While immunotherapy has been shown to greatly improve survival rates for certain types of cancer, in some cases, it can lead to a dangerous over-activation of the immune system. In a recent review published in Journal for ImmunoTherapy of Cancer, potential therapies have been identified, which might make it possible to continue with immunotherapy even when facing severe side effects.
The rare immunotherapy side effect of over-activation was only clinically recognised during regular clinical use rather than in clinical trials or animal experiments. To better understand this over-activation, Lisa Liu, Marco Gerling, and colleagues analysed data from all published international reports on this issue after cancer immunotherapy. Their findings indicate that potentially life-threatening inflammation may occur more frequently than previously thought, and might be treatable with existing drugs such as steroids or anti-inflammatory therapies commonly used for rheumatoid arthritis.
“It will be exciting to follow up on the main findings of our systematic review, says Marco Gerling at the Department of Biosciences and Nutrition, Karolinska Institutet and lead author.
“We believe that inhibition of a specific inflammatory molecule, interleukin-6, could allow patients to continue immunotherapy despite strong, systemic activation of the immune system”, he continues. “But we need more data to support the regular use of interleukin-6 inhibitors. We also want to thank Narcisa Hannerz and Sabine Gillsund from Karolinska University Library for their invaluable help with finding articles for this review.“
A common method of detecting prostate cancer may not be accurate enough as a reliable screening tool by itself, scientists in Germany have warned. The digital rectal exam (DRE) is widely used by medical professionals to check the prostate gland with a finger for unusual swelling or lumps in the rectum as an initial check for the signs of prostate cancer in men.
But new research by scientists of the PROBASE trial coordinated at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg, suggests the technique may be missing many cancers in their early stages.
The findings, presented at the European Association of Urology Annual Congress in Milan, could have implications for the early detection of prostate cancer, say the researchers. They are calling for other testing methods to be used in routine screening instead.
“One of the main reasons for screening for prostate cancer is to detect it in patients as early as possible as this can lead to better outcomes from treatment,” said Dr Agne Krilaviciute, a researcher at DKFZ and lead author of the study. “But our study suggests that the DRE is simply not sensitive enough to detect those early stage cancers.”
The PROBASE trial is a multicentre German prostate cancer screening study involving 46 495 men aged 45 years who were enrolled between 2014 and 2019. The men have since been had follow ups to assess their health in the years after the screening. Half of the participants in the trial were offered prostate specific antigen (PSA) blood test immediately at age 45 while the other half were initially offered DRE with delayed PSA screening at age 50.
Ultimately, 6537 men in the delayed screening group underwent DRE and only 57 of these men were referred for a follow-up biopsy due to suspicious findings. Only three were found to have cancer.
When compared to the detection rate using other methods, such as a PSA test, the rate of detection using DRE was substantially lower, says Dr Krilaviciute.
“The DRE was giving a negative result in 99% of cases and even those that were deemed to be suspicious had a low detection rate,” says Dr Krilaviciute. “Results we’ve seen from the PROBASE trial show that PSA testing at the age of 45 detected four times more prostate cancers.”
The researchers believe one of the reasons why the DRE might be failing to detect cancers, particularly in younger men, is because the changes in the tissue in the prostate may be too slight to detect with a finger. In addition, some cancers occur in a part of the prostate that cannot be easily reached by a finger.
“Early stage cancer may not have the size and stiffness to be palpable,” said Professor Peter Albers, a urologist at Düsseldorf University who was the senior author of the study.
“Separate analysis that used MRI scans before biopsies to locate cancers in the prostate showed that about 80% of these are in an area that should be easy to reach with a finger and still cancers were not detectable by DRE.”
The researchers are now calling for widespread use of PSA testing and MRI scans as part of screening programmes instead of DRE.
“If the aim of a screening programme is to pick up cancers as early as possible and the current screening tool isn’t doing that job, then that is a fundamental failure of that approach,” said Professor Albers. “We speculate in our paper that not only is the DRE not useful for detecting cancer, but it may also be one reason why people don’t come to screening visits – the examination probably puts a lot of men off.
