therapies in combination.
RNActive® is an mRNA-based vaccination approach, which uses chemically unmodified, sequence-optimized mRNA to encode TAAs for cancer treatment [5,6,7,8]. BI1361849 (CV9202) is an RNActive®-based cancer immunotherapy containing sequence-optimized mRNAs encoding different cancer antigens in free and complexed form with the cationic protein protamine; this facilitates antigen expression and activation of the immune system through interaction with toll-like receptor TLR7, TLR8, and intracellular RNA sensors, essentially conferring self-adjuvanting activity, and subsequently inducing an adaptive cellular and humoral immune response .
A previous phase I/IIa study has shown that treatment with RNActive®-derived CV9201 cancer immunotherapy in patients with NSCLC was safe and well tolerated, and immune responses against all five encoded antigens were reported . BI1361849 includes the five antigens encoded by CV9201 (cancer/testis antigen 1B [New York esophageal squamous cell carcinoma, NY-ESO-1], melanoma antigen family C1 [MAGE-C1] and C2 [MAGE-C2], baculoviral inhibitor of apoptosis repeat-containing 5 [survivin], and trophoblast glycoprotein [5T4]), together with the mucin-1 (MUC-1) antigen . MUC-1 is frequently overexpressed in NSCLC, and triggering immune responses to this antigen in other clinical trials in this indication has not raised any safety concerns [2, 11]. NY-ESO-1, MAGE-C1 and MAGE-C2 are highly tumor-specific antigens expressed in up to 30% of NSCLC samples, while survivin, 5T4 and MUC-1 are all detected at low levels in healthy tissues but expressed in more than 90% of NSCLC tumors . Based on the frequency of expression of individual antigens in NSCLC, it is estimated that 99.6% of the patient population will express at least one of the antigens encoded by BI1361849 [12, 13].
Radiotherapy can induce immunogenic cell death and stimulate tumor-specific immune responses, resulting in regression of non-irradiated lesions . However, such abscopal responses observed outside the field of radiation remain relatively rare in the clinic after radiotherapy alone. Nevertheless, the ability of radiotherapy to induce immunogenic cancer cell death and to promote recruitment and function of T cells within the immunosuppressive tumor microenvironment, provides a rationale for combining radiotherapy with immunotherapy [15, 16]. Preclinical data provide evidence for synergy between radiotherapy and active immunotherapy [17,18,19,20,21], and there is also evidence of synergy in the clinical setting, including in metastatic NSCLC [22,23,24,25,26]. While active immunotherapy may support an abscopal effect of radiation, preclinical data suggest that the tumor response varies with the size of radiotherapy dose per fraction .
This article describes results from a phase Ib clinical trial that aimed to assess the safety and tolerability of BI1361849 mRNA-based active cancer immunotherapy combined with fractionated local radiation and different standard of care maintenance treatments in patients with stage IV NSCLC.
Details of the study design, which have been published previously , are summarized below.
This was an exploratory, open-label, multicenter, phase Ib study of mRNA-based active cancer immunotherapy BI1361849 (CV9202) and local radiation as consolidation and maintenance treatment in patients with stage IV NSCLC and a response or stable disease (SD) after first-line chemotherapy or therapy with the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) erlotinib or gefitinib (ClinicalTrials.gov identifier: NCT01915524).
The study was performed according to Good Clinical Practice and in line with the Declaration of Helsinki and local regulations.
Eligible patients were ≥ 18 years old with histologically or cytologically confirmed stage IV NSCLC and, for those with non-squamous cell histology, a confirmed EGFR mutation status. All patients should have achieved a partial response (PR) or SD according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1 after receiving first-line therapy. Patients had to have at least one tumor lesion eligible for radiation, and at least one additional measurable tumor lesion according to RECIST version 1.1 (see further details in Additional file 1: Supplementary methods). Patients also had Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1, and adequate organ function.
Exclusion criteria (considered in more detail in Sebastian et al. 2014 ) included previous active immunotherapy for NSCLC (including immunotherapy with anti-CTLA4 antibodies) and an estimated life expectancy of ≤3 months.
Patients were enrolled into one of three study arms (stratum 1, 2, or 3) based on their molecular and histological subtype of NSCLC (Fig. 1a and b). Stratum 1 involved patients with non-squamous NSCLC without activating EGFR mutations, who had PR or SD after at least four cycles of platinum- and pemetrexed-based treatment, and had an indication for maintenance therapy with pemetrexed. Stratum 2 contained patients with squamous NSCLC, who had PR or SD after at least four cycles of platinum-based and non-platinum compound treatment. Stratum 3 comprised patients with non-squamous NSCLC and an activating EGFR mutation, who had PR or SD after at least 3, and up to 6 months of EGFR-TKI treatment.
Patients started screening 2 weeks after their last cycle of first-line chemotherapy (in strata 1 and 2) or within 6 months of starting EGFR-TKI therapy (stratum 3). BI1361849 was administered on study days 1 and 8, followed by radiation therapy on days 9–12 (Fig. 1a). Patients in strata 1 and 3 subsequently received three further treatments with BI1361849, on days 15, 36, and 57, whereas those in stratum 2 received four, on days 15, 29, 43, and 57, after which patients in all three strata were treated with BI1361849 at 3-week intervals for the first 6 months, then every 6 weeks thereafter. Treatment with BI1361849 was continued until disease progression requiring the start of systemic second-line treatment or patients experiencing unacceptable toxicity.
Preclinical data support a vaccination schedule comprising frequent and continued vaccination with an interval of 1 week in the priming phase in combination with a fragmented radiation regimen. The synergistic anti-tumor effect of immunotherapies with radiotherapy has been shown in different preclinical models [17, 18, 20, 21, 28]. Importantly, complete primary tumor regression as well as abscopal effects were only observed in a mouse breast cancer model when radiation was given as a fractionated regimen together with anti-CTLA4 but not when the antibody was given either alone or in combination with single-dose radiotherapy .
The vaccination regimen employed in this study is in line with a vaccination regimen used in a trial with CV9201, a precursor mRNA-based lung cancer vaccine . Since expected progression free survival (PFS) was shorter in patients with squamous cell carcinoma (stratum 2) and no concomitant maintenance treatment was administered, a slightly more intense vaccination schedule was applied in this stratum. This more intense schedule is also supported by preclinical data, suggesting that more frequent administrations may enhance the generation of antigen-specific immune responses (unpublished observations). Pre-clinical studies, however, only provide an indication of vaccination efficacy and clinical studies are required to determine the most efficacious treatment regimen for patients.
