Tag: immunotherapy

Categories : Cancer Cardiovascular DiseaseTags :

How Checkpoint Immunotherapy also Increases the Risk of Cardiovascular Disease

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Source: Wikimedia CC0

Cancer immunotherapy is known to also make patients more vulnerable to heart attack and stroke. A new study led by researchers at NYU Langone Health points to a possible explanation for this side effect: the treatment interferes with immune regulation in the heart’s largest blood vessels.

This new work focused on immune checkpoint inhibitors, which work by blocking molecules embedded on the surface of cells – immune checkpoints – which normally serve as “brakes” that prevent excess immune activity, or inflammation. Some tumours are known to hijack these checkpoints to weaken the body’s defences, so by blocking the checkpoints, the treatments enable the immune system to kill tumour cells.

Unfortunately, this treatment type may also trigger damaging levels of inflammation in the heart, brain, stomach, and other organs, the researchers say. For example, past studies have shown that about 10% of those with atherosclerosis have a heart attack or stroke following cancer treatment. Until now, the specific mechanisms behind this issue had remained unclear.

To address this question, the research team explored at a cellular level how immune checkpoint inhibitors interact with immune cells within arterial plaques. A genetic analysis by the study authors showed that the same type of immune checkpoints targeted by cancer therapies also appear in arterial immune cells, establishing a link between checkpoint inhibitors and cardiovascular events.

“Our findings provide new insight into how a drug intended to target tumours can also prompt a heightened immune response in arteries and increase risk of heart disease,” said study co-senior author Chiara Giannarelli, MD, PhD. “Cancer patients and their physicians should be aware that they may need to monitor for new heart concerns following cancer treatment,” added Dr Giannarelli.

For the current study, published in Nature Cardiovascular Research, the researchers analysed the genetic activity of thousands of immune cells collected from the plaques of 50 men and women undergoing a surgical procedure to address atherosclerosis.

The investigators also explored how type 2 diabetes, a known risk factor for both cancer and heart disease, may make those with atherosclerosis even more vulnerable to the ill effects of checkpoint inhibitors, adds Dr Giannarelli, also an associate professor in the Department of Pathology at NYU Grossman School of Medicine. As part of the study, the team assessed immune checkpoint activity in arterial tissue collected from eight patients with diabetes and four healthy volunteers. Notably, none had a history of atherosclerosis. The results showed that the diabetes patients had less measurable communication between checkpoints, which in turn can prompt increased inflammation.

Other experiments further revealed that taking immune checkpoint inhibitors might make it harder to combat atherosclerosis. Under normal circumstances, physicians typically prescribe low-fat diets to reduce plaque buildup and inflammation. Indeed, the researchers’ experiments in rodents confirmed that such diets boost communication between immune checkpoints within arteries. However, cancer patients may be at a disadvantage because their therapy, by blocking these same checkpoints, may counteract the anti-inflammatory benefits of fat reduction.

“Our findings highlight how cancer, diabetes, and heart disease do not exist in a vacuum, and that it is critical to consider how targeting one of these conditions can affect the others,” said study co-senior author Kathryn J. Moore, PhD. “Now that experts have a better understanding of the interplay between these diseases, they can begin to explore new strategies to lower the risk of unintended health concerns caused by their treatment,” added Dr Moore. She cautions that the study did not directly assess immune checkpoint behaviour in cancer patients. The team plans to do so in future investigations, she adds.

Source: NYU Langone Health

Categories : Cancer NeurologyTags :

A Way to Make Glioblastoma Cells Visible to Immune Cells

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MRI scan showing brain cancer. Credit: Michelle Monje, MD, PhD, Stanford University

Patients with glioblastoma typically survive less than two years after diagnosis, even with cutting-edge therapies. The latest immunotherapies have been unsuccessful, likely because glioblastoma cells have few, if any, natural targets for the immune system to attack.

In a cell-based study, scientists at Washington University School of Medicine have forced glioblastoma cells to display immune system targets, potentially making them visible to immune cells and newly vulnerable to immunotherapies. The strategy involves a combination of two drugs, each already FDA-approved to treat different cancers.

The study is online in the journal Nature Genetics.

