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Novel immune-oncology approach for potential cancer treatment

A research collaboration between Monash University and Lava Therapeutics details a novel immune-oncology approach for the potential treatment of cancer. Instrumental to the study was co-first author Dr Roeland Lameris from Amsterdam UMC and colleagues from the University of Melbourne.

Published in Nature Cancer, the study, co-led by Monash Biomedicine Discovery Institute’s ARC Laureate Fellow Professor Jamie Rossjohn and Dr Adam Shahine,  highlights the synergy between an antibody fragment, known as a nanobody, that not only acts as a bridge helping to link together two key immune cell receptors but also takes advantage of their interaction, enabling the body to enhance its immune response to cancer.

These antibody fragments, denoted as nanobodies, act by targeting the interaction between a molecule known as CD1d and Natural Killer T cells (NKT) in a stable and long-lasting manner, against tumour samples of patients with multiple myeloma and acute myeloid leukemia.

The new findings will serve as a model for the potential generation of new and effective therapies against a broad range of cancers.

Using the Australian Synchrotron, the team at Monash University provided detailed atomic insight into how the nanobodies exerted their effect on immune cells in a cancer model. “We were able to precisely visualize how the nanobody simultaneously recognized CD1d and the NKT TCR, thereby providing a molecular basis for their anti-tumour properties” Professor Rossjohn stated.

Hans van der Vliet, professor in medical oncology at Amsterdam UMC and chief scientific officer of Lava Therapeutics says “By targeting and boosting natural immune cells that are inherent in all humans, such as NKT cells and gamma-delta T cells, for an enhanced therapeutic effect, we believe our approach could ultimately translate into a broadly applicable immunotherapeutic approach for a range of cancer indications.”

“This collaborative work paves the way for rationally developing improved therapeutics to treat a range of cancers” said co-first author Dr. Shahine.

Read the full paper in Nature Cancer titled: “A single domain bispecific antibody targeting CD1d and the NKT T cell receptor induces a potent anti-tumour response
DOI: 10.1038/s43018-020-00111-6

Original paper

Image: Nanobodies targeting of a tumour cell.

Image Credit: Erica Tandori

Discovery of new T-cell raises prospect of ‘universal’ cancer therapy

Researchers at Cardiff University have discovered a new type of killer T-cell that offers hope of a “one-size-fits-all” cancer therapy.

T-cell therapies for cancer – where immune cells are removed, modified and returned to the patient’s blood to seek and destroy cancer cells – are the latest paradigm in cancer treatments.

The most widely-used therapy, known as CAR-T, is personalised to each patient but targets only a few types of cancers and has not been successful for solid tumours, which make up the vast majority of cancers.

Cardiff researchers have now discovered T-cells equipped with a new type of T-cell receptor (TCR) which recognises and kills most human cancer types, while ignoring healthy cells.

This TCR recognises a molecule present on the surface of a wide range of cancer cells as well as in many of the body’s normal cells but, remarkably, is able to distinguish between healthy cells and cancerous ones, killing only the latter.

The researchers said this meant it offered “exciting opportunities for pan-cancer, pan-population” immunotherapies not previously thought possible.

How does this new TCR work?

Conventional T-cells scan the surface of other cells to find anomalies and eliminate cancerous cells – which express abnormal proteins – but ignore cells that contain only “normal” proteins.

The scanning system recognises small parts of cellular proteins that are bound to cell-surface molecules called human leukocyte antigen (HLA), allowing killer T-cells to see what’s occurring inside cells by scanning their surface.

HLA varies widely between individuals, which has previously prevented scientists from creating a single T-cell-based treatment that targets most cancers in all people.

But the Cardiff study, published today in Nature Immunology, describes a unique TCR that can recognise many types of cancer via a single HLA-like molecule called MR1.

Unlike HLA, MR1 does not vary in the human population – meaning it is a hugely attractive new target for immunotherapies.

See original article here

Image: T-cells attacking cancer

 

Our recent coeliac disease research featured in the Age

Coeliac disease linked to bacteria exposure

The Age article by Liam Mannix. Original article

Exposure to bacteria that mimics gluten can confuse the immune system and trigger coeliac disease, Melbourne scientists have shown for the first time.

The results raise the possibility of using probiotics or developing a vaccine to prevent the disease, which affects nearly 400,000 Australians.

Some of the suspect bacteria lives naturally in our guts – which might explain why people with coeliac disease can still suffer even after eliminating gluten from their diet.

“This is the first time we have shown a potential mechanism for why the microbiome may be involved in the initiation of this disease,” says Hugh Reid, the Monash University researcher who led the multi-institute study.

The study also has big-picture implications. If bacteria have proteins that mimic gluten, they probably have proteins that mimic lots of things people are allergic to. Could it be that bacteria and viruses trigger many common autoimmune conditions?

Molecular mimics

Coeliac disease occurs when the body’s immune system begins reacting to gluten, a protein found in wheat, rye and barley.

When someone with the disease eats gluten, their immune system misidentifies it as a foreign invader. It mounts a huge immune response in the gut, trying to “kill” the gluten – which can lead to bloating, diarrhoea and intestinal damage.

About 50 per cent of people carry the genes that make them susceptible to coeliac disease, but these people are not born allergic to gluten. Only one in 70 with the genes ever develops it.

