Tag: immunotherapy

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

Categories : HIVTags :

New Trial Highlights Incremental Progress Towards a Cure for HIV-1

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Colourised transmission electron micrograph of an HIV-1 virus particle (yellow/gold) budding from the plasma membrane of an infected H9 T cell (purple/green).

Antiretroviral therapies (ART) stop HIV replication in its tracks, allowing people with HIV to live relatively normal lives. However, despite these treatments, some HIV still lingers inside cells in a dormant state known as “latency.” If ART is discontinued, HIV will awaken from its dormant state, begin to replicate, and cause acquired immunodeficiency syndrome (AIDS). To create a cure, researchers have been attempting to drive HIV out of latency and target it for destruction.

A new clinical trial led by Cynthia Gay, MD, MPH, associate professor of infectious diseases, David Margolis, MD, the Sarah Kenan Distinguished Professor of Medicine, Microbiology & Immunology, and Epidemiology, and other clinicians and researchers at the UNC School of Medicine suggests that a combination of the drug vorinostat and immunotherapy can coax HIV-infected cells out of latency and attack them.

The immunotherapy was provided by a team led by Catherine Bollard, MD, at the George Washington University, who took white blood cells from the study participants and expanded them in the laboratory, augmenting the cells’ ability to attack HIV-infected cells, before re-infusion at UNC.

Their results, published in the Journal of Infectious Diseases, showed a small dent on the latent reservoir, demonstrating that there is more work to be done in the field.

“We did show that this approach can reduce the reservoir, but the reductions were not nearly large enough, and statistically speaking were what we call a “trend” but not highly statistically significant,” said David Margolis, MD, director of the HIV Cure Center and senior author on the paper. “We need to create better approaches to flush out the virus and attack it when it comes out. We need to keep chipping away at the reservoir until there’s nothing there.”

DNA inside cell nuclei is kept in a tightly packed space by chromosomes, which act as highly organised storage facilities. When you unfurl a chromosome, you’ll find loop-de-loop-like fibres called chromatin. If you keep unfurling, you’ll see long strands of DNA wrapped around scaffold proteins known as histones, like beads on a string. Finally, when the unfurling is complete, you will see the iconic DNA double helix.

Vorinostat works by inhibiting a lock-like enzyme called histone deacetylase. By stopping this mechanism, tiny doors within the chromatin fibres unlock and open up, effectively “waking up” latent HIV from its slumber and making it vulnerable to an immune system attack. As a result, a tiny blip of HIV expression shows up on very sensitive molecular assays.

But the effects of vorinostat are short lived, only lasting a day per dose. For this reason, Margolis and other researchers are trying to find safe and effective ways to administer the drug and keep the chromatin channels open for longer periods of time.

For the study, six participants were given multiple doses of vorinostat. Researchers then extracted immune cells from the participants and expanded the cells that knew how to attack HIV-infected cells.

This immunotherapy method, which has been successful against other viruses such as Epstein-Barr virus and cytomegalovirus, involves giving participants back their expanded immune cells in the hopes that these cells will further multiply in number and launch an all-out attack on the newly exposed HIV-infected cells.

However, in the first part of this study, only one of the six participants saw a drop in their HIV reservoir levels. To test whether the result was simply random or something more, researchers gave three participants their usual dose of vorinostat, but introduced five times the amount of engineered immune cells. All three of the participants had a slight decline in their reservoirs.

But, statistically speaking, the results were not large enough to be definitive.

“This is not the result we wanted, but it is research that needed to be done,” said Margolis. “We are working on improving both latency reversal and clearance of infected cells, and we hope to do more studies as soon as we can, using newer and better approaches.”

Many of the participants in the study have been working with Margolis’s research team for years, sacrificing their own time and blood for research efforts. Their long-term partnership and commitment have been essential for data collection. The data, which follows the size of the viral reservoir in these people over years prior to this study, makes the small changes found more compelling.

“People living with HIV come in a couple of times a year, and we measure residual traces of virus in their blood cells, which doesn’t have any immediate benefit to them,” said Margolis. “It’s a very altruistic action and we couldn’t make any progress without their help.”