“In Germany, for example, the participation rate is less than 20% in the screening programme for men 45 to 50 years. If we were to offer PSA testing instead, more of them might be willing to come.”
A study published in the Journal of Orthopaedic Research has identified a bone matrix protein called Secreted phosphoprotein 24 kD (Spp24) that may help to treat osteosarcoma, the most common type of bone cancer.
In experiments conducted in cells and mice, investigators found that Spp24 inhibits the proliferation and invasiveness of osteosarcoma tumour cells and promotes their apoptosis, or death. Mechanistically, Spp24 binds to and neutralises a protein called bone morphogenetic protein 2, which has tumour-enhancing properties.
“Spp24 and its proteolytic products have a number of effects on bone metabolism that have been elucidated to various degrees. They have the potential to be engineered into bone therapeutics, and this anti-tumour effect through bone morphogenetic protein 2 sequestration is only one such example,” said co–corresponding author Haijun Tian, MD, PhD, of Shanghai Jiao Tong University School of Medicine. “Like many other bone matrix proteins, the more we look into the function of Spp24, the more surprising roles we find even though the primary function of Spp24 remains uncertain.”
A new study from Copenhagen University may have found a new treatment for the sickest patients with sarcomas. Sarcomas are cancer tumours found in bones, muscles or fatty tissue. Sarcomas are cancer tumours found in bones, muscles or fatty tissue. Complex and difficult to treat, it is a rare type of cancer seen in only one per cent of cancer patients.
Researchers noticed that people with certain rare disorders were both more likely to have early grey hairs and wrinkles as well as having a high risk of developing cancer.
“We have learned that sarcoma patients whose cancer cells have a high expression of the cep135 protein are worse off. But inhibiting a gene called plk1 also inhibits growth of the sarcoma cells, and this suggests that we can target the treatment of the sickest sarcoma patients,” says Associate Professor Morten Scheibye-Knudsen, lead researcher of the new study which is published in Nature.
Methods for identifying sarcoma patients’ prognoses are already available, as are different forms of treatment. But the new study has identified a new method.
“This is a new way of stratifying and possibly a new and better way of treating sarcoma. And the introduction of yet another method is always good news to patients. Because no two cancers are alike. Ideally, treatment should always be tailored to the individual patient,” Morten Scheibye-Knudsen stresses.
He hopes other researchers with access to the necessary test facilities will study his results in more detail and eventually design a new treatment. If the method turns out to work, he believes a new treatment may be available to patients in five to 10 years.
Grey hair, wrinkles and loss of fatty tissue at an early age
Morten Scheibye-Knudsen and his colleagues started out by studying patients suffering from the rare neurological disorders Werner’s syndrome, Nijmegen breakage syndrome and Ataxia-telangiectasia syndrome.
These patients experience symptoms of early ageing such as grey hair, wrinkles and loss of fatty tissue – and they have a high risk of developing cancer at an early age.
“Age-associated diseases such as cancer is one of my main areas of interest as a researcher at the Center for Healthy Aging. As we grow older, a lot of things happen to the body, and determining causality can be difficult. But in people suffering from, eg Werner’s syndrome, it is easier to see which genes are responsible for which processes. This gives us a molecular handle, so to speak,” says Morten Scheibye-Knudsen.
In order to establish why these patients develop cancer at an early age, the researchers compared gene expressions across the three disorders. Here they worked together with the company Insilico Medicine, whose large Pandaomics platform made it possible to identify gene mutations in thousands of different disorders. It turned out that cep135 is a common denominator for the cancer genes of the three disorders.
“This made us study the gene expressions of various cancers, and we learned that cep135 is associated with high mortality in, inter alia, sarcoma, but also in bladder cancer. Sarcoma was particularly interesting, as many Werner’s syndrome patients develop sarcoma,” explains Morten Scheibye-Knudsen.
