Tag Archives: immunity

Immune targets for chemotherapy-resistant breast cancers identified

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Scientists have identified immune cell types that could be targeted to develop specific immunotherapies in chemotherapy-resistant breast cancers.

Researchers from King’s College London and The Institute of Cancer Research, London, with support from Breast Cancer Now, have performed a deep dive into the different immune markers within tumour tissues and blood samples of early breast cancer patients whose cancer failed to respond to chemotherapy given to them prior to surgery.

The research, published today in Clinical Cancer Research, a journal of the American Association for Cancer Research, gives insight into the function of immune cells in patients with chemotherapy-resistant breast cancers. While chemotherapy may not kill cancer cells in these high-risk patients, immunotherapy, a type of treatment that helps the immune system to attack cancer cells, may provide a benefit.

To investigate the immune environment that surrounds these chemotherapy resistant tumours, researchers employed multiple and novel complementary technologies looking at proteins and genes on both pre-treatment and post-treatment breast cancer tissue. They also measured how 1,330 cancer and immune-related genes within cancer tissues were affected by chemotherapy.

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They found that chemotherapy resistant cancer cells had very few immune cells around them, but chemotherapy did induce changes in several immune cell types. Specifically, they found increases in the number of “innate” (first responder) cells such as neutrophils and natural killer (NK) cells. NK cells help the body to fight infection and cancer. But analysis found the increased NK cells in patients with chemotherapy resistant disease lacked cytotoxic activity – the ‘killing instinct’.

Researchers also found immune-related genes associated with NK cells were those associated with cell inhibition or exhaustion, which meant NK cells were unable to fight cancer cells. This new insight into the behaviour of NK cells could be used to develop specific immunotherapies for these high-risk patients. This would need to be investigated in future clinical trials.

These findings also show that blood monitoring during chemotherapy may help predict chemotherapy response early, potentially allow for tailoring of treatment prior to surgery.

Lead author Dr Sheeba Irshad, Cancer Research UK Clinician Scientist at King’s College London said: “Chemotherapy resistance in aggressive early breast cancers is a major reason why cancer regrows after treatment, contributing significantly to people not surviving their disease. In order to find the right targets for drug developments, it’s important to have a deep understanding of the complex mechanisms that allow some cancer cells to resist treatment, then hide from our immune system to only re-emerge later when they’re harder to eradicate.

“Our work has identified several cell types that would be worth investigating further to understand how they are interacting with the resistant cancer cell and how we can tweak that for our benefit. I am excited to continue to investigate these findings further.”

chemotherapy

Professor Andrew Tutt, Director of the Breast Cancer Now Toby Robins Research Centre at The Institute of Cancer Research, London, and of the Breast Cancer Now Research Unit at King’s College London, said: “Great strides have been made in harnessing immunotherapies to treat several types of cancer, but we need to do better to realise their potential for patients with breast cancer.

“This exciting work advances our understanding of the interaction between cancer cells and the immune system during treatment, and why existing treatments work well for some patients, but not others. I hope this research will help us to enhance the anti-cancer immune response in breast cancer, particularly for patients whose cancer has not responded well to chemotherapy.”

Dr Kotryna Temcinaite, Senior Research Communications Manager at Breast Cancer Now, said: “With an estimated 35,000 people living with incurable secondary (metastatic) breast cancer in the UK, it’s vital we develop smarter, more effective treatments to ensure fewer people hear the devastating news the disease has returned and spread to other parts of the body. This exciting early-stage research, which has been part-funded by Breast Cancer Now, helps to lay the groundwork for discovering a way to target breast cancer cells that resist chemotherapy treatment. We hope by building on these findings, scientists will ultimately be able to develop immunotherapy treatments that may help more people survive breast cancer.”

Antibody protects against Zika and dengue, mouse study shows

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Brazil and other areas hardest hit by the Zika virus – which can cause babies to be born with abnormally small heads – are also home to dengue virus, which is spread by the same mosquito species.

A new study led by researchers at Washington University School of Medicine in St. Louis shows that an antibody that protects against dengue virus is also effective against Zika in mice.

Antibodies remain in the bloodstream for weeks, so one or a few doses of an antibody-based drug given over the course of a woman’s pregnancy potentially could protect her fetus from Zika, with the added benefit of protecting her from both Zika and dengue disease, the researchers said. Dengue causes high fever, severe headaches, and joint and muscle pain in children and adults but does not directly harm fetuses.