The recommended dose of BI1361849 was based on the recommended dose per individual mRNA as determined in a phase I/IIa trial of CV9201, a precursor mRNA vaccine (NCT00923312, ). At each BI1361849 administration time point, patients received 320 μg mRNA per antigen resulting in a total dose of 1920 μg mRNA. The six components (one per encoded antigen) were administered separately, with patients receiving 2 × 200 μL intradermal injections per component. The 12 injections were distributed across four lymph node targeting areas, i.e. three injections in each of the right and left upper inner arm, as well as in the right and left inner thigh. In addition, patients in stratum 1 received pemetrexed maintenance therapy every 21 days, while erlotinib/gefitinib continuation was available for those in stratum 3.
Radiation therapy was delivered to a dose of 20 Gy over four consecutive days with a daily fraction of 5 Gy. The administration of 4 × 5 Gy represents a well-established palliative radiation regimen that can be applied to pulmonary lesions, bone and soft tissue lesions with low toxicity . Radiation target definitions are described in Additional file 1.
The primary endpoint was the number of patients who experienced BI1361849- and/or radiation-related adverse events (AEs) of ≥ grade 3 according to National Cancer Institute–Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 4.0. The pre-defined margin for acceptable safety and tolerability for this endpoint was ≤30% of patients. Secondary safety endpoint evaluation included consideration of other treatment-emergent AEs (TEAEs), as well as clinical and laboratory assessments.
Other secondary endpoints involved assessment of immune responses (as defined in the section below) — consideration of cellular and humoral immune responses to the antigens encoded by the six BI1361849 mRNA components, as well as humoral immune responses to a panel of antigens not covered by the immunotherapeutic (for assessment of ‘broadening of the humoral immune response’).
Secondary efficacy endpoints were tumor response according to RECIST version 1.1 , time to start of, and response to, second-line cancer treatment, PFS, and overall survival (OS) from time of first BI1361849 administration.
Assessments and immunological assays
Safety assessments included monitoring of AEs and hematological and biochemical tests. They are described in detail together with immune response analysis and efficacy assessment in Additional file 1. Based on the prediction that 99.6% of the patient population will express at least one of the antigens encoded by BI1361849, individual patient tumors were not assessed for antigen expression.
Intracellular cytokine staining (ICS) and flow cytometry
Antigen-specific T cells were assessed by ICS measuring interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) production, and CD107a translocation by CD4+ and CD8+ T cells. Peripheral blood mononuclear cells (PBMCs) were thawed and stimulated ex vivo with overlapping 15-mer peptide libraries each covering the full open reading frame of the six BI1361849-encoded antigens (JPT Peptide Technologies GmbH, Germany) including literature-selected short class-I peptides (Additional file 2: Table S1). Short-term cell culture was performed for 6 h in the presence of anti-CD28 (CD28.2), anti-CD49d (L25), phycoerythrin (PE) anti-CD107a (H4A3) antibodies (BD Biosciences, Germany) and GolgiPlug/GolgiStop (BD Biosciences). Cells stimulated with culture medium X-Vivo 15 (Lonza, Switzerland) and dimethyl sulfoxide (Sigma-Aldrich Chemie GmbH, Germany) served as background controls. In addition, each experimental run included a positive control consisting of PBMCs stimulated with a peptide mix including epitopes from cytomegalovirus, Epstein-Barr virus and flu virus (CEF; JPT Peptide Technologies GmbH, Germany) and Staphylococcus enterotoxin B (SEB) (Sigma-Aldrich Chemie GmbH, Germany). Stimulated PBMCs were incubated with Fc-receptor block (Miltenyi Biotec GmbH, Germany) and labeled with LIVE/DEAD® Fixable Aqua Dead Cell Stain Kit (Thermo Fisher Scientific, USA) and Brilliant Violet650 anti-CD8 (RPA-T8), APC-H7 anti-CD3 (SK7), PE-Cy7 anti-CD4 (MP4-25D2), AlexaFluor700 anti-CD14 (M5E2), or AlexaFluor700 anti-CD19 (HIB19) (BD Biosciences). Cells were fixed and permeabilized using Cytofix/Cytoperm (BD Biosciences) and ICS was performed for the activation marker CD69 (Brilliant Violet605 anti-CD69, clone FN50, BioLegend, Germany) and cytokines using fluorescein isothiocyanate anti-IFN-γ (B27) (BD Biosciences), PerCP-Cy5.5 anti-TNF-α (Mab11), or Brilliant Violet 421 anti-IL-2 (MQ1-17H12) (BioLegend) antibodies.
Immune response analysis included determination of cellular immune responses ex vivo by enzyme-linked immunosorbent spot (ELISpot) assay and intracellular cytokine staining (ICS). Antigen-specific antibodies were assessed via enzyme-linked immunosorbent assay (ELISA). Seromic profiling, using the Serametrix NSCLC-specific antigen microarray, was performed to investigate broadening of humoral immunity. Efficacy was assessed by radiological tumor assessments.
Criteria to identify cellular and humoral immune responses included an at least two-fold increase of either functional T cells or antibody levels over background in addition to empirically determined minimum thresholds (e.g. percentages of functional T cells > 0.1% or at least 10 events in the functional gate). Depending on the specific assay, in the absence of official guidance or recommendations, further empirical rules for definitions were applied, in addition to the aforementioned increases, as described in Additional file 1. In addition, the frequencies of patients were determined with cellular or humoral immune response magnitudes at least two-fold higher compared to baseline (day 1).
A formal sample size calculation was not applicable — a planned sample size of 36 patients was chosen, based on previous observations with predecessor vaccines of BI1361849, whereby a minimum of eight patients per stratum was considered necessary to evaluate the frequency of immune responses.
The safety and efficacy evaluations were performed on all patients who received at least one dose of study medication (safety analysis set [SAF]).
Assessments of immune responses were performed on patients in the SAF who received at least three administrations of BI1361849 and 4 × 5 Gy radiotherapy according to the protocol, had at least one post-vaccine immune sample collected, and did not receive relevant immunosuppressive concomitant medication (i.e. evaluable population). The evaluable population included 25 patients overall.
SAS, GraphPad Prism 6 and Microsoft Excel 2010 were used for statistical data analysis.
