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Espaço de publicação e discussão sobre oncologia. GBM IMMUNOTHERAPY ONCO-VIRUS ONCOLOGY CANCER CHEMOTHERAPY RADIOTHERAPY


Quinta-feira, 23.07.15

Emory University immunologists identify long-lived antibody-producing cells in bone marrow

 

Emory University immunologists identify long-lived antibody-producing cells in bone marrow

Published on July 16, 2015 at 2:40 AM · 

Immunologists from Emory University have identified a distinct set of long-lived antibody-producing cells in the human bone marrow that function as an immune archive.

The cells keep a catalog of how an adult's immune system responded to infections decades ago in childhood encounters with measles or mumps viruses. The results, published Tuesday, July 14 in , could provide vaccine designers with a goalpost when aiming for long-lasting antibody production.

"If you're developing a vaccine, you want to fill up this compartment with cells that respond to your target antigen," says co-senior author F. Eun-Hyung Lee, MD, assistant professor of medicine at Emory University School of Medicine and director of Emory Healthcare's Asthma, Allergy and Immunology program.

The findings could advance investigation of autoimmune diseases such as lupus erythematosus or rheumatoid arthritis, by better defining the cells that produce auto-reactive antibodies.

Co-senior author of the Immunity paper is Iñaki Sanz, MD, professor of medicine and pediatrics, chief of the Division of Rheumatology, Mason I. Lowance Chair of Allergy and Immunology and a Georgia Research Alliance Eminent Scholar. The research was started when Lee, Sanz and colleagues were investigators at the University of Rochester Medical Center, and continued when they arrived at Emory in 2012. The first author of the paper is Jessica Halliley, MS from Rochester.

As described in part of the Immunity paper, the researchers studied 11 older individuals (aged 43 to 70) who had not been immunized against measles or mumps, but who had antibodies in their blood indicating infection by those viruses in childhood. Measles and mumps vaccines first became available in the 1960s.

Antibodies in the blood have a half-life of just a few weeks, so researchers thought these individuals had long-lived plasma cells, or white blood cells secreting antibodies, dating from the childhood infection.

Examining bone marrow samples obtained from these volunteers, researchers divided plasma cells into four different groups based on the proteins found on their surfaces. Only one group ("subset D", CD19-, CD38high, CD138+) contained the cells that produce antibodies that react with measles or mumps virus.

"I like to call this group of cells the 'historical record' of infection or vaccination," Lee says.

In contrast, cells producing anti-influenza antibodies were found spread across three of the subsets. Because study participants were likely to have been exposed to influenza by annual vaccination or infection more recently than measles or mumps, the researchers inferred that cells specific to recent exposures can reside in multiple subsets while subset D represents the long-lived plasma cells.

In separate experiments, volunteers who were vaccinated against tetanus did have some plasma cells producing anti-tetanus antibodies within three weeks in several subsets, but over time tetanus-specific plasma cells were found in subset D.

The team proved that subset D cells were exclusively responsible for producing the measles- and mumps-specific antibodies in the blood of one of the older volunteers, through proteomics and RNA sequencing techniques.

Compared with other subsets, subset D cells are more quiescent: they displayed less signs of proliferation. In addition, subset D cells have a distinct "fried egg" appearance, containing bubble-like vacuoles or lipid droplets, which are rare in bone marrow cell samples, and a tighter, more condensed nucleus than other white blood cells.

Plasma cells differ from many other cells in the body in that they undergo changes in their DNA -- specifically, their antibody genes. In the patients the researchers examined, antibody genes from subset D are much more diverse than those from other plasma cells. Lee says this finding also reflects subset D's role as an archive, which does not devote too much cellular space to any one vaccination or infection.

Source:

Emory Health Sciences

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por cyto às 22:43

Terça-feira, 21.07.15

Genetics May Determine Success of HIV Vaccines

 

Genetics May Determine Success of HIV Vaccines

 
Genetics May Determine Success of HIV Vaccines
Genetics May Determine Success of HIV Vaccines

HealthDay News — Genetics may help determine whether an HIV vaccine will work, a new study published in Science Translational Medicinesuggests. 

Daniel Geraghty, PhD, a scientist with the Fred Hutchinson Cancer Research Center in Seattle, and colleagues analyzed results of a vaccine trial in Thailand that concluded in 2009. Over 42 months, the vaccine protected against HIV infection 31% of the time.

The new analysis revealed that the vaccine was effective only in people with a specific gene variant. In others, the vaccine appeared to raise the risk of infection. To better understand this discrepancy, the researchers analyzed the HLA genotypes of 760 study participants. Those with an HLA gene variant called DPB1*13 were protected 71% of the time, they found.

"The gene identified in this study is one of those that has long been known to be directly involved in the immune response to infection," Geraghty, president and CEO of Scisco Genetics, told HealthDay. It's essential to a process that helps cells tell the immune system if they're healthy or infected, he explained. The genetic variation is common, he added. 