“For patients whose tumours do not naturally produce targets for immunotherapy, we showed there is a way to induce their generation,” said co-senior author Ting Wang, PhD, professor of medicine and Department of Genetics head at WashU Medicine. “In other words, when there is no target, we can create one. This is a very new way of designing targeted and precision therapies for cancer. We are hopeful that in the near future we will be able to move into clinical trials, where immunotherapy can be combined with this strategy to provide new therapeutic approaches for patients with very hard-to-treat cancers.”

To create immune targets on cancer cells, Wang has focused on stretches of DNA in the genome known as transposable elements. In recent years, transposable elements have emerged as a double-edged sword in cancer, according to Wang. His work has shown that transposable elements play a role in causing tumours to develop even as they present vulnerabilities that could be exploited to create new cancer treatment strategies.

For this study, Wang’s team took advantage of the fact that transposable elements naturally can cause a tumour to churn out random proteins that are unique to the tumour and not present in normal cells. Called tumour antigens or neoantigens, these unusual proteins could be the targets for immunotherapies, such as checkpoint inhibitors, antibodies, vaccines and genetically engineered T cell therapies.

Even so, some tumours, including glioblastoma, have few immune targets produced naturally by transposable elements. To address this, Wang and his colleagues, including co-senior author Albert H. Kim, MD, PhD, neurosurgery professor, have demonstrated how to purposely force transposable elements to produce immune system targets on glioblastoma cells that normally lack them.

The researchers used a combination of two drugs that influence the epigenome, which controls gene activation. When treated with the two epigenetic therapy drugs, the tightly packed DNA molecules of the glioblastoma cells unfurled, triggering transposable elements to begin making the unusual proteins that could be used to target the cancer cells. The two drugs were decitabine, which is approved to treat myelodysplastic syndromes, a group of blood cancers; and panobinostat, which is approved for multiple myeloma, a cancer of white blood cells.

Before investigating this strategy in people, the researchers are seeking ways to target the epigenetic therapy so that only the tumour cells are induced to make neoantigens. In the new study, the researchers cautioned that normal cells also produced targets when exposed to the two drugs. Even though normal cells didn’t produce as many neoantigens as the glioblastoma cells did, Wang and Kim said there is a risk of unwanted side effects if normal cells create these targets as well.

In ongoing work, Wang and Kim are investigating how to use CRISPR molecular editing technology to induce specific parts of the genome in cancer cells to produce the same neoantigens from transposable elements that are common across the human population. Such a strategy could give many patients’ tumours – even different cancer types – the same targets that could respond to the same immunotherapy, while sparing healthy cells. There are then multiple possible ways to go after such a shared target, including checkpoint inhibitors, vaccines, engineered antibodies and engineered T cells.

Source: Washington University School of Medicine

Categories : CancerTags :

Oestrogens are Implicated in More than Just Breast Cancers

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Photo by National Cancer Institute on Unsplash

Oestrogens are known to drive tumour growth in breast cancer cells that carry its receptors, but a new study by Duke Cancer Institute researchers unexpectedly finds that oestrogens play a role in fuelling the growth of breast cancers without the receptors, as well as numerous other cancers.

Writing in the journal Science Advances, the researchers describe how oestrogens not only decrease the ability of the immune system to attack tumours, but also reduce the effectiveness of immunotherapies that are used to treat many cancers, notably triple-negative breast cancers. Triple-negative breast cancers are an aggressive form of disease that are negative for oestrogen, progesterone, and the HER2 receptor proteins.

Informed by retrospective analysis of patient data and experiments in mice, the researchers found that anti-oestrogen drugs reversed the effects of oestrogens, restoring potency to immunotherapies.

“The treatment for triple-negative breast cancer has been greatly improved with the advent of immunotherapy,” said senior author Donald McDonnell, PhD, professor at Duke University School of Medicine.

“Developing ways to increase the anti-cancer activity of immunotherapies is a primary goal of our research,” McDonnell said. “Here we have found a simple way bolster the effectiveness of immunotherapy for this type of breast cancer and the benefit was even seen in other cancers, including melanoma and colon cancers.”

McDonnell and colleagues, including lead author Sandeep Artham, a postdoctoral associate in the McDonnell lab, focused on a type of white blood cell called eosinophils, which are typically activated during allergic reactions and inflammatory diseases.