Survival data was estimated from the time of treatment initiation using Kaplan-Meier methodology.
Patient disposition and characteristics
The study was conducted at 13 centers in Germany, Austria and Switzerland, and enrolled 32 patients; six patients failed screening (see Additional file 3: Table S2) and 26 were assigned to the different strata (Fig. 1b). The first patient was recruited in April 2013; the last patient completed the study in July 2016.
The recruitment goal of eight patients to stratum 3 could not be achieved within a reasonable time frame and recruitment was stopped prematurely, with only two patients enrolled in this stratum. This was because only few patients had eligible lesions for radiation after initial therapy with EGFR-TKIs (erlotinib and gefitinib).
Patients’ baseline characteristics, reflecting those of a stage IV NSCLC population, are shown in Table 1.
Treatment exposure and overall safety
The mean number of successful BI1361849 administrations, defined as successful administration of at least 10 of the 12 injections per treatment, was 8.4 (range 2–25). The median duration of BI1361849 treatment was 81 days (range 8–806 days). All patients received a radiation dose of 20 Gy in four fractions of 5 Gy per protocol. Further details of treatment exposure are given in Additional file 4: Table S3.
For the primary study endpoint, BI1361849- and/or radiation- related AEs of ≥grade 3 were reported in four (15.4%) of the 26 patients, overall: two patients (12.5%) in stratum 1 (one event each of dysphagia and fatigue), one patient (12.5%) in stratum 2 (fatigue), and one patient (50.0%) in stratum 3 (pyrexia) had grade 3 events. For strata 1 and 2, these frequencies were below the pre-defined margin of ≤30% of patients; the small sample size of stratum 3 (n = 2) did not allow determination of meaningful percentages in this group. Three of the four events (fatigue [two events] and pyrexia) were related to administration of BI1361849, while one (dysphagia) was related to study radiation. There were no serious TEAEs related to BI1361849 and no TEAEs leading to death. No immune-related TEAES were reported.
Table 2 provides an overview of the TEAEs. The most frequently reported TEAEs were injection-site reactions, transient flu-like symptoms or, for stratum 1 only, AEs typically associated with pemetrexed therapy; no immune-related TEAEs were reported. Common TEAEs (occurring in ≥10% of patients overall) are summarized in Additional file 5: Table S4.
Clinically relevant changes in autoimmunity parameters were not reported.
Humoral and cellular immune assessments
According to the mechanism of action of BI1361849 as an active cancer immunotherapy, pre-existing and post-vaccine immune responses were measured ex vivo without prior expansion by in vitro stimulation. Representative IFN-γ ELISpot results for a patient reacting to the antigen 5T4 are shown in Additional file 6: Figure S1a). Antigen-specific CD4+ and CD8+ T cells were analyzed by ICS (Representative CD8+ analysis in Additional file 6: Figure S1b, c).
Twenty-five patients were evaluable for immunomonitoring, of whom 84.0% (21/25) fulfilled the criteria of exhibiting an at least two-fold increase in immune response magnitude compared to baseline against one or more of the BI1361849 antigens (Fig. 2a). In detail, a total of 10/25 (40%) evaluable patients fulfilled the pre-specified criteria of at least two-fold increased magnitudes of functional CD4+ and/or CD8+ T cells determined by ICS or ELISpot and 20/25 (80%) met the criteria of a two-fold increased antigen-specific IgM and/or IgG level compared to baseline on at least one post-vaccine time point (Fig. 2a). Patients with at least two-fold increased immune response magnitudes have been detected in all three strata (see Additional file 7: Table S5). Immune responses directed against each of the six antigens encoded by BI1361849 were detected (Fig. 2b), while 52% of patients (13/25) reacted against multiple antigens (Fig. 2c).
We defined functionality of T cells as their ability to induce antigen-specific immune responses if the magnitude of their response exceeded the background control (PBMCs that have received only cell-culture medium) by at least two-fold. Additional exploratory post-hoc analysis of such immune responses showed that the frequencies of functional CD4+ and CD8+ T cells following BI1361849 immunotherapy combined with radiotherapy increased over time (Fig. 3a). Detectable increases of CD4+ and CD8+ T cells to BI1361849 antigens post-vaccine were mostly driven by CD4+ T cells (Fig. 3a, left-hand panel). The magnitude of the responses to individual antigens detected post-vaccination varied among patients (Fig. 3b and c) with most responses detected by ICS but not ELISpot. In one patient corresponding CD4 and CD8 T cell responses against the same antigen were observed by ICS (patient 6, MAGE-C2). The majority of the T cell responses detected by ICS were mono-functional.
We hypothesized that the combination of radiotherapy with active tumor immunotherapeutic BI136184 can initiate an antigen cascade to broaden the anti-tumor immune response . To address this question, we profiled the antibody repertoire against NSCLC antigens using an antibody array containing 32 known NSCLC TAAs. Broadening of the antibody repertoire against antigens not covered by BI1361849 was observed in 50.0% of all evaluable patients (12/24; any post-vaccine time point; Additional file 8: Figure S2) and in eight of the 14 analyzable pemetrexed treated patients (57.1%) in stratum 1. Some patients had already high numbers of pre-existing antibodies against TAAs. In most cases, such repertoires did not increase during treatment, but were generally maintained.
Of the 26 patients in the safety set (SAF) evaluated for efficacy, overall, 46.2% (12/26) demonstrated SD as the best confirmed overall response (Table 3). One patient achieved a confirmed PR with decreasing measurable tumor size up to the last follow-up visit. This patient received concomitant pemetrexed (stratum 1) and had already shown a PR to the previous chemotherapy. Another patient (also from stratum 1) exhibited decreasing target lesion sizes not formally qualifying as a PR. Shrinkage of non-irradiated lesions > 15% occurred in six patients, five in stratum 1, and one in stratum 2. Figure 4a shows the percentage change in target lesion sizes (sum of longest diameters) by stratum. Best overall response according to lesion type (target/non-target) is shown in Additional file 9: Table S6.
Second-line cancer treatment was received by 73.1% of patients overall (n = 19). The median times to the initiation of second line therapy were 14.4 weeks (range 7–46) in stratum 1, 15.6 weeks (range 7–30) in stratum 2, and 62.6 weeks (range 8–117) in stratum 3. Most patients responded to the second-line cancer treatment with SD or PD (31.6% [6/19] and 36.8% (7/19], respectively]. One patient, treated with crizotinib and trastuzumab emtansine, achieved a PR. Five patients were not evaluable.