Finally, the researchers sought to find ways to inhibit the sarcoma. Cep135 is not a useful target, as it is a so-called structural protein, which are difficult to target. Instead, the researchers learned that by inhibiting the plk1 gene they were able to target the sarcoma.
“The study indicates that we can use genetic diseases that exhibit accelerated aging to identify new treatment targets. In this study, we investigated cancer, but the method can in principle be used for all age-related diseases such as dementia, cardiovascular diseases and others,” says Morten Scheibye-Knudsen.
New research indicates that for patients with breast cancer, the cancer’s stage and receptor status can help clinicians predict whether and when cancer might recur after initial treatment. The findings are published in the journal cancer CANCER.
For the study, Heather Neuman, MD, MS, of the University of Wisconsin, and her colleagues analysed data on 8007 patients with stage I–III breast cancer who participated in nine clinical trials from 1997–2013 and received standard of care therapy.
Time to first cancer recurrence varied significantly between cancers with different receptors – including oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Within each receptor type, cancer stage influenced time to recurrence.
Risk of recurrence was highest and occurred earliest for ER−/PR−/HER2− (triple negative) tumours. Patients with these tumours diagnosed at stage III had a 5-year probability of recurrence of 45.5%. Risk of recurrence was lowest for ER+/PR+/HER2+ (triple positive) tumours. Patients with these tumours diagnosed at stage III had a 5-year probability of recurrence of 15.3%.
Based on their findings, the investigators developed follow-up recommendations by cancer stage and receptor type. For example, patients with the lowest risk should be seen by their oncology team once annually over five years, whereas those with the highest risk should be seen once every three months over five years.
“Our developed follow-up guidelines present an opportunity to personalize how we deliver breast cancer follow-up care,” said Dr Neuman. “By tailoring follow-up based on risk, we have the potential to have a strong, positive impact on both survivors and their oncology providers by improving the quality and efficiency of care.”
Previous research has hinted at a possible link between head injury and increased rates of gliomas, rare but aggressive brain tumours. A University College London team has now identified a possible mechanism to explain this link, implicating genetic mutations acting in concert with brain tissue inflammation to change the behaviour of cells, making them more likely to become cancerous.
Publishing in Current Biology, the researchers have now identified a possible mechanism to explain this link, implicating genetic mutations acting in concert with brain tissue inflammation to change the behaviour of cells, making them more likely to become cancerous. Although this study was largely carried out in mice, it suggests that it would be important to explore the relevance of these findings to human gliomas.
The study was led by Professor Simona Parrinello (UCL Cancer Institute), Head of the Samantha Dickson Brain Cancer Unit and co-lead of the Cancer Research UK Brain Tumour Centre of Excellence. She said: “Our research suggests that a brain trauma may contribute to an increased risk of developing brain cancer in later life.”
Gliomas are brain tumours that often arise in neural stem cells. More mature types of brain cells, such as astrocytes, have been considered less likely to give rise to tumours. However, recent findings have demonstrated that after injury, astrocytes can exhibit stem cell behaviour again.
Professor Parrinello and her team therefore set out to investigate whether this property may make astrocytes able to form a tumour following brain trauma using a pre-clinical mouse model.
Young adult mice with brain injury were injected with a substance which permanently labelled astrocytes in red and knocked out the function of the p53 gene, known to have a vital role in suppressing many different cancers. A control group was treated the same way, but the p53 gene was left intact. A second group of mice was subjected to p53 inactivation in the absence of injury.
Professor Parrinello said: “Normally astrocytes are highly branched – they take their name from stars – but what we found was that without p53 and only after an injury the astrocytes had retracted their branches and become more rounded. They weren’t quite stem cell-like, but something had changed. So we let the mice age, then looked at the cells again and saw that they had completely reverted to a stem-like state with markers of early glioma cells that could divide.”
This suggested to Professor Parrinello and team that mutations in certain genes synergised with brain inflammation, which is induced by acute injury and then increases over time during the natural process of ageing to make astrocytes more likely to initiate a cancer. Indeed, this process of change to stem-cell like behaviour accelerated when they injected mice with a solution known to cause inflammation.