Eosinophils have recently been identified as important in tumours, and a phenomenon called tumour associated tissue eosinophilia, or TATE, is associated with better outcomes among patients with multiple types of cancer, including colon, oesophageal, gastric, oral, melanoma and liver cancers.

In their studies, the Duke team described how oestrogens decrease the number of eosinophils and TATE in mice. The hormone contributes to increased tumour growth in oestrogen receptor-negative breast cancer tumours and in melanoma tumours, which do not rely on oestrogen receptors for tumour growth.

Conversely, anti-oestrogen therapies inhibited oestrogen receptor signalling and enhanced the efficacy of immunotherapies, slowing tumour growth.

“These findings highlight the importance of oestrogen-receptor signalling as a regulator of eosinophil biology and TATE and highlight the potential near-term clinical application of anti-oestrogen drugs to increase the benefits of immunotherapies in multiple tumour types,” McDonnell said.

He said clinical trials are being planned using an investigational anti-oestrogen drug called lasofoxifene among patients with triple-negative breast cancers.

Source: Duke University Medical Center

Categories : CancerTags :

Better Response to Lung Cancer Immunotherapy with Combination Treatment

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Lung cancer metastasis. Credit: National Cancer Institute

In research published in Nature Communications, scientists have tested a combination of treatments in mice with lung cancer and shown that these allow immunotherapies to target non-responsive tumours.

The study findings, from Francis Crick Institute, in collaboration with Revolution Medicines, show that targeting tumours in different ways simultaneously might increase response to treatments.

The scientists tested a combination of tool compounds in mice with lung cancer. These compounds were used to represent:

  • Targeted drugs which block a cancer-causing protein called KRAS G12C. These have been approved for use in lung cancer, but often fail to benefit patients in the long term because the tumours develop resistance to these medicines over time.
  • Immunotherapy drugs. These are designed to stimulate the immune system to fight the tumour, but only 20% of people with lung cancer respond, as tumours often block immune cells from entering.

The researchers combined a newly identified KRAS G12C inhibitor, with a compound that blocks a protein called SHP2, which inhibits cancer cells and can also activate tumor immunity.

These two inhibitors were combined with an immune checkpoint inhibitor, which blocks proteins that help the cancer cells hide from the immune system.

Source: Francis Crick Institute

Categories : Cancer Metabolic DisordersTags :

The Outcomes of Cancer Therapies and BMI Have a Complex Relationship

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Risk of mortality during cancer treatment in relation to BMI. For non-small cell lung cancer treatment, immunotherapy seems to pose less risk for persons under a certain BMI, while conventional chemotherapy appears optimal for persons who might be overweight or obese. Credit: Osaka Metropolitan University

While being overweight increases the risk of developing lifestyle-related diseases, there is a phenomenon known as the obesity paradox where a decreased risk of death has been seen during cancer therapy. However, that paradox might not hold true for all cancer therapies, an Osaka Metropolitan University team reports in JAMA Network Open, a publication of the American Medical Association.

Led by graduate student Mr Yasutaka Ihara and Professor Ayumi Shintani of the Graduate School of Medicine’s Department of Medical Statistics, the team used a Japanese administrative claims database of more than 500 000 lung cancer patients and examined the relation between body mass index (BMI) and the risk of mortality during immunotherapy and conventional chemotherapy.

Focusing only on patients with advanced non-small cell lung cancer, the team found that the higher the BMI, the lower the risk of mortality when undergoing both immunotherapy and chemotherapy, though it does a U-turn around a BMI of 24. Patients with a BMI under 28 showed lower risk of mortality when undergoing immunotherapy compared to conventional chemotherapy, but for those at or over that figure, the risk increases with immunotherapy while it continues to get lower with chemotherapy.

“Immunotherapy might not always be the optimal treatment method for obese patients with advanced non-small cell lung cancer, so the use of conventional chemotherapy should also be considered,” Mr. Ihara stated. “In addition to BMI, age, hormones, and gut microbiota have been reported as factors that influence the effectiveness of immunotherapy. Evaluation of whether immunotherapy or conventional chemotherapy improves survival in the presence of these factors is expected to contribute to the development of precision medicine.”