Information for the individual patients by stratum is provided in Fig. 4b, which shows a swimmer plot, illustrating PFS time and OS time, in addition to response kinetics. Overall, median PFS was 2.87 months (95% confidence interval [CI] 1.43–4.27) (Additional file 10: Figure S3a). Overall, the median OS time from first BI1361849 treatment was 13.95 months (95% CI 8.93–20.87; Additional file 10: Figure S3b).
To our knowledge, this study is among the first to combine mRNA-based immunotherapy with fractionated local radiotherapy for the treatment of cancer . In our study, BI1361849 (CV9202) a cancer immunotherapy based on sequence-optimized mRNA formulated with protamine was combined with fractionated local radiation treatment in patients with stage IV NSCLC and appeared safe and well tolerated with or without maintenance pemetrexed; only four patients experienced a grade 3 BI1361849- and/or radiation-related AE and there was no evidence of autoimmune events. Based on only two patients enrolled in the stratum with EGFR-TKIs, no definitive conclusion on safety of this combination is possible, but there was no overt evidence of increased toxicity.
As we did not observe occurrence of radiation pneumonitis in our study, testing of BI1361849 in combination with fractionated radiotherapy and pemetrexed therapy in further trials is supported.
The immunomonitoring results appear comparable to those observed previously with the protamine formulated precursor vaccine CV9201 alone without radiation in a phase IIa study in patients with NSCLC where antigen-specific immune reactions against at least one antigen were detected in 63% of evaluable patients . However, differences in study methodologies, e.g. sample time points, and the overall small sample sizes limit the comparability between the trial results.
About half of the patients had increases in T cell or antibody magnitudes against multiple antigens post treatment. In addition, a broadening of the antibody repertoire against tumor antigens not covered by BI1361849 was observed after treatment in a subgroup of patients which could be an effect of the radiation, BI1361849 and/or other concomitant cancer treatments resulting in immunogenic cell death of cancer cells. Other studies have shown improved outcomes for cancer patients who respond to multiple TAAs [33,34,35]. Although these results do not prove causality, it is conceivable that induction of immune responses against multiple TAAs might be of therapeutic benefit.
We observed that the frequency of patients with increased antigen-specific T cells to the individual antigens, in particular CD8+ T cells, was rather low. For four of the antigens (NY-ESO-1, 5T4, MAGE-C1, MAGE-C2) fewer than 10% of the treated patients displayed an increase in antigen-specific T cells over baseline. A putative explanation for the low frequencies of tumor antigen-specific T cell responses could be that all of our cellular immune assays were performed ex vivo. Whereas ex vivo assays predominantly assess the functionality of effector T cells, other vaccine antigen-specific T cell subsets including memory T cells may remain undetected [36, 37]. Evidence suggests that central memory T cells which differentiate into effector T cells during the culture period can be detected after prolonged in vitro re-stimulation, whereas circulating effector memory T cells are quantified by ex vivo immune assays. It can be argued that in vitro re-stimulation increases the sensitivity of the assay by increasing the detection of low frequency antigen-specific T-cell responses but there have been reports of inducing de novo priming of naïve T cells during the cell culture. Due to the limited amount of PBMCs available repetition of T cell assays after in vitro stimulation was not possible.
Increases in tumor antigen-specific T cells and antibodies were detected in all three strata suggesting that the different concomitant treatments may not confound this active cancer immunotherapeutic strategy. Elevated antibody responses against cell surface antigens may contribute to antitumor efficacy e.g. through antibody- or complement-dependent cytotoxicity (ADCC, CDC). Radiation may impact the expression of antigens targeted by tumor-specific antibodies  and could further enhance the ADCC response in this clinical scenario.
Whereas a putative lack of sensitivity of our ex vivo cellular immune assays could represent a partial explanation for the overall rather low frequency of CD4 and particular CD8 responses, the following factors are probably more relevant and will be addressed in future trials with BI1361849.
Firstly, self-tolerance to the encoded endogenous antigens as well as the presence of immune-suppressive cell populations including myeloid-derived suppressor cells, regulatory T cells, or anti-inflammatory M2 macrophages may counteract the induction of high frequencies of functional T cells. It may be interesting to see if a higher immunogenicity can be achieved in combination with immune checkpoint inhibitors, in particular anti-CTLA4 or anti-PD1/-PD-L1 antibodies, to help break the tolerance against endogenous antigens, e.g. by enhancing effector T cell function and inhibition of regulatory T cells . Also, it may be useful to investigate whether RNActive® immunotherapies encoding patient-specific lung cancer or shared neoantigens might result in higher frequencies of antigen-specific CD8 T cells as suggested by recent studies [40, 41].
Secondly, a critical factor to consider for future trials with protamine-based mRNA immunotherapies is the mode of administration as shown by recent data. A first-in-human trial of a protamine-formulated mRNA-based rabies vaccine showed that needle-syringe injection of this vaccine failed to induce protective virus-neutralizing antibody titers. However, intradermal injection using a needle-free injection device induced antibody titers above the World Health Organization defined protective threshold in 71% of subjects. The serological protection correlated with the induction of multi-functional rabies-specific CD4+ T cells assessed with the same ex vivo ICS methodology as described here . Preclinical data showed that needle-free jet injection increases the expression of the mRNA encoded antigens in the skin and improves immunogenicity of protamine formulated mRNA vaccines (CureVac AG, unpublished observations).
Based on these findings, BI1361849 is being investigated in an ongoing phase I/II trial in combination with the anti PD-L1 antibody durvalumab, and the anti CTLA4 antibody tremelimumab and a needle-free injection device is being used for the intradermal injection.
While the design of our phase I trial does not allow us to draw conclusions on the therapeutic benefit of the combination, shrinkage of non-irradiated lesions and prolonged disease stabilization was observed in a subset of patients, mainly in combination with pemetrexed. Two patients on pemetrexed maintenance therapy remained progression free for a period of 21 and 27 months each, and one patient in stratum 3 (EGFR-TKI therapy) in whom a new lesion was detected on follow-up imaging after 14 months of treatment continued BI1361849 for more than 1 year beyond RECIST-defined disease progression. One of the eight patients in stratum 2 who did not receive concomitant maintenance therapy experienced a decrease in target lesion size, but none experienced an objective response.