Source: University of North Carolina Health Care

Categories : CancerTags :

Wait for Green: Why Immunotherapy Often Fails to Work

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Photo by National Cancer Institute on Unsplash

An international study has uncovered a mechanism by which cancer cells prevent the immune system from activating and attacking the cancerous invaders. The study, published in the peer-reviewed journal Cell Reports, sheds light on why immunotherapy treatments don’t work for all people or all diseases.

Certain types of cancers, such as colon, pancreatic, prostate and brain cancers, have stubbornly resisted immunotherapy.

And while breast, oesophageal and head and neck cancers often respond favourably, sometimes the treatments don’t work as planned.

Researchers still don’t understand exactly why, but the study, co-authored by University of Texas at Arlington scientists, may offer a clue.

“Immunotherapy is an incredibly promising new treatment avenue for cancer, but we still have work to do determining why it doesn’t work for all people or types of cancer,” said Jon Weidanz, UTA associate vice president for research and innovation.

He and Soroush Ghaffari, a UTA postdoctoral fellow, were co-authors of the study, along with colleagues at Leiden University in Leiden, Netherlands, and Karolinska University in Solna, Sweden.

The team determined that a key checkpoint in the immune system, called NKG2A, doesn’t engage with its specific binding molecule expressed in cancer cells until the appropriate signal is received.

“The team reasoned that monotherapy agents targeting the NKG2A receptor may not be effective without receiving an inflammatory trigger,” Ghaffari said.

“This might explain why drugs designed to bind to the NKG2A receptor to disrupt this immune checkpoint have been only effective when used in combination with other agents that can induce the necessary inflammatory signal.”

A second major finding of the study revealed how certain cancers can inhibit the immune system from activating its macrophages.

“These data give us a new molecular understanding of why some immunotherapies work and some don’t,” said Weidanz, who also is a professor kinesiology with an appointment in bioengineering and a member of the Multi-Interprofessional Center for Health Informatics.

“These results will help us identify and treat more cancers effectively with immunotherapy, helping more people live longer lives despite a cancer diagnosis.”

These findings have implications for immune system research and the development of more effective immunotherapy drugs, said Kate C. Miller, vice president of research and innovation at UTA.

“These are exciting new research results that have the potential to impact people living with cancer,” Miller said. “This is another great example of the calibre of biomedical research we’re performing both here at UTA and with our partners at other institutions.”

Source: University of Texas at Arlington

Categories : Cancer GastrointestinalTags :

Researchers Figure out Why Cancer Immunotherapy can Cause Colitis

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Gastrointestinal inflammation. Credit: Scientific Animations CC4.0

Researchers have identified a mechanism behind immunotherapy sometimes causing colitis. They also found a way to deliver immunotherapy’s cancer-killing impact without the unwelcome side effect. The researchers, from the University of Michigan Health Rogel Cancer Center, published their findings in Science.

“This is a good example of how understanding a mechanism helps you to develop an alternative therapy that’s more beneficial. Once we identified the mechanism causing the colitis, we could then develop ways to overcome this problem and prevent colitis while preserving the anti-tumour effect,” said senior study author Gabriel Nunez, MD, professor of pathology at Michigan Medicine.

Immunotherapy is a promising treatment for several types of cancer. But immune checkpoint inhibitors can also cause severe side effects, including colitis. Colitis can cause severe gastrointestinal discomfort, causing some patients to discontinue their cancer treatment because of it.

The problem facing researchers was that while patients were developing colitis, the laboratory mice were not, preventing them from studying the cause of this side effect.

To get past this, the Rogel team, led by first author Bernard C. Lo, PhD, created a new mouse model, injecting microbiota from wild-caught mice into the traditional mouse model.

In this model, the mice did develop colitis after administration of antibodies used for tumour immunotherapy. Now, researchers could trace back the mechanism to see what was causing this reaction.

In fact, colitis developed because of the composition of the gut microbiota, which caused immune T cells to be hyper-activated while regulatory T cells that put the brakes on T cell activation were deleted in the gut. This was happening within a specific domain of the immune checkpoint antibodies.

Researchers then removed that domain, which they found still resulted in a strong anti-tumour response but without inducing colitis.

“Previously, there were some data that suggested the presence of certain bacteria correlated with response to therapy. But it was not proven that microbiota were critical to develop colitis. This work for the first time shows that microbiota are essential to develop colitis from immune checkpoint inhibition,” Nunez said.