Source: Osaka Metropolitan University

Categories : Cancer Immune SystemTags :

How Cancer Reprograms Immune Cells to Join the Enemy

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Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash

Cancer has been described as “a wound that does not heal,” implying that the immune system is unable to wipe out invading tumour cells. A new discovery reported in PNAS confirms that a key molecule can reprogram immune cells into turncoats that promote cancer growth.

Studying the behaviour of these “pro-tumour” immune cells is important because they could be targets for therapies that block their harmful activity, said Minsoo Kim, PhD, corresponding author of the study and a research leader at the Wilmot Cancer Institute.

Kim led a team of scientists investigating the dynamic interactions that occur between cells in the tumor environment, and the underlying factors that cause the harmful transformation of immune cells from good to bad.

They found that PAF (platelet-activating factor) is the key molecule that controls the destiny of the immune cells. PAF not only recruits cancer-promoting cells, but it also suppresses the immune system’s ability to fight back. In addition, they found that multiple cancers rely on the same PAF signals.

“This is what could be most significant,” said Kim. “Because if we find a treatment that could interfere with PAF, it could potentially apply to many types of cancer.”

Much of the team’s work focused on pancreatic cancer cells. It is one of the most deadly cancers, with a five-year survival rate of about 12%, and is notoriously hard to treat because pancreatic tumours are surrounded by a toxic stew of proteins and other tissues that protect the cancer from the immune system’s natural role to attack invaders. They also studied breast, ovarian, colorectal, and lung cancer cells, using advanced 3D imaging technology to watch the behaviour of immune cells as they swarmed to the cancerous region.

Source: University of Rochester Medical Center

Categories : CancerTags :

Advanced Lung Cancer Mortality Plunged Since Standardisation of Immunotherapy

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The largest population-based study to date supports the survival benefits of immunotherapy for people with metastatic non–small cell lung cancer.

Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash

Since the first immunotherapy drug to boost the body’s immune response against advanced lung cancer was introduced in the United States in 2015, survival rates of patients with the disease have improved significantly. That’s the conclusion of a recent real-world study published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

For the research, a team led by Dipesh Uprety, MD, FACP, of the Barbara Ann Karmanos Cancer Institute and the Wayne State University School of Medicine, analysed data from the National Cancer Institute Surveillance, Epidemiology, and End Results database, which compiles cancer-related data covering approximately 48% of the US population. The investigators’ analysis focused on non–small cell lung cancer (NSCLC), which accounts for up to 90% of all cases of lung cancer and is the leading cause of cancer-related death among both men and women in the United States.

In a comparison of 100 995 patients with metastatic NSCLC treated in 2015–2020 (after immunotherapy was deemed the standard of care) and 90 807 patients with metastatic NSCLC in the pre-immunotherapy era of 2010–2014, patients in the immunotherapy era were less likely to die from any cause. The overall survival rates at one, three, and five years were 40.1% versus 33.5%, 17.8% versus 11.7%, and 10.7% versus 6.8%. The median overall survival was eight months in patients in the immunotherapy era and seven months in those in the pre-immunotherapy era.

Similarly, patients treated after immunotherapy was available were less likely to die specifically from cancer than those treated before immunotherapy. The one-, three-, and five-year cancer-specific survival rates were 44.0% versus 36.8%, 21.7% versus 14.4%, and 14.3% versus 9.0%, with a median survival of 10 months versus eight months.

Survival rates remained significantly better in the immunotherapy era even after accounting for factors including age, sex, race, income, and geographical area.

“By utilizing a large national database, our study provided real-world evidence of the positive impact of immunotherapy in patients with lung cancer,” said Dr Uprety. The investigators stressed that additional studies are needed, however. “Immunotherapy provides long-term benefits. Since the durable benefits of immunotherapy are limited to a small subset of patients, future research should aim to optimize immunotherapy with new agents that can benefit a broader population,” said lead author Yating Wang, MD, of Ascension Providence Hospital.

Source: Wiley

Categories : CancerTags :

‘Potentially Game Changing’ Immunotherapy Trial for Colorectal Cancer

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Human colon cancer cells. Credit: National Cancer Institute

Results from a new trial indicate that immunotherapy could successfully be used to treat the most common form of colorectal cancer, also known as bowel cancer.