A limitation of our analysis is the lack of a control group (either radiation, BI1361849, or chemotherapy/EGFR-targeted agent alone), and it is not possible to conclude whether the detected increases in T cells and antibodies observed were solely due to BI361849, radiation or the combination of both. Furthermore, only two patients were recruited to the EGFR-TKI stratum, as most screened patients had no eligible lesions for radiotherapy due to the high response rate to initial therapy.
mRNA-based active cancer immunotherapies, as used in the current study, can be designed to encode for a variety of endogenous cancer antigens from different cancer types. This will help to maximize the chance that an individual patient’s tumor expresses these antigens, and patients with different antigen expression patterns may thus derive benefit from the therapy. The value of targeting neoantigens for cancer immunotherapy has been extensively considered [43,44,45,46]. Recently, two studies investigating neoantigen vaccines demonstrated immunogenicity and reported encouraging clinical safety and efficacy data in patients with stage III/IV melanoma in phase I studies [40, 41]. These initial data provide a rationale for testing of neoantigens for active cancer therapy, whereby the combination with radiotherapy and novel therapies such as immune checkpoint inhibitors may further improve the outcomes for cancer patients. Additional research is required to determine how radiotherapy and immunotherapy can be most effectively combined, considering, for instance, optimal fractionation, dose, and the sequencing of radiotherapy and immunotherapy.
In conclusion, BI1361849 (CV9202) combined with local radiation treatment with or without pemetrexed was well tolerated and antigen-specific immune responses were detected. Available evidence supports further investigation of BI1361849 (CV9202) using needle-free administration technique and combination with immune checkpoint inhibitors.
Antibody-dependent cellular cytotoxicity
Eastern Cooperative Oncology Group
Epidermal growth factor receptor
- ELISA :
Enzyme-linked immunosorbent assay
- ELISpot :
Enzyme-linked immunosorbent spot
Intracellular cytokine staining
Melanoma antigen family C1/C2
Messenger ribonucleic acid
National Cancer Institute–Common Terminology Criteria for Adverse Events
Non-small cell lung cancer
New York esophageal squamous cell carcinoma
Peripheral blood mononuclear cell
Programmed death-ligand 1
- PFS :
Response Evaluation Criteria for Solid Tumors
Safety analysis set
Sum of longest diameters
Tumor associated antigens
Tyrosine kinase inhibitor
Tumor necrosis factor alpha
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The authors thank all patients, staff, and investigators of the participating hospitals. We thank the team from Serametrix Ltd., UK for performing lung cancer antigen microarray analysis and ELISA, Sanja Holz, Kerstin Sahlmann, Kathrin Hoch, Helen Dietrich, Simone Eppler, Matthias Scholl for sample logistics, providing support for technical aspects of the study, sample preparation, and immunomonitoring. We thank Dr. Eike Niehaus for clinical project management of the trial. We also thank Jamie Ashman and Andy Lockley of Prism Ideas for editorial support in the preparation of this manuscript, and Dr. Michael Merger, Boehringer Ingelheim Pharma GmbH & Co. KG, and Prof. Dr. Daniel Speiser, University of Lausanne for their review and contribution to the manuscript.
This study, and editorial support for the preparation of this manuscript, were sponsored by CureVac and co-funded by Boehringer Ingelheim. BI1361849 is being developed by CureVac and Boehringer Ingelheim.
Availability of data and materials
The datasets generated and/or analyzed during the current study are not publicly available because this is a phase I study of an experimental compound in early development. Data remains confidential.
Ethics approval and consent to participate
This study was approved by local ethics committees. The names and reference numbers are provided in Additional file 11: Table S7.
All patients provided written informed consent before receiving any study-related procedures.
Consent for publication
AP declares non-financial support from CureVac during the conduct of the study. MS declares personal fees from Boehringer Ingelheim, BMS, MSD, Lilly, Pfizer, Astra Zeneca, Roche, Celgen, and Novartis and non-financial support from Boehringer Ingelheim, BMS, and Novartis outside the submitted work. MP declares personal fees from Astra Zeneca, BMS, Boehringer Ingelheim, Merck, Novartis, Pfizer, and Roche outside the submitted work. FG declares grants and personal fees from Astra Zeneca, Boehringer Ingelheim, Pfizer, Lilly, BMS, MSD, Novartis, Celgene, and Roche and personal fees from Ariad, Takeda, and Chugai outside the submitted work. AZ declares study fees from CureVac during the conduct of the study and research funding from BeyondSprings, Secarna, and Roche outside the submitted work. UK, MFM, BS, CS, AM, TS, FD and UG-V are employees of CureVac. AS, MMH, HSH and SDK were employees of CureVac during the conduct of this study. K-JK was a consultant to CureVac until 2015 and was an employee at CureVac until 2012. K-JK, MFM and UG-V jointly hold patent WO/2015/024666. MF, CW, RC, WH, GP, TW, JA, HB, and MG have no conflicts of interest to declare.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Materials and Methods. (PDF 465 kb)
Table S1. Peptide sequences of short class-I peptides. (PDF 79 kb)
Table S2. Screening failures. (PDF 250 kb)
Table S3. Treatment exposure during the study. (PDF 322 kb)
Table S4. Treatment-emergent adverse events occurring in ≥10% of patients overall by preferred term (safety analysis set). (PDF 309 kb)
Figure S1. Evaluation of cellular immunity in patients receiving BI1361849 immunotherapy combined with local radiation treatment: representative examples. (PDF 3990 kb)
Table S5. Immune responders per assay at any post-vaccine time point in different strata. (PDF 96 kb)
Figure S2. Heatmap showing broadening of the humoral immune response against antigens in several of the evaluated patients. (PDF 411 kb)
Table S6. Best overall response by lesion type (safety analysis set). (PDF 256 kb)
Figure S3. Survival following BI1361849 immunotherapy combined with local radiation treatment. (PDF 438 kb)
Table S7. Name of the Ethics Committees that approved the study and approval numbers. (PDF 255 kb)
About this article
Cite this article
Papachristofilou, A., Hipp, M.M., Klinkhardt, U. et al. Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer. j. immunotherapy cancer 7, 38 (2019). https://doi.org/10.1186/s40425-019-0520-5
- Clinical trial
- Hypofractionated radiotherapy
- mRNA active cancer immunotherapy
- Non-small cell lung cancer

