Turning autoimmunity drugs into anti-cancer treatments

Why did you choose to research autoimmunity drugs and cancer treatments?

I am interested in immunotherapy, using the immune system to treat disease, and often cancer and autoimmunity are the opposite sides of the coin, one side where the immune system is suppressed and the other where it is too active.
Understanding one typically helps to understand the other.

What current treatment options are available for autoimmunity and cancer?

There are many varied treatments ranging from steroids, chemotherapy, small molecule targeted drugs as well as biologics such as antibodies, which is my main focus.

What is CD40?

CD40 is a receptor expressed on the cell surface of several immune cell types, known as antigen-presenting cells (APC) such as B cells and dendritic cells.
It is a member of the Tumor Necrosis Factor Receptor Super-Family (TNFRSF) and is essential for the initiation and regulation of adaptive immunity.  
The interaction between CD40 and its endogenous ligand CD40L is critical for mounting an effective immune response against exogenous pathogens and naturally arising tumors.

How does its role differ in autoimmunity and cancer?

CD40 over-stimulation is implicated in various autoimmune syndromes such as lupus and colitis as well as transplant rejection, driving B cell and T cell stimulation leading to inappropriate activation, and tissue destruction.
In contrast, CD40 under-stimulation reduces the activation of the APCs and reduces the generation and expansion of CD8+ T cells that control tumors.

How do these antibody drugs affect the CD40 immune pathway in autoimmunity?

The drugs used in autoimmunity are designed to block the interaction between CD40 and its ligand (CD40 ligand; CD40L). This prevents immune signaling in the APC, reducing immune activation.

In your research you developed an antagonist CD40 antibody that could be used to treat cancer, how did you do this?

We did not develop this antibody – it had already been developed and used in the clinic to treat autoimmunity.
We simply used the V region sequences to make a series of modified antibodies that differed in their Fc domains – displaying human IgG1, 2, or 4 isotypes.

We then explored how these antibodies modified immune responses, showing that the hIgG1 and 4 antibodies reduced immune stimulation whereas the hIgG2 antibody did the opposite and boosted the immune responses.

What else did you learn about the mechanism of CD40 in your research?

We learned how transformative just changing the Fc domain can be for the function of the antibody; converting a “blocking” antibody into a super-active one.
We also highlighted this property of the hIgG2 isotype is FcgR-independent and is related to its unique hinge region which allows disulfide shuffling.
The converted antagonist showed curative antitumor synergy with cell therapy and vaccination strategies.

Why could this antibody drug be more effective at treating cancer than other CD40 antibody therapies currently being used?

Firstly, it was more active at stimulating immune responses in our various assays than the current most active antibody available in the clinic. Moreover, we think the really exciting thing is that it does not require interaction with Fc receptors for its activity whereas other antibodies do.
Fc receptor expression is variable in different people and different tumors which may explain why some people do or do not respond to these drugs.
By generating an antibody-drug that does not require Fc receptors, we hope to be able to get strong responses in more patients.

Do you believe that this antibody could help to transform the lives of many people suffering from cancer? Are there any other conditions that you could apply your research to?

We hope that this drug and others like it could help pave the way for more effective treatments.
We hope that this research could potentially apply to vaccination, as we can also boost antibody responses to foreign antigens with this drug.

What are the next steps that need to be taken before this treatment could be used in hospitals?

First, more extensive experiments to assess how best to deliver the drug. Then, we need to perform the usual early human studies, first assessing safety and finding a safe and effective dose before it can progress to use in patients.

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Cancer 'vaccine' shows promise in human trial of lymphoma patients

An experimental cancer "vaccine" showed promising results in a small clinical trial of patients with lymphoma, according to a study.

Researchers tested the treatment in 11 patients with lymphoma. Their results were successful enough to warrant another clinical trial in March on lymphoma patients as well as breast and head-and-neck cancer.

Researchers said some patients in the initial human trial went into full remission for months or even years.

The treatment "has broad implications for multiple types of cancer," said lead author, the director of the lymphoma immunotherapy program. "This method could also increase the success of other immunotherapies such as checkpoint blockade.

They refer to it as a vaccine because it causes a person's immune system to fight the disease, though it's not preventive like the flu shot. In this case, the treatment teaches the body to recognize tumors and attack them.

Researchers created the treatment directly inside the tumor. To do this, they injected one tumor with a stimulant to recruit immune cells, treated the tumor with a low dose of radiation then injected it with a stimulant to activate immune cells. These activated immune cells then travel throughout the body, killing tumors wherever they find them.