The findings of the new study, a phase 1 trial involving the immunotherapy drugs botensilimab and balstilimab, have been published in the journal Nature Medicine, and it is the first time that consistent and durable responses to immunotherapy have been reported in difficult-to-treat patients.

Co-authored by Professor Justin Stebbing of Anglia Ruskin University (ARU), who describes the results as “potentially game changing”, the study focused on the most common type of colorectal tumours, known as MSS mCRC, or microsatellite stable metastatic colorectal cancer.

Although immunotherapy has previously been shown to work on patients with specific mismatch repair deficient (dMMR) tumours, only a small percentage of colorectal cancer patients have this type of tumour, and immunotherapy has so far been ineffective in patients with more common MSS mCRC tumours.

The new study involved using the immunotherapy drug botensilimab in conjunction with balstilimab on a group of patients in the United States. These drugs are both monoclonal antibodies, which work by triggering the body’s immune system to attack the cancer.

Of the patients in the phase 1 trial, 101 took part in a six-month follow-up and of these, 61% of them saw their tumour shrink or remain stable after receiving a combination of botensilimab (BOT) and balstilimab (BAL). The most common side-effects, or treatment-related adverse events, were diarrhoea and fatigue.

Justin Stebbing, Professor of Biomedical Sciences at Anglia Ruskin University (ARU) and communicating author of the study, said:

“These results are incredibly exciting. Colorectal or bowel cancer is one of the most common forms of cancer worldwide and this is the first time there has been convincing evidence that immunotherapy can work in all forms of colorectal tumours, so this is potentially game changing.

“This is now progressing into later phase clinical trials and we hope the FDA in the United States approve its use very soon. And because this is such an important area, affecting so many people, we hope authorities in the UK are also able to move quickly.”
Joint first author Dr Andrea Bullock, Assistant Professor in Medicine at Beth Israel Deaconess Medical Center, said:

“This study sheds light on the potential of the BOT/BAL combination to treat microsatellite stable metastatic colorectal cancer, the most common form of colorectal cancer which has historically not responded to immunotherapy, and we hope our results will offer new hope for those diagnosed.”
Joint last author Dr Anthony El-Khoueiry, Associate Director of Clinical Research and Chief of Section of Developmental Therapeutics at the USC Norris Comprehensive Cancer Center, said:

“This phase 1 study of botensilimab highlights its promising anti-tumour activity that encompasses immunologically cold tumours such as MSS colorectal cancer. The efficacy noted highlights the potential of botensilimab through its broader engagement of anti-tumour immunity.”

The full open access paper, published in , is available here 

Source: Anglia Ruskin University

Categories : AllergiesTags :

Certain Gut Bacteria Assist in Immunotherapy for Milk Allergy

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Gut Microbiome. Credit Darryl Leja National Human Genome Research Institute National Institutes Of Health

Researchers in Japan have discovered a link between gut bacteria and the success of milk-allergy oral immunotherapy. Published in the scientific journal Allergology International, the study found that Bifidobacterium – a genus of beneficial bacteria in the gut – was associated with a higher chance of successful treatment. The finding may help in the development of more effective oral immunotherapies, perhaps by combining them with probiotic supplements.

Many children have allergic reactions to certain milk proteins. Most grow out of it but some have to contend with lifelong allergy. Milk allergy can be improved by oral immunotherapy – taking small, increasing doses of milk. Unfortunately, while allergic reactions are controlled during treatment, in most cases, tolerance disappears soon after the treatment ends.

Gut bacteria are thought to help reduce allergic reactions to some foods, but little is known about the link between these bacteria and oral immunotherapy for milk allergy. Hiroshi Ohno led a team at the RIKEN Center for Integrative Medical Sciences to find out why. The researchers examined 32 children with cow’s milk allergy who received oral immunotherapy, with the first month being conducted in a hospital. “Oral immunotherapy is not without risk,” explains Ohno. “We closely monitored the children in the hospital, and in fact 4 children had such severe reactions to the milk that we could not allow them to continue the treatment.”