domain: literature


text:
Zombies Want My PizzaFree
Zombies and Pizza is a pixel art scary(not so much) surviving game where you find yourself in an infinite search to satiate your pizza hunger. Unfortunately(as it always happens in post-apocalyptic zombie games), herds of zombies are getting in your way. You came to the realization that getting rid of those zombies will give you free time to enjoy a couple of slices.
Downloads: 283+Report app for spam or abuse!
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The main heroes of the game are a plumber Mario and his brother Luigi
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Happy Wheels Free Free
Happy Wheels is now available for android divice . Happy Wheels is a side-scrolling, physics-based
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Do you like truck games? This truck simulator allows you to drive different kinds of heavy trucks.

domain: game


ProCon Member Login
Enter your email address and password to login to your ProCon Member Account.
Custodians of Thurmaston Industrial Estate for almost 50 years, Charles Street Buildings has now transformed the site, home to Walkers Crisps for more than three decades, to a new masterplan.
The masterplan by Stephen George & Partners included plots allocated for existing tenants Arriva Midlands and Qualvis Litho and attracted new residents Costco and Advance Tapes.
The buildings at Thurmaston Industrial Estate had served their purpose for many years but had come to the end of their useful lifespan.
Charles Street Buildings decided to demolish as much as possible while retaining some old buildings that housed existing tenants until they could be relocated in new premises.
The masterplan allocated plots for the existing tenants, Arriva Midlands and Qualvis Litho, to accommodate their respective businesses safely as the development progressed.
Arriva Midlands took the opportunity for a £5m investment in a new depot for 101 buses with 91 staff based at the site and a further 220 drivers. Costco Wholesale is in a 140,000 square feet build completed on a 21 week programme. It employs 130 people at the warehouse.
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47 Westview Avenue, Glen Parva, Leicester. LE2 9JU. Company number: 5420643


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domain: finance


Weather in Pakistan is forecasted to remain dry for the next 24 hours, the Met Department said on Thursday.
Karachi's current temperature is recorded at 26° Celsius, while the sky is partly cloudy. Humidity in the air was registered at 77%.
Highest temperature forecast by the Met Department is set at 33° Celsius, while strong winds of 18 km/h are blowing inwards from the country's South Western areas.
For the next 24 hours, Kashmir and adjoining mountainous areas are expected to have strong winds and light rain, with thunder and lightning. The same is forecasted for Malakand, Mirpurkhas, FATA, and Gilgit-Baltistan for the next 48 hours. Strong, dusty winds are anticipated in Hyderabad and Mirpurkhas.
On Wednesday, highest rainfall was recorded in Parachinar in 27 mm, while highest temperatures were registered in Shaheed Benazirabad at 45° Celsius, Sukkur at 44° Celsius, and Larkana, Sibi, Jacobabad, and Dadu all at 43° Celsius.


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Currently available in the United States; coming soon in 31 countries in Europe.
Quant Conversion Calculator
Quant To USD
What is Quant?
The heart of the Quant project is the Quant Network, which automates the trust functions between multiple blockchains with the help of the Overledger operating system. Overledger has been billed as the first operating system to be built specifically to connect blockchains and other networks to improve interoperability on a global scale. The Quant token comes into play as the currency used to pay for the platform license and service fees.
The ideal use case for the Quant token is the cryptocurrency that networks with other networks. It can act as the backbone infrastructure for most use cases, with various companies designing apps that can function across multiple blockchains. Doing so will make it easier to facilitate transactions among and between the various networks and blockchains. Proof-Of-Concept has already been established within the Quant Network, as it has proven that it has the ability to read and monitor transactions across multiple ledgers, including Bitcoin, Ethereum, and Ripple.
The Quant Token serves the role of providing digital access to a particular service or application on the network. This access is granted to both developers and users. This is how the network generates revenue: by selling access to their network, where decentralized apps are available to use across multiple blockchains and paid for with various cryptocurrencies.
Quant has developed a network that they are deeming “future proof.” Because Overledger doesn't replace a blockchain, but merely connects one to another means that a new blockchain that is developed can easily be fitted into the Quant Network and take advantage of the Overledger system, making Quant the defacto cryptocurrency that interoperates with all other cryptocurrencies.
Quant Market Price Ticker Chart
Not currently supported on BlockCard; data on currently unsupported cryptocurrencies is included for your convenience.
Quant Frequenty Asked Questions
Where does Quant (QNT) rank among in terms of popularity? How relevant is it compared to competitors?
In terms of popularity, Quant currently ranks in position 136 out of the top 1000 cryptocurrencies. Another important factor in popularity is Quant‘s market capitalization – in general, the higher the market cap of a cryptocurrency, the more dominant it is considered to be in the market. Quant has a market cap of $ 578,460,139, which compares to Bitcoin (the most popular cryptocurrency by several metrics) with a market cap of $ 1,063,451,465,201, Litecoin at $ 17,771,559,068, Ethereum at $ 320,591,530,652, Tether at $ 51,086,073,937, and XRP at $ 72,561,083,681.
What is the price of Quant (QNT) today (updated in realtime)?
The current price of Quant is $ 44.93 in USD. (The price in Euros is 36,99 €; and the price in Bitcoin is Ƀ 0.00079000 BTC.)
How has Quant (QNT) performed recently?
Quant‘s price has increased in the last 24 hours by 9.27%. The change in price over the last seven days was 8.13%. The trading volume over the last 24 hours was $ 6,987,087. Trading volume indicates how many units of a currency are being bought and sold on specific exchanges. High trading volumes are likely to drive more on-chain activity, for example when people deposit and withdraw funds, and it is considered a good indicator of popular interest in the currency.
What is Quant‘s (QNT) market supply?
The total circulating (available) supply of Quant is 12,873,333 QNT. The total supply of Quant is 14,612,493 QNT.
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Quant‘s official website, social accounts, blockchain explorer, and Github repository if applicable.
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3/4 NIGHTS • 1400km
This adventure begins with the train’s departure from Rovos Rail Station in Pretoria. Travel north through Warmbaths (Bela-Bela), so named for its mineral waters, and Nylstroom (Modimolle), christened by the Voortrekkers as the source of the Nile River as the town’s river happened to be north flowing. Cross the Tropic of Capricorn and Limpopo River towards Bulawayo, second city of Zimbabwe, capital of Matabeleland and industrial capital of the country. Enjoy a game drive (4-night journey only) in Matobo National Park, a World Heritage Site with bushmen caves, rock art and dramatic granite hills. It is also the site of Cecil John Rhodes’ grave atop the summit of Malindidzimu – ‘hill of benevolent spirits’ with a ‘view of the world’. Travel along one of the world’s longest stretches of straight railway line – 114km – before traversing Hwange National Park, a rich and diverse wildlife sanctuary where a game drive excursion is enjoyed. Arrive at the incomparable Victoria Falls on the mighty Zambezi River where this sojourn ends. The surrounding areas offer travellers many recreational opportunities including cruises, whitewater rafting as well as superb game viewing and photo safaris. Available in reverse. Depending upon railway capacity, this journey could be routed through Botswana.
- Hwange Reserve game drive
- Traverse the edge of the Kalahari Basin
- Traverse the Limpopo province
- Matobo National Park game drive
- Victoria Falls