Meanwhile, another genetic variation (DQB1*06)  — one the researchers say is more common in the general population than in Thailand — made infection more likely.

Reference

  1. Prentice HA et al. Sci Transl Med. 2015; doi:10.1126/scitranslmed.aab4005. 

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por cyto às 18:54

Terça-feira, 23.06.15

NW Bio releases promising new data on DCVax-Direct Phase I trial for inoperable solid tumors

NW Bio releases promising new data on DCVax-Direct Phase I trial for inoperable solid tumors

Published on June 2, 2015 at 10:00 AM · 

Northwest Biotherapeutics (NASDAQ: NWBO) ("NW Bio"), a U.S. biotechnology company developing DCVax® personalized immune therapies for solid tumor cancers, over the weekend in Chicago released promising new data on their Phase I trial of DCVax-Direct for direct injection into all types of inoperable solid tumors.

The patients enrolled in the trial had late stage cancers, with an average of three inoperable tumors. The patients had failed multiple prior therapies and had a poor prognosis.

The trial enrolled 40 patients, and 39 were evaluable. A conservative treatment regimen was used. Although the patients had multiple inoperable tumors, only 1 tumor was injected with DCVax-Direct. The treatments included only 3 injections in the first 2 weeks (Day 0, 7 and 14), and up to 3 additional injections spaced months apart thereafter (Weeks 8, 16 and 32), over a total period of 8 months.

Patients typically received their first injection about 1-1/2 months after recruitment. Four patients are still in the process of completing the study visits, and data collection is ongoing on all of the patients.

The trial tested three different dose levels of DCVax-Direct, two different methods of activating the dendritic cells that comprise DCVax-Direct, and a dozen different cancers. Findings to date include encouraging survival data and substantial induction of immune checkpoint expression (PDL-1).

The webcast and presentation by Dr. Bosch can be found on the Company's website at nwbio.com/webcast

Findings to date include the following:

  • 27 of 39 patients are still alive at up to 18 months after first injection.
  • Patient survival correlates with the method of dendritic cell activation used. With the preferred method, 18 of 21 patients are still alive.
  • Treatment effects have been observed in diverse cancers, including lung, breast, colorectal, pancreatic, sarcoma, melanoma, neuro-endocrine and other cancers.
  • Patient survival correlates with the number of DCVax-Direct injections.
  • Patient survival also correlates with stabilization of disease at Week 8 (4th injection visit). Among patients treated with the preferred method of dendritic cell activation, 16 of 19 achieved stable disease (i.e., less than 25% increase in tumor size from baseline) at Week 8.

Findings to date relating to immunological responses include the following:

  • Induction of PDL-1 immune checkpoint expression was seen in 64% of evaluable patients (14 of 22) following DCVax-Direct treatment. This suggests that the tumors are putting up defenses against the immune responses induced by DCVax-Direct, and marks these patients as potential candidates for treatment with checkpoint inhibitor therapies.
  • An increase in T-cell infiltration into tumors, by functionally active T-cells, was seen following DCVax-Direct treatment.
  • Both local effects (in the injected tumor) and systemic effects were observed.

Based on the findings from the Phase I trial, the Company plans to enhance its Phase II trials in several ways, including by:

  • Using only the preferred activation method of the DCVax dendritic cells.
  • Injecting multiple inoperable tumors at each treatment visit, not just one.
  • Providing more frequent treatments and a larger total number of treatments.

The Company plans to pursue Phase II trials in non-small cell lung cancer and sarcoma, as well as a Phase II trial for multiple diverse types of cancers similar to the Phase I study. The Company also plans to expand the trial sites to include countries beyond the U.S.

"We are quite encouraged to see these results across diverse types of cancers, in late stage patients with multiple inoperable tumors who have exhausted other treatment options, and with quite a conservative DCVax-Direct treatment regimen," commented Linda Powers, CEO of NW Bio. "We are looking forward to proceeding with Phase II trials applying the lessons learned from this informative Phase I trial."

Source:

Northwest Biotherapeutics, Inc.

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por cyto às 17:20

Segunda-feira, 18.05.15

new strategy to combat cancer

CNIO researchers identify new strategy to combat cancer

Published on May 14, 2015 at 4:23 AM · 

Scientists from the Spanish National Cancer Research Centre (CNIO) have discovered a new strategy to fight cancer, which is very different from those described to date. Their work shows for the first time that telomeres -- the structures protecting the ends of the chromosomes -- may represent an effective anti-cancer target: by blocking the TRF1 gene, which is essential for the telomeres, they have shown dramatic improvements in mice with lung cancer.