The team then looked for evidence to support their hypothesis in human populations. Working with Dr Alvina Lai in UCL’s Institute of Health Informatics, they consulted electronic medical records of over 20 000 people who had been diagnosed with head injuries, comparing the rate of brain cancer with a control group, matched for age, sex and socioeconomic status. They found that patients who experienced a head injury were nearly four times more likely to develop a brain cancer later in life, than those who had no head injury. It is important to keep in mind that the risk of developing a brain cancer is overall low, estimated at less than 1% over a lifetime, so even after an injury the risk remains modest.
Professor Parrinello said: “We know that normal tissues carry many mutations which seem to just sit there and not have any major effects. Our findings suggest that if on top of those mutations, an injury occurs, it creates a synergistic effect. In a young brain, basal inflammation is low so the mutations seem to be kept in check even after a serious brain injury. However, upon ageing, our mouse work suggests that inflammation increases throughout the brain but more intensely at the site of the earlier injury. This may reach a certain threshold after which the mutation now begins to manifest itself.”
Researchers have discovered that the difference between people who do and do not respond to immunotherapy may have to do with an immune cell known as CD5+ dendritic cells, because they bear the protein CD5 on their outer surfaces. Their research, published in Science, showed that survival was longer in patients with a range of cancers, including melanoma, if they had more CD5+ dendritic cells in their tumours, and that mice lacking CD5 on their dendritic cells failed to respond well to immunotherapy.
The findings suggest that a supplementary therapy designed to increase the number or activity of CD5+ dendritic cells potentially could extend the lifesaving benefits of immunotherapy to more cancer patients.
“Immunotherapy has revolutionized the field of cancer therapy, but there are a lot of patients with cancer who don’t benefit from it,” said senior author Eynav Klechevsky, PhD, an assistant professor of pathology & immunology and a researcher at Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “Part of the reason some people do not respond well to some forms of immunotherapy is because this population of dendritic cells is reduced dramatically. We’re developing some novel immune-based approaches to boost the activation of these CD5-expressing dendritic cells with a goal of helping more patients respond to immunotherapy.”
The immune system defends the body against cancer by activating immune cells known as T cells to recognise and kill tumour cells. In response, tumour cells manipulate the immune checkpoint system — a safeguard that prevents T cells from mistakenly attacking healthy cells — to hoodwink T cells into leaving them alone. Immune checkpoint blockade therapy works by thwarting tumour cells’ manipulations, thereby freeing T cells to recognise and destroy tumours. But even with therapy, some people’s T cells are unable to do their job effectively.
Klechevsky and colleagues — including first author Mingyu He, PhD, a staff scientist, and co-author Kate Roussak, MD, a postdoctoral researcher — suspected that people who don’t respond to immunotherapy may have a problem with their dendritic cells. Without dendritic cells, T cells are subdued and aimless.
By analysing data in The Cancer Genome Atlas, Klechevsky and colleagues discovered that patients with types of skin, lung, bone and soft tissue, breast and cervical cancers fared better if they had higher levels of CD5+ dendritic cells in their tumours.
Further work with human cells and mice showed that CD5+ dendritic cells are required for effective T cell activity against tumours. CD5+ dendritic cells from people powerfully induced T cells to activate and multiply. Mice with tumours responded only weakly to immunotherapy and failed to reject the tumors if they lacked CD5 on their dendritic cells.
The findings suggest that the amount of CD5+ dendritic cells inside tumours could be used to help doctors assess which patients are most likely to benefit from immunotherapy. They also suggest that increasing the numbers or the activity of such dendritic cells potentially could help more people benefit from immunotherapy. As part of this study, the researchers discovered that the immune protein IL-6 increases the amounts of CD5+ dendritic cells.
“We still don’t completely understand how immunotherapies work,” Klechevsky said. “This study indicates that there is more we can do to increase the efficacy of these treatments. I’m confident that if we can find ways to harness these cells or expand these cells in patients, we can help more people.”