domain: geography


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” … an uncompromising voice, both enervating and exciting to hear in an age when contemporary composition is finding it difficult to sustain interest, let alone an audience.”
CLIVE O’CONNELL. O’CONNELL THE MUSIC.
Brendan Colbert (b. 1956) performed with various progressive-rock bands in the 1970s as keyboard player and songwriter, then in the ’80s undertook private composition studies; initially with Brenton Broadstock & later with Riccardo Formosa.
After a series of early commissions (most notably from ELISION) he was selected twice for the National Orchestral Composers’ School (1991 & 1995 – tutors Gerard Brophy, Richard Mills, and Carl Vine) which led to the premieres of Machinations and Jericho’s Strange by the Queensland Symphony Orchestra.
The following years saw the resolution and assimilation of such disparate influences, the revision or withdrawal of several early works, and the emergence of an uncompromising individual voice. His output currently comprises about a hundred works, and includes commissions from local and international artists, ensembles, and orchestras, with concert and festival performances throughout Australia, Europe and the USA.
Commissions from Symphony Australia – for the West Australian Symphony Orchestra – and from US flautist Linda Wetherill (both assisted by grants from the Australia Council) saw the premieres of Eirenicon (the West Australian Symphony Orchestra conducted by Kenneth Young, Perth, 2000), and Shades of Futures Past (flute concerto – soloist Linda Wetherill on flute, alto flute & piccolo in a version for soloist and CD, New York, 2004). Shades of Futures Past was subsequently given its first full performance in Melbourne in August 2011, with Arcko Symphonic Ensemble conducted by Timothy Phillips, featuring Sarah Beggs as soloist.
A commission from Arcko’s artistic director Timothy Phillips resulted in the premiere of …like a Maelstrom (Double Concerto) with Arcko Symphonic Ensemble, featuring soloists Peter Dumsday (piano) & Bruno Siketa (trumpet), as part of a Composer Portrait Concert in Melbourne in February 2015.
The portrait concert also included the premieres of Proxima (Silo String Quartet), The Palest Light (Timothy Phillips – glockenspiel), & Torque (Phoebe Green – viola). A CD is available through Crackbell Records.
A recent commission from Michael Kieran Harvey saw the completion of Dancing to the Tremors of Time, a 25 minute single-movement work for solo piano. Somewhat challenging for both performer and audience alike, it was successfully premiered in November 2018 at the Museum of Old and New Art in Hobart.
Other recent premieres include Repose (for Absent Friends) (Michael Kieran Harvey – piano: Melbourne, April 2018), movements I, V, and IX from Figuration in Search of Identity (James Townsend, Madi Chwasta & Mathew Levy – percussion: Melbourne, May 2017), Contre-Temps (Peter Dumsday – piano: Melbourne, December 2016), and re-fract (Michael Kieran Harvey – piano: Sydney, September 2016).
Others to have commissioned, performed, and/or recorded works include ELISION Ensemble, Speak Percussion, Libra Ensemble, Smash Ensemble, Six Degrees Ensemble, Topology, Duo Contemporain, Ensemble Traiect, Trio Altrove 1.3, the New York Miniaturist Ensemble, Pedro Carneiro, Mario Teixeira, Barrie Webb, Peter Neville, Carl Rosman, Michael Kieran Harvey, Sisco Aparici, John McMurtery, Marshall McGuire, Geoffrey Morris, Michael Hooper, Carla Rees & David Black, Brigid Burke & David McNicol, Elizabeth Barcan, Stefano Cardi, Norio Sato, and Anne Norman.
Works available on CD include Dancing to the Tremors of Time (piano solo), …like a Maelstrom (Double Concerto for piano, trumpet & small orchestra), Proxima (string quartet), Torque (viola solo), Quicksand (piano solo), …floating in the void… (string orchestra), & Schräg (trombone solo) among others.
Scores are available from the Australian Music Centre, or from the composer.


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Like with any other major medical condition, no one ever expects to be personally affected by a stroke. However, being prepared for the instance in which one will occur increases the likelihood of making a full recovery. Dr. Paulinder Rai, our expert of stroke rehab near Babylon at Physical Medicine and Rehabilitation of Long Island, knows this, which is why he’d like to share the warning signs that point to this condition. By recognizing the presence of a stroke right away, you’ll be able to stay calm in the face of this unfortunate situation.
When someone is suffering from a stroke, the quicker treatment is received, the better the outlook of making a full recovery with stroke rehab near Babylon at our office. That is why Dr. Rai implores everyone to use the acronym F.A.S.T. to help remember the warning signs of a stroke, and what needs to be done when they are present. By thinking F.A.S.T., you just may save a life:
- Face: One of the common signs of a stroke is a drooping face. When you suspect a loved one may be suffering from one, ask them to smile and watch to see if one side droops.
- Arms: Weakness or numbness in the arms can also point to this condition. To be sure it’s an issue, have them raise their arms above their heads. If they are unable to do so, or if the arm droops as they are holding it up, they could be suffering from a stroke.
- Speech: Those suffering from a stroke will often have issues with their speech. If you notice the victim starts to slur their words, ask them to repeat a simple phrase to you. When they continue to slur or their speech sounds strange, an issue is present.
- Time: If any of the previously mentioned signs are present, contact 911 or get medical help right away. Getting your loved one the help they need immediately will make all the difference. Once the patient’s condition has been stabilized, Dr. Rai can begin administering various methods of stroke rehab near Babylon to help them make a full recovery.
Additional Warning Signs
Issues with the face, arms, and speech are not the only signs that could point towards a stroke occurring. If you or a loved one experiences any of the below, contact a medical professional immediately:
- Blurred or blackened vision in one or both eyes.
- A severe headache that comes along with vomiting, dizziness, or altered consciousness.
- Constant stumbling or loss of balance.
Stroke Rehab near Babylon With Dr. Rai
At Physical Medicine and Rehabilitation Of Long Island, we’re committed to helping all patients who need stroke rehab near Babylon. Dr. Rai, our specialist in the field of physical medicine and rehabilitation, will help guide patients through every step of the rehabilitation process. To learn more about the warning signs of strokes, or what will go into your loved one’s stroke rehabilitation process, contact us today!Leave a reply →