“We found that this antibody not only neutralizes the dengue virus but, in mice, protects both adults and fetuses from Zika disease,” said Michael S. Diamond, MD, PhD, the Herbert S. Gasser Professor of Medicine and the study’s senior author.

The study is published Sept. 25 in Nature Immunology.

Since dengue and Zika are related viruses, the researchers reasoned that an antibody that prevents dengue disease may do the same for Zika. Diamond and graduate student Estefania Fernandez collaborated with Gavin Screaton, MD, DPhil, of Imperial College London, who had generated a panel of human anti-dengue antibodies years before.

The scientists infected nonpregnant adult mice with Zika virus and then administered one of the anti-dengue antibodies one, three or five days after infection. For comparison, another group of mice was infected with Zika virus and then given a placebo. Within three weeks of infection, more than 80 percent of the untreated mice had died, whereas all of the mice that received the anti-dengue antibody within three days of infection were still alive, and 40 percent of those that received the antibody five days after infection survived.

To find out whether the antibody also could protect fetuses from infection, the researchers infected female mice on the sixth day of their pregnancies with Zika virus and then administered a dose of antibody or a placebo one or three days later.

On the 13th day of gestation, the amount of Zika’s genetic material was 600,000 times lower in the placentas and 4,900 times lower in the fetal heads from the pregnant mice that were treated one day after infection, compared with mice that received the placebo. However, administering the antibody three days after infection was less effective: It reduced the amount of viral genetic material in the fetal heads nineteenfold and in the placentas twenty-threefold.

These findings suggest that for the antibody to effectively protect fetuses from Zika infection, it must be administered soon after infection. Such a goal may be unrealistic clinically because women rarely know when they get infected.

However, giving women the antibody as soon as they know they are pregnant could provide them with a ready-made defense against the virus should they encounter it. Antibody-based drugs have been used for decades to provide temporary protection against infectious diseases such as rabies when there is no time to vaccinate or, as in the case of Zika, when there is no vaccine available.

The key to using this antibody as a preventive drug would be to make sure that antibody levels in a woman’s bloodstream stay high enough to protect her fetus for the duration of her pregnancy.

Diamond and colleagues are working on identifying how much antibody a pregnant woman would need to ensure that her fetus is protected from Zika. They also are exploring ways to extend the antibody’s half-life in the blood, to reduce the number of times it would need to be administered.

Having anti-dengue antibodies circulating in the bloodstream for months on end poses a risk, though, because antibodies that protect against one strain of dengue virus sometimes worsen symptoms if a person is infected by another dengue strain.

To avoid the possibility of accidentally aggravating an already very painful disease, the researchers mutated the antibody in four spots, making it impossible for the antibody to exacerbate dengue disease.

“We mutated the antibody so that it could not cause antibody enhancement of dengue infection, and it was still protective,” said Diamond, who is also a professor of pathology and immunology, and of molecular microbiology. “So now we have a version of the antibody that would be therapeutic against both viruses and safe for use in a dengue-endemic area, because it is unable to worsen disease.”

New hope for ‘bubble baby disease’

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Babies born with Severe Combined Immune Deficiency (SCID) syndrome are defenceless against bacterial and viral infections that would be virtually harmless to most healthy people. If untreated, SCID is often fatal within a baby’s first year of life.

Research led by the University of Hong Kong has resulted in a new testing regime that could speed up the diagnosis of SCID, allowing more infants to receive life-saving treatment within a critical timeframe.

For the best chance of survival, infants with SCID should be treated as soon after birth as possible, and preferably within three-and-a-half months. However, poor recognition of SCID by front-line doctors is leading to delays in diagnosis, later treatments and poorer outcomes.

The authors of a recent study, published in open-access journal Frontiers in Immunology, have developed a “checklist” of potential SCID markers: a family history of early infant death, persistent candidiasis (often presenting as persistent thrush), Bacillus Calmette-Guérin (BCG) infections, and low absolute lymphocyte counts. “Flagging” an infant showing any one of these four factors would allow potential SCID patients to be fast-tracked for further tests and treatment.