A Bloomberg investigation has revealed that Glaxo, which went on to form pharmaceutical giant GSK, was aware of the possible carcinogenic content of its popular heartburn drug Zantac for over 40 years.
The once-popular heartburn drug Zantac (ranitidine) was developed in the 1970s by the then-small British pharmaceutical company Glaxo. It was marketed as better and safer than Tagamet (cimetidine) and it soon outsold it and became one of the company’s best-selling drugs.
NDMA belongs to a class of compounds known as nitrosamines, came to light in cancer research when it was found that nitrites could combine with amines in the stomach, giving rise to cancer-causing compounds. This led to calls for restrictions of sodium nitrites, found in various cured foods, but the food industry has resisted this.
This all came to an end in 2019, when Zantac was found to be contaminated by the chemical N-Nitrosodimethylamine (NDMA), a pale yellow liquid at room temperature. NDMA is a known carcinogen at high concentrations and a possible one at low concentrations. This contamination was not due to a manufacturing error, however: NDMA can form from other reactions and in this case came from within the drug itself. Around the world, Zantac was pulled from shelves, and in 2020 the drug was banned by the FDA. NDMA currently is only produced in small amounts to induce cancer in rats. Whether it is carcinogenic at very low levels is still a matter of debate, but Zantac products contained NDMA at levels which could increase over time.
According to Bloomberg, Glaxo was aware of this, as the possibility of ranitidine being converted in the stomach to nitrosamines being raised in 1980. Tests with human subjects taking ranitidine showed this. Even though NDMA is widely held to be a carcinogen in humans, it is difficult to prove that a particular chemical is responsible for mutations leading to cancers. Glaxo simply took the view that ranitidine did not cause cancer in rodent studies, and that any possible cancer risk was minimised by short exposure. In fact, users would take Zantac for extended periods, even years or decades.
The company was thus warned over 40 years by its own scientists as well as independent researchers, with thousands of pages of documentation seen by Bloomberg for the first time. One 1981 Lancet study showed that Zantac mixed with nitrite in the stomach (as from a meal) would produce nitrosamines. Glaxo scientists countered by saying that the nitrite levels in the study were far above those found in a human stomach, a defence which would become their standard response.
While Glaxo was preparing for FDA approvals in 1982, another study came to their attention. Concerned, Glaxo asked one of their scientists, Richard Tanner, to replicate it and he found that some samples contained 232 000ng of NDMA – the FDA approved limit for each drug was 96ng, though with lower nitrite levels, no NDMA was detected. The daily FDA exposure limit from all sources for NDMA is 190ng, which includes NDMA from all sources, including other medications (which may produce their own NDMA over time) as well as biological processes.
This report would remain secret for more than 40 years. More trouble came from the fact that NDMA could be formed from exposure to either heat or humidity. When it went through the FDA approval process, it did not mention the Tanner report and the notion of storage was glossed over: approved in 150mg doses for eight weeks, storage requirements were listed as a dry place at a temperature no higher than 86°F (30°C).
Zantac surged in popularity, turning the company into a multi-billion dollar enterprise, though the FDA took action over Glaxo’s claims. An over-the-counter 75mg version was launched in 1996. It was coloured pink due to issues of discolouration with white pills turning yellow or brown over time.
While discolouration issues were briefly investigated, it was only in 2019 when there were concerns over NDMA contamination, spurred by recalls of a blood pressure drug, valsartan. A private laboratory warned the FDA over NDMA discovery in Zantac and ranitidine generics, and after the FDA conducted its own tests, the company that was now GSK turned over its documentation.
Within a month, distribution of ranitidine was halted nearly worldwide, and the FDA took the drastic further stop of ordering its production halted. Shortly afterward, the FDA stated that the evidence for NDMA in ranitidine was inconclusive, and clarified that the NDMA concerns were from contamination being produced during its storage, not production in the stomach.