In three of the patients, the treatment shrunk not only the tumor that was treated but also other ones throughout the body, putting these patients into remission.

"It's really promising, and the fact you get not only responses in treated areas, but areas outside the field [of treatment with radiation] is really significant," said a Dr. who was not involved in the study and is working on a similar treatment.

While promising, the effect was observed in only three people and will need to be tested in larger trials before even going before the Food and Drug Administration for review.

The Dr. said the results are exciting but cautioned more research needs to be done. 

"It's definitely proof of concept, but larger studies are definitely needed and additional strategies to try to get more than three out of 11 patients to respond," he said,  who is also developing a lymphoma vaccine, though with a slightly different approach.

Researchers for decades have tried but failed to create cancer vaccines. New research on immunotherapy, or training a person's immune system to fight disease, has reinvigorated their efforts.
The vaccine activates dendritic cells, which are responsible for initiating immune responses. These cells then instruct T-cells to attack tumors in a person's body, like generals instructing soldiers how to fight.

"Generals don't really fight wars, they make the plans," the Dr. said.

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Researchers Have Identified Why Our Bodies Reject Transplanted Organs

Researchers have identified a previously hidden link between our immune system and the activation of cells that lead to organ rejection.

The discovery opens the way for scientists to develop new forms of treatment that could prevent immune responses from attacking life-saving tissue transplants without leaving the body so open to infection or cancer.

A type of receptor on bone marrow cells called signal regulatory protein alpha  (SIRPα) has been identified by scientists, as the body's watchdog responsible for dispatching the lymphocytes that target and destroy foreign cells.

In simple terms, whenever we take cells from another person's body and put them into our own, white blood cells see them as foreign and attempt to break them apart.

Not only is this bad news for the transplanted tissues, the swelling and fever that comes with the immune response isn't exactly a picnic either.

The mechanisms behind the white blood cell assault are fairly well understood – molecules on the outside of the cells belonging to what's called the major histocompatibility complex (MHC) identify them as different.

A type of white blood cell called a T lymphocyte has receptors on its surface capable of recognising unknown MHC proteins and responds by attempting to break up the foreign material they're attached to.

Lymphocytes aren't born knowing what's foreign and what's not; they need to be taught. Which is the job of another part of the immune system called a dendritic cell. 

Dendritic cells chew up foreign proteins and weave them into their own MHC before displaying them on their surface like a microscopic 'wanted' poster. They then migrate into the body's lymph nodes where they interact with the gun-slinging T lymphocytes.

Exactly how dendritic cells identify foreign materials, however, has been something of a mystery.

To learn more, the researchers studied the transplanted tissues in mice engineered to lack certain white blood cells such as their T lymphocytes.

They found that differences between the mice donor's and recipient's SIRPα gene correlated with the recipient's immune responses.

SIRPα isn't an unknown protein, already understood to bind to another protein called CD47 that triggers a range of immune responses in different white blood cells.

Joining the dots, the researchers believe CD47 on monocytes – the white blood cells that grow into dendritic cells – interact with SIRPα receptors on foreign tissues, setting off the entire ID check process.

"Once these cells are activated, then they turn around and activate the rest of the immune system, and that leads to the full-blown rejection of the organ," lead researcher.

"What we would like to do is sequence the SIRP-alpha gene in many humans who are donors and recipients of organ or bone marrow, and then ask whether a mismatch affects the outcome after transplantation."

A better match between the donor's and recipient's SIRPα genes could help reduce the risk of the immune response being sparked in the first place.



Even when organs are chosen to have closely matching MHC proteins, subtle differences can still produce immune responses. For example, one in 10 hearts and nearly one in 20 kidneys will show signs of being rejected by the body within the first year in spite of being declared compatible.

To avoid rejection, organ recipients need to be on treatments that suppress the immune system, not only making them prone to infection and cancer but often raising the risk of heart attacks and strokes by increasing blood pressure.

New treatments focusing on SIRPα might help reduce the doses or types of medications, and possibly help prolong the organ's life.

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Gut neurons help prevent tissue over-inflammation

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As the guardian of our health, the immune system has to sense and react to pathogens to eliminate them, but not so fiercely as to over-inflame and damage tissue. The need for this balance is most apparent in the gut - which is continually under threat from bacteria like Salmonella that could be lurking in the food and drink that we ingest.

 The researchers say they now have a much better idea of how neurons and macrophages in the gut work together to help prevent damage from inflammation.
 