Many countries – including much of Asia and the UK – do not test for SCID in their newborn health-screening programmes, with front-line doctors often left to diagnose the fatal condition. By using this checklist, the authors believe that identification, and hence treatment, of SCID patients will be possible much sooner.

Without a working immune system, newborns with SCID are highly vulnerable, and many will repeatedly visit doctors with serious and recurring infections before being diagnosed.

“The recognition of SCID by doctors is poor in Asia, resulting in delayed diagnoses that jeopoardize the chance of treatment success,” explains lead author Professor Yu Lung Lau, who focused his research on Asian and North African patients. “We wanted to see if we could identify any clinical features that would help doctors to diagnose SCID earlier.”

The study of 147 patients looked at how long it took for doctors to diagnose SCID, relative to the age the babies were first brought to their doctors, and what symptoms they had.

They found that it took an average of two months for babies to be diagnosed, and that the average age at diagnosis was four months old – beyond the critical age for treatment (which is usually stem cell transplants or gene therapy) to begin.

As the researchers examined the data, four SCID “markers” emerged. Taken in isolation, none helped reduce the time taken for a diagnosis. However, 94% of the patients studied showed at least one of the four factors.

“Family history of early infant death due to infection was useful to aid earlier diagnosis, but it was not due to doctors realizing the importance of the family history, but rather due to the family taking the child to see the doctors earlier,” says Lau. “This demonstrates the failure of our medical training and systems in using family history to aid earlier SCID diagnosis.”

Candidiasis emerged as one of the most common infections. Unfortunately, as thrush is relatively common in all infants, its presence actually slowed down the time to diagnosis.

Complications from the BCG vaccination also appeared frequently, and over 88% of the patients in the study had a very low absolute lymphocyte counts (ALC).

“Our main recommendation is to perform lymphocyte subsets for any infant with one or more of the following clinical features: family history, persistent candidiasis, BCG infections and ALC less than 3×10^9/L”, explains Lau. “This would confirm the diagnosis of SCID, if present”.

For the time being, newborn screening remains out of reach in much of Asia, so education of front-line doctors and parents is key.

“Our recommendations may help earlier diagnosis of SCID, and need to be communicated to doctors as well as to ordinary citizens, who can then urge the doctors along our recommendation,” concludes Lau.

Measles-Rubella (MR) Campaign widens its reach

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2nd phase of MR vaccination campaign rolled out.

India, along with ten other WHO South East Asia Region member countries, have resolved to eliminate measles and control rubella/congenital rubella syndrome (CRS) by 2020. In this direction, Ministry of Health & Family Welfare has initiated measles-rubella (MR) vaccination campaign in the age group of 9 months to less than 15 years in a phased manner across the nation. The campaign aims to cover approximately 41 crore children and is going to be the largest ever vaccination campaign worldwide. All children from 9 months to less than 15 years of age will be given a single shot of Measles-Rubella (MR) vaccination during the campaign. Following the campaign, MR vaccine will become a part of routine immunization and will replace measles vaccine, currently given at 9-12 months and 16-24 months of age of child.

The first phase of measles-rubella vaccination campaign has been successfully completed in five states, namely, Tamil Nadu, Karnataka, Goa, Lakshadweep and Puducherry. More than 3.3 crore children were vaccinated, reaching out to 97% of the intended age group. The campaign was carried out in schools, community centers and health facilities. The next round is starting in 8 states/UTs (Andhra Pradesh, Chandigarh, Dadra & Nagar Haveli, Daman & Diu, Himachal Pradesh, Kerala, Telangana and Uttarakhand) from August 2017, aiming to cover 3.4 crore children.

The campaign aims to rapidly build up immunity for both measles and rubella diseases in the community so as to knock out the disease, therefore, all the children should receive MR vaccine during the campaign. For those children who have already received such vaccination, the campaign dose would provide additional boosting to them. In order to achieve maximum coverage during the campaign, multiple stakeholders have been involved, which includes, apart from Ministry of Health & Family Welfare, other Ministries, development partners, Lions clubs, professional bodies, for example, Indian Association of Pediatrics, Indian Medical Association, Civil Society Organizations etc.

The Measles-Rubella campaign is a part of global efforts to reduce illness and deaths due to measles and rubella/CRS in the country. Measles immunization directly contributes to the reduction of under-five child mortality, and in combination with rubella vaccine, it will control rubella and prevent CRS.