It seems they come across some sort of trigger as children, activating the condition before their immune system has fully matured. Scientists have long suspected mimics are to blame.

A small number of viruses and bacteria produce protein fragments that look almost identical to parts of gluten – “molecular mimics”, scientists call them.

The team used molecular databases to assemble a set of protein fragments produced by bacteria that looked near-identical to gluten. They ended up with about 20, many produced by species that live naturally – and harmlessly – within our gut.

Then researchers at the Walter and Eliza Hall Institute took blood from people with coeliac disease, and exposed the immune cells to the gluten mimics the team had found.

Immediately, the immune cells went on the attack – just like if they had spotted a molecule of gluten. “It’s a case of mistaken identity,” says Dr Reid.

To confirm the results, they used the Synchrotron, a 200-metre-long tube buried under the Melbourne suburb of Clayton that shoots out light 1 million times brighter than the sun, to take a high-resolution molecular photograph of the bacterial protein fragments as they reacted with immune system molecules.

The images looked identical to the way the gluten fragments reacted with the same molecules. “That nailed it,” says Dr Reid.

The smoking gun

The team’s paper, published in Nature Structural and Molecular Biology, is the smoking gun for the molecular mimic theory, but there are lots of questions still to be answered.

The big one: if these mimic-bacteria live in many people’s guts, why doesn’t everyone with susceptible genes get coeliac disease?

The answer may have to do with the number of bacteria, Dr Reid says.

The immune system might happily tolerate a small number of mimic bacteria living in our guts. But if there are too many, it might go on the attack.

It might then remember that attack – our immune systems are designed to remember viruses and bacteria they come across – and mount an offensive whenever it sees a similar molecule. Like gluten.

That would explain why studies have shown children who develop coeliac disease tend to have abnormal microbiomes.

Using antibiotics, which kill off healthy gut bugs and open space for other ones to thrive, is also linked to developing coeliac disease.

Perhaps this allows the number of mimic bacteria to grow high enough to trigger the disease?

“There are a lot of questions that are not answered by this,” says Dr Reid. “But we have paved the way for developing strategies for preventing this disease.

“We could vaccinate people against this particular bacteria, potentially, or use probiotics.”

Hugh on Channel 9 news speaking about our latest paper on coeliac disease

Researchers are a step closer to finding what causes the debilitating coeliac disease, which affects around one in 70 Australians.

Read the press release here.

Read the publication in Nature Structural & Molecular Biology here.

 

Bacterial link in coeliac disease

Bacterial exposure has been identified as a potential environmental risk factor in developing coeliac disease, a hereditary autoimmune-like condition that affects about one in 70 Australians.

It is estimated that half of all Australians are born with one of two genes that cause coeliac disease, and approximately one in 40 are likely to develop the condition. People with coeliac disease must follow a lifelong gluten-free diet, as even small amounts of gluten can cause health problems.

While environmental factors are known to trigger Coeliac Disease in those with the genetic predisposition, exactly how that works has remained unclear.

Scientists from the Monash Biomedicine Discovery Institute (BDI) and ARC Centre of Excellence in Advanced Molecular Imaging, have now provided a molecular foundation for microbial exposure as a potential environmental factor in the development of coeliac disease.

The results of the study, done in collaboration with researchers at Leiden University Medical Centre and the Walter and Eliza Hall Institute of Medical Research, have been published in the journal Nature Structural and Molecular Biology.

Co-Lead researcher Dr Hugh Reid, from Monash University, said the team showed, at the molecular level, how receptors isolated from immune T cells from coeliac disease patients can recognise protein fragments from certain bacteria that mimic those fragments from gluten.

Exposure to such bacterial proteins may be involved in the generation of aberrant recognition of gluten by these same T cells when susceptible individuals eat cereals containing gluten, he said.

“In coeliac disease you get aberrant reactivity to gluten and we have provided a proof-of-principle that there’s a link between gluten proteins and proteins that are found in some bacteria,” he said.

“That is, it’s possible that the immune system reacts to the bacterial proteins in a normal immune response and in so doing develops a reaction to gluten proteins because, to the immune system, they look indistinguishable – like a mimic.”

Dr Reid said the findings could eventually lead to diagnostic or therapeutic approaches to coeliac disease.

About coeliac disease

Coeliac disease is caused by an aberrant reaction of the immune system to gluten, a protein which occurs naturally in grains such as wheat, rye, barley and oats, and therefore is typically found in bread, pastries and cakes. Immune system cells, known as T cells, regard gluten as a foreign substance, and initiate action against it. In patients with CD, activation of these T cells leads to an inflammatory response in the small intestine causing a wide range of symptoms including diarrhoea, bloating and malabsorption of nutrients, to name a few.

People with coeliac disease must follow a lifelong gluten-free diet, as even small amounts of gluten can cause health problems.  If left untreated, the disease can cause serious issues including malnutrition, osteoporosis, depression and infertility, and there is a small increased risk of certain forms of cancer, such as lymphoma of the small bowel.

Image: “Mimicry”. Artwork depicting the way bacterial proteins mimic gluten proteins, causing an immune response to coeliac disease. Artwork by Dr Erica Tandori.

Original article