Now, a new study - by researchers at Rockefeller University, New York, NY, and published in Cell - shows that neurons in the gut appear to work with cells of the immune system to fine-tune this balance and prevent over-inflammation of intestinal tissue.

Senior author Daniel Mucida, an assistant professor and head of Rockefeller's mucosal immunology lab, says:
"Resistance to infections needs to be coupled with tolerance to the delicacy of the system. Our work identifies a mechanism by which neurons work with immune cells to help intestinal tissue respond to perturbations without going too far."

 He and his colleagues believe their findings could help develop new treatments for gastrointestinal diseases, such as irritable bowel syndrome (IBS).

Prof. Mucida explains that the lining of the human gut - known as the human intestinal mucosae - has a total surface area of about 300 m² and is the largest surface of the body that is exposed to potential pathogens from the environment. The gut absorbs around 100 g of dietary proteins a day and is home to around 100 trillion "friendly" bacteria.

To maintain immune protection over such a large area, there are more white blood cells in the gut than in the whole of the rest of the human body.

The study concerns itself with two types of large white blood cell known as macrophages: lamina propria macrophages (found close to the lining of the gut and thus close to the food as it is digested) and muscularis macrophages (found in much deeper-sited tissue, further away from food as it digests).

Muscularis macrophages 'almost hug the neurons'

Using a 3D imaging system, the researchers looked for differences in the cell structures of the two types of macrophage. As well as noticing differences in the structure and movement of the cells, the team found they surround neurons in the gut wall.

With the help of "transcriptional profiling tools," the researchers also found the different types of macrophage had different groups of genes switched on and off - they had different gene expression profiles - in the presence of an infection.

The lamina propria macrophages appeared to express more pro-inflammatory genes, while the muscularis macrophages favored anti-inflammatory genes.

Prof. Mucida says they wanted to know what was telling the macrophage genes to have these different responses to infection and explains:
"We came to the conclusion that one of the main signals seems to come from neurons, which appear in our imaging to almost be hugged by the muscularis macrophages."


In further tests, the team found that receptors on the surface of the muscularis macrophages respond to norepinephrine, a signaling chemical or neurotransmitter that is released by neurons. They suggest this be could a route through which gut neurons control inflammation.

The team also found the muscularis macrophages are activated much faster via the neuron route than when summoned by other immune cells. They suggest this is how the cells are able to respond to infection very quickly - within 1 or 2 hours - despite being deeply embedded in the gut wall and far away from the source of infection.

Prof. Mucida says they now have a much better idea of how neurons and macrophages in the gut work together to help prevent damage from inflammation, and he concludes:

"It's plausible that a severe infection could disrupt this pathway, leading to the tissue damage and permanent gastrointestinal changes that are seen in diseases like irritable bowel syndrome. These findings could be harnessed in the future to develop treatments for such diseases."

New studies are also uncovering that the friendly bacteria that live in and on our bodies help regulate immunity. For instance, Medical News Today recently learned of a study that shows how - once considered as sterile - the lungs are home to bacteria that help regulate the immune system through interaction with specialized cells called dendritic cells.

Nanotherapy brings diabetes vaccine a step closer

Researchers have for the first time used nanoparticles that imitate naturally dying cells to prevent diabetes in mice, an advance that may pave the way for a human vaccine to protect against the disease.
 
Previously, researchers at The Germans Trias i Pujol Research Institute in Spain modified an individual's immune cells, known as dendritic cells, to avoid the destruction of the insulin-producing pancreatic cells (beta cells) in the body and prevent type 1 diabetes.

This requires the extraction of the subjects' dendritic cells for their subsequent manipulation and re-injection. The process is complex and costly.

In a new study with mice, the researchers said they have achieved the same effect with a much simpler process.

The researchers, in collaboration with the Catalan Institute for Nanoscience and Nanotechnology located on the Universitat Autonoma de Barcelona (UAB) Campus, created nanoparticles called liposomes in the laboratory which imitate cells in the process of natural death.

Liposomes are droplets with an external fat membrane, similar to cell membranes.

They can be made using a very specialised process, but one that is easy and safe and also easy to scale up.

In mice, liposomes arrested the destruction of the beta cells after being introduced into the body to prevent the development of diabetes.

This technique could be a much better candidate for a human vaccine, researchers said.

"After showing that liposomes prevent the onset of type 1 diabetes in mice, the next steps are to test it in human cells in vitro, to start clinical trials on human candidates for preventive vaccination and to cure the disease by combining the vaccine with regenerative therapies," researchers said.

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