For GSK, the damages from the thousands of plaintiffs may range from US$5 to 17 billion, but damages are likely to be reduced and previous lawsuits of this type have struggled to prove that the relevant compound caused cancer. For Zantac, however, this will be less of an obstacle as NDMA is almost universally accepted as a carcinogen.
A phase II clinical trial has demonstrated that patients with advanced cutaneous squamous cell carcinoma can benefit from the immune checkpoint inhibitor nivolumab. The findings were published in the journal CANCER.
Two other immune checkpoint inhibitors, cemiplimab and pembrolizumab, have been approved by the US Food and Drug Administration for the treatment of advanced cutaneous squamous cell carcinoma in recent years. This new study is the first to report clinical trial results for nivolumab.
The single-arm trial included 24 patients who received nivolumab at 3mg/kg every two weeks until they experienced cancer progression, developed unacceptable toxicity, or had received 12 months of treatment.
During the trial, 14 patients (58.3%) benefited from the treatment, with their cancers demonstrating a response. Treatment-related adverse events of any grade occurred in 21 patients (87.5%) and, for and grade ≥ 3, in six patients (25%). One patient discontinued nivolumab due to toxicities. Prior radiotherapy exposure was associated with a worse response.
“This is the first study to investigate nivolumab in this patient population, and it provides further evidence supporting the use of immune checkpoint blockers as standard therapies in cutaneous squamous cell carcinoma,” said lead author Rodrigo R. Munhoz, MD, of the Hospital Sírio-Libanês, in Brazil.
An accompanying editorial notes that although the trial was small, its results were similar to those reported with pembrolizumab and cemiplimab. “In addition to providing more assurance to the clinical activity of different [immune checkpoint] inhibitors in this disease, this replicated data may permit a more widespread utilisation of these agents in managing a common disease with global implications,” the authors wrote.
Despite colorectal cancer being highly treatable, especially when detected early, many people do not undergo recommended screening, even with the availability of at-home stool faecal immunochemical test (FIT) kits. New research published in CANCER reveals that people who react defensively to the invitation to get screened are less likely to take part.
For the study, Nicholas Clarke, PhD, of Dublin City University in Ireland, surveyed individuals in Dublin who had been invited to participate in a FIT screening program in 2008–2012. Questionnaires were mailed in September 2015 to all individuals who were invited to participate (over two screening rounds) but had declined and a random sample of individuals who had participated. Following two reminders, questionnaires were completed by 1988 people who participated in screening and 311 who did not.
Those who did not do FIT-based screening were more likely to provide responses indicating greater defensiveness. This was apparent for all questions related to the different domains of what is called defensive information processing (DIP). The four domains of DIP include:
attention avoidance (reducing risk awareness by avoidance),
blunting (active mental disengagement through avoidance and accepted denial),
suppression (acknowledging others’ risk but avoiding personal inferences through self-exemption beliefs), and
counter-argumentation (arguing against the evidence).
“People who react defensively to the invitation to colorectal cancer screening are less likely to take part, and this seems to be due to such misconceptions that having a healthy lifestyle or having regular bowel movements means that they do not need to be screened. Similarly, some people believe testing can be delayed while they wait for a ‘better’ test (even though the current test works very well) or wait until their other health concerns are under control,” explained Dr Clarke. “Some people also react defensively because they believe cancer is always fatal, which is not true. All of these factors can result in people making a decision not to take the home-based screening test.”
Dr Clarke noted that the study’s findings indicate that even well-designed health communication campaigns and proactive screening programs may be hindered by individuals’ defensive beliefs. “The measures used in this study could be used to help identify people who may need extra support to take part in colorectal cancer screening programs worldwide,” he said. “The results suggest that screening programs need strategies to decrease procrastination and address misconceptions about colorectal cancer and screening.”
He also stressed the importance of trying to make colorectal cancer screening something that everyone routinely does when they reach middle age.
An accompanying editorial by Beverly Beth Green MD, MPH advocates for additional research to test different strategies, such as financial incentives, for decreasing DIP in participants.