The remaining 28 children then completed an additional 12 months of treatment at home. Next, they avoided milk for two weeks, and were then tested on a double-blind, placebo-controlled food challenge to see if they could still tolerate milk without any allergic reactions. During the food challenge, children were initially given a tiny amount of placebo or milk (only 0.01mL) which was gradually increased every 20 minutes until they had an allergic reaction or until they could drink the final 30mL without a reaction.

The researchers focused their analyses on immunological and bacterial changes during the treatment and the relationship between gut bacteria and successful treatment—which was defined as showing milk tolerance that lasted beyond the treatment period by passing the food challenge. They found that during treatment, immunological markers for cow’s milk allergy improved, and bacteria in the gut changed. Nevertheless, after two weeks of avoiding milk, only 7 of the 28 children passed the food challenge, even though they had been able to drink milk safely at the end of the treatment.

To understand why the treatment worked for these seven children but not the others, the team looked for the clinical factors and types of gut bacteria that were related to successful treatment. Of the clinical factors, unsuccessful treatment was more likely in children who were being treated for eczema or asthma and in children who initially had higher levels of milk-protein antibodies. Among the gut bacteria, the presence of Bifidobacterium, a genus of beneficial bacteria in the Bifidobacteriaceae family was related to a higher chance of successful treatment. In fact, only children who passed the final food challenge showed an increasing trend in these bacteria over the course of treatment. When considering ways to improve oral immunotherapy, this is good news because while the first two factors are difficult to change, the types of bacteria in one’s gut are not set in stone.

“With this study, we have identified gut environmental factors that help establish immune tolerance against cow’s milk allergy via oral immunotherapy,” says Ohno. “The next step is to examine the mechanisms underlying this phenomenon and to develop ways to improve the effectiveness of oral immunotherapy, such as the addition of probiotic supplements.”

Source: RIKEN

Categories : Cancer New Compounds and TreatmentsTags :

Dual Immunotherapy Drugs Show Promise vs a Range of Advanced Cancers

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Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash

In an early phase clinical trial, a combination of antibody-based medications targeting the immune system generated promising safety data and anti-tumour activity in individuals with various types of advanced cancer. The findings appear online in CANCER, a peer-reviewed journal of the American Cancer Society.

Both medications tested in the trial are checkpoint inhibitors, and support immune responses against tumour cells. CS1002 increases the activation and proliferation of T immune cells by binding to a T cell receptor called CTLA-4. CS1003, also called nofazinlimab, blocks the programmed cell death protein 1 that is expressed on various types of immune cells and plays a role in suppressing the immune system.

In this first-in-human multicentre, open-label study conducted from April 26, 2018 to January 18, 2022 at 9 study sites in Australia and China, phase Ia involved monotherapy dose-escalation (Part 1), which was followed by phase Ib combination therapy dose escalation (Part 2) and expansion (Part 3). Various dosing schedules of CS1002 (0.3, 1, or 3mg/kg once every three weeks, or 3mg/kg once every 9 weeks) were evaluated with 200mg CS1003 once every three weeks.

Parts 1, 2, and 3 of the trial included 13, 18, and 61 patients, respectively, who had advanced/metastatic solid, relapsed, or refractory tumors. During treatment, investigators did not observe any dose-limiting toxicities or a maximum tolerated dose. Treatment-related side effects such as diarrhoea, fatigue, and rash were reported in 30.8%, 83.3%, and 75.0% of patients in Parts 1, 2, and 3, respectively. Serious side effects such as intestinal inflammation and severe skin reactions were experienced by 15.4%, 50.0%, and 18.3% of patients in each part.

Of 61 patients evaluable for treatment efficacy, 23 (37.7%) with different types of tumours experienced a positive response. Higher response rates occurred with conventional and high-dose CS1002 regimens (1mg/kg once every three weeks or 3mg/kg once every 9 weeks) compared with low-dose CS1002 (0.3mg/kg once every three weeks) in certain cancers such as melanoma and skin cancer.

“CS1002 in combination with CS1003 had manageable safety profile across a broad dosing range and showed promising anti-tumor activities across CS1002 dose levels when combined with CS1003,” the investigators wrote. They concluded that this warranted more testing of CS1002 in combination with CS1003 for the treatment of solid tumours.

Source: Wiley