"Telomere uncapping is emerging as a potential mechanism to develop new therapeutic targets for lung cancer," mention the authors with equal contribution in EMBO Molecular Medicine; Maria Garcia-Beccaria, Paula Martinez and Marinela Mendez, from the CNIO Telomeres and Telomerase Group led by Maria Blasco, who is also an author in the article. The research was also carried out in collaboration with the Experimental Therapeutics Programme, the Experimental Oncology Group and the Histopathology, Molecular Imaging and Microscopy Units at the CNIO, as well as with the Animal Medicine and Surgery Department at the Universidad Complutense de Madrid.

Every time a cell divides, it must duplicate its genetic material, the DNA, which is packed inside the chromosomes. However, given how the mechanism of DNA replication works, the end of each chromosome cannot be replicated completely, and, as a result, telomeres shorten with each cell division. Excessively short telomeres are toxic to cells, which stop replicating, and eventually, the cells are eliminated by senescence or apoptosis.

This phenomenon has been known for decades, as well as the fact that it usually does not occur in tumour cells. Cancer cells proliferate without any apparent limits, and therefore, they are constantly dividing, but their telomeres do not gradually become shorter; the key behind this mechanism is that the telomerase enzyme in cancer cells remains active, while in most healthy cells telomerase is turned off. The constant repair of telomeres by telomerase is, in fact, one of the mechanisms that allows tumour cells to be immortal and divide endlessly.

Hence, an obvious strategy to fight cancer is to inhibit the telomerase enzyme in tumour cells. This approach has been tested before, but with worrisome results: telomeres do shorten, but this shortening is lethal to tumour cells only after a variable number of cell divisions necessary for telomeres to become completely eroded-- thus the effects are not instantly seen.

In the study now published, the researchers also target telomeres, but their approach is completely different from the telomerase one.

A NEW APPROACH FOR THE ACUTE TELOMERE UNCAPPING

Telomeres are made up of repeating patterns of DNA sequences that are repeated hundreds of times -- this is the structure that shortens with each cellular division. Telomere DNA is bound by a six-protein complex, called shelterin (from the term shelter or protection), which forms a protective covering. The CNIO team strategy consisted of blocking one of the shelterins, namely TRF1, so that that the telomere shield was destroyed.

The idea of targeting one of the shelterins has not been tried so far, due to the fear of encountering many toxic effects caused by acting on these proteins that are present in both healthy and tumour cells.

"Nobody had explored the idea of using one of the shelterins as an anti-cancer target," explains Blasco. "It is difficult to find drugs that interfere with protein binding to DNA, and the possibility exists that drugs targeting telomere caps could be very toxic. For these reasons, no one had explored this option before, although it makes a lot of sense."

FEWER THAN EXPECTED SIDE-EFFECTS

The present work subtitled 'Shelterin as a novel target in cancer,' shows that blocking TRF1 only causes minor toxicities that are well tolerated by mice. "It does however prevent the growth of lung carcinomas already developed in mice," write the authors inEMBO Molecular Medicine.

"TRF1 removal induces an acute telomere uncapping, which results in cellular senescence or cell death. We have seen that this strategy kills cancer cells efficiently, stops tumour growth and has bearable toxic effects," explains Blasco.

TRF1 has been inhibited both genetically -- in mice where the gene has been removed -- and chemically using selected compounds from CNIO's proprietary collection of active compounds. These compounds, including the inhibitor ETP-470037 developed by the CNIO Experimental Therapeutics Programme, may provide a starting point for the development of new drugs for cancer therapy.

"We've shown that we can find potential drugs able to inhibit TRF1 that have therapeutic effects when administered orally to mice," says Blasco.

A CANCER WITH NO CURRENTLY AVAILABLE THERAPEUTIC TARGETS

The scientists worked with mouse models for lung cancer, the cancer type that has the highest death rates worldwide. Specifically, they used a mouse with a very aggressive type of lung cancer for which no drug targets have been found to date: the tumours have an active K-Ras oncogene and the p53 tumor suppressor is missing. TRF1 is the first target that is able to inhibit the growth of these highly aggressive tumours.

The work process has been long. The researchers first selected TRF1 among the shelterin family. TRF1 is one of the most studied shelterins that is present exclusively at the telomeres and has potential as a good anti-cancer target -- its inhibition also affects the so-called cancer stem cells that might be responsible for tumour recurrence over time.

The next aim was to demonstrate that TRF1 is really an anti-cancer target. To do so, the researchers genetically blocked its activity in mice with lung cancer as well as in healthy mice, in order to test the toxicity of the procedure.

Having established the effectiveness and low toxicity of the new target, the researchers searched for chemical compounds that could have activity against TRF1. Two types of compounds have been found. "We are now looking for partners in the pharmaceutical industry to bring this research into more advanced stages of drug development," says Blasco.

Source:

Centro Nacional de Investigaciones Oncologicas (CNIO)

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por cyto às 13:46


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