domain: medical


text:
A group of local kickboxers brought home silverware for the Northern Ireland team from the recent world championships.
Newtownabbey-based Bodyshots Kickboxing club was well represented at the tournament, with seven new world champions being crowned from the local team.
The finals were staged from August 27 until September 1 in the Killarney Convention Centre.
The winners from Bodyshots were Etta Choi (world champion in all three disciplines semi/light/full -30kg under 12), Carson Carmichael (world champion full contact -30kg under 12), Sophie Curry (world champion full contact -35kg 12-14, silver medal light contact -35kg and bronze medal light contact -40kg 12-14), Summer Fleming (world champion full contact under 12 -35kg and bronze medal under 12 -35kg), Katie Scott (bronze medal in full contact 12-14 +55kg), Casey Martin (bronze medal full contact 15-17 +60kg) and Ben Patterson world champion full contact 15-17 -60kg).
Commenting on the team’s success in a post on social media, a club spokesperson said: “So proud of our students who competed the 2017 WKU World Championships in Killarney.
“Seven world champions, one silver and four bronze. You never cease to amaze us, we knew you could do it. Well done kids.”
Three of the medal winners were praised by their school, Glengormley High.
Commenting on Facebook, a spokesperson for the Ballyclare Road school said: “Massive congratulations to three of our pupils who recently returned from World Kick Boxing Championships held in Killarney.
“With two gold medals, a silver and a bronze, Year 11 student Ella Cassells was crowned World Champion in the 55kg Full Contact competition.
“Leia Cassells (Year 14) won gold in the 60kg+ Light Contact competition and silver in the 60kg full contact event.
“Katie Scott (Year 11) won bronze in the 55kg category. Brilliant achievement girls! Keep it up!”
Abbey Community College also took to social media to congratulate Sophie Curry.

domain: sports


Some bling for my bike.
Can you find the three 'cool' mods in the picture?
here I was squinting trying to see themOriginally Posted by jsharr
nice bling bling XD
Dang, I thought this thread was gonna be on Bicycle Smiles.
Lessee, the smilie, the homemade fender and that tube/cable heading into the fork cap?
Tell me, is one of them an old brake stiffener? Looks like something I had on my Mtn bike in the early 90's.
Btw, love the pun, Hon
Don't know MTB's well enough to recognize mods, but I love the smilie. I'd like to put on of those on the rear of my saddle. Then I'd hear the poseurs sneakin' up behind me cause they'd be laughin'!
How many grams is it? <serious Vega weight-wienie look>
Cap. grease port mod, plastic homemade fender.
Good! It's actually an air balance kit for the Zoch fork. They're air over oil with a schrader valve on each leg. I got this kit from Progressive Suspension to make it a single fill port, thus the legs are always equally balanced. The fender is to keep stuff of that balance tube, I made it from a plastic rock salt container.Originally Posted by jyossarian
Quite 'fred' if I say so myself
I always look like that. =/Originally Posted by VegaVixen
We figured they'd be laughing as you pulled away after having caught 'em, passed 'em, and left 'em for dead.Originally Posted by VegaVixen
"I'm in shape -- round is a shape." Andy Rooney
I ahve one of those brake siffeners laying about right now. It used to be on my folder, to make the stupid fake roller-cam brakes to not deflect so badly when in use.
---- (*)/ (*)
Ring Ring, Ring Ring, the bell went Ring Ring Ring.
does tom s. have smiles on his bikes


text:
Pecan Nation launches in the U.S. this Fall. Colorful stand up shippers and a smaller than expected 8-oz re-sealable bag highlights the new brand, Pecan Nation as it encourages more trial at point of purchase and breathes new energy into a booming category.
Reinforced by the American Pecan Council’s multi-million dollar nationwide consumer awareness campaign, pecans are making a comeback in the U.S. from indulgent to healthy. Pecans are setting the stage to be transformed from a baking ingredient to a year-round healthy snack and staple of consumers’ overall wellness program.
Pecan Nation kicks off this Fall targeting consumers who are already seeking their seasonal go-to nut while transitioning the pecan nut lover to an every-day consumer. The Pecan Nation brand team will work with retail partners to establish America’s only indigenous nut as a year-round produce department staple and build category sales. Pecan Nation has a healthy array of marketing support materials and programs to assist produce departments grow America’s next super-nut: the pecan.
“The pecan category is missing that bell cow … a destination brand that consumers can rely on year after year. That’s why we’ve created Pecan Nation. We needed a way to share these amazing pecan varieties so other families can share in the same passion we have for pecans. The timing is perfect to introduce a nut of this quality to the retail trade,” notes Duke Lane, 5th generation pecan and peach farmer and Managing Partner of The Genuine Georgia Group.
Pecan Nation features flavor that is fresh and unique: naturally sweet, buttery and moist instead of dark brown, chalky and dry. Pecan Nation hand selects the best varieties that are grown including the Elliot and Caddo varieties.
“Our families grow many varieties of pecans but we let our moms and grandmothers pick the special varieties that fill the bags of Pecan Nation. All pecans are not created equal and the matriarchs of our families have the most discerning pecan palettes on earth. They choose the best of the best each season and, like an obedient child, we do exactly what they say! You’ve never eaten pecans that taste this good, I guarantee it,” shares Will McGehee, 5th generation pecan and peach farmer and Founding Partner of The Genuine Georgia Group.
Pecan Nation is shipping now for Holiday Sales in a 24-unit case or a 48-unit pre-packed display shipper.
For more information:
Tel: +1 478.822.9210

domain: agronomy


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Vibetone - Hustle Ft. OladipsBy KellyChi November 3, 2021, 04:36 pm Comments
Are you here to Download Vibetone - Hustle Ft. Oladips mp3? then scroll below.
DOWNLOAD MP3: Vibetone - Hustle Ft. Oladips
Rising Inventive Nigerian singer and music magician and intriguing melodywriter, Vibetone has unlocks his brand new intriguing melody named “Hustle” on which he added the services the versatile rapper, Oladips.
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Vibetone Hustle Ft. Oladips
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More For You: VIDEO: Praiz Ft. Stonebwoy - Hustle