To follow up what they saw in mice, researchers reanalysed previously reported data from studies of human cells from patients treated with immune checkpoint antibodies, which reinforced the role of regulatory T cells in inducing colitis.

The Rogel team plans additional studies to further understand the mechanisms causing colitis and seeks clinical partners to move this knowledge to a clinical trial.

Source: Michigan Medicine – University of Michigan

Categories : CancerTags :

New Combination Salvages Immunotherapy Drug for Breast Cancer

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Immunotherapy in combination with chemotherapy has become an important therapeutic treatment option in some patients with metastatic breast cancer. Which patients will benefit the most, however, remains unclear; current biomarkers such as PD-L1 that are used to predict response are mediocre at best. Vanderbilt researchers led a clinical trial combining atezolizumab, an immunotherapy, in combination with chemotherapy in patients with metastatic triple-negative breast cancer to both evaluate the efficacy of the treatment combination and to understand biomarkers of response to immunotherapy.

Atezolizumab became the first approved immunotherapy for breast cancer when the Food and Drug Administration granted it accelerated approval in 2019, but two years later, its maker voluntarily withdrew the indication after additional data from a follow-up clinical trial failed to corroborate its efficacy. Atezolizumab had been approved for metastatic PD-L1-positive triple-negative breast cancer in combination with the chemotherapy nab-paclitaxel. Results from Vanderbilt’s clinical trial, published in JAMA Oncology, indicate that this immunotherapy does have a clinically meaningful benefit with a different chemotherapy partner and the correlative analyses provide insight to which patients will respond.

The clinical trial combined atezolizumab with carboplatin – a chemotherapy that works differently than nab-paclitaxel. The new combination significantly improved progression-free and overall survival of patients with metastatic triple-negative breast cancer. Atezolizumab with carboplatin lengthened progression-free survival from a median of 2.2 months to 4.1 months. Overall survival increased from a median of 8.6 months for the control group, who received carboplatin alone, to 12.6 months for those who received the combination therapy.

The phase 2 randomized clinical trial was conducted at six cancer centers through the Translational Breast Cancer Research Consortium and involved 106 patients of diverse ethnicities.

“Triple-negative breast cancer is difficult to treat because we don’t have a clear target, and understanding the underlying factors that affect response to a treatment is key. This study is so important because we were able to collect biopsies in all of the participants and really understand factors that affect response,” said Vandana Abramson, MD, the Donna S. Hall Professor in Cancer Research and co-leader of the Breast Cancer Research Program at Vanderbilt-Ingram Cancer Center.

The researchers hypothesised that atezolizumab would have superior efficacy to carboplatin because the chemotherapy is a platinum agent, which causes structural DNA changes and generates neoantigens that may stimulate an immune response. Nab-paclitaxel chemotherapy works differently: it is a microtubule-stabilising agent that stops cancer cell division.

“The tremendous knowledge gained from our multidisciplinary analyses of the patients and their tumours will continue to be important for clinical decision-making. After our first description of the triple-negative breast cancer subtypes over 10 years ago, more recently, we refined the subtypes further into four, which were analysed in this study: two basal-like subtypes, a mesenchymal subtype and a lumen androgen receptor-expressing subtype. When we refined the triple-negative breast cancer subtypes, we revealed an immune-modulatory descriptor or correlation.

“This JAMA Oncology study and others continue to confirm that lymphocytes, as measured by the immune-modulatory correlation, have predictive value for better relapse-free survival for triple-negative patients. Further, this study provides evidence that the luminal androgen receptor subtype is more like oestrogen receptor-positive (or ER+) disease. Prior studies investigating immunotherapy in breast cancers have shown that patients with ER+ disease have less benefit from immunotherapy, and we found that to be the case with patients with luminal androgen-positive tumours in this trial,” said Jennifer Pietenpol, PhD, the study’s corresponding author.

Interestingly, patients with higher body mass indexes and uncontrolled blood glucose levels had greater benefit from atezolizumab with carboplatin. The researchers noted that these patients may have more immune cells upon which anti-PD1/PD-L1 therapies can act. A lower risk of disease progression was also associated with high mutation burden and increased tumour-infiltrating lymphocytes.

“In this study, we observed that patients received benefit with atezolizumab even if the tumours were PD-L1 negative. We also show that, like prior clinical trials in melanoma and renal and lung cancers, tumours with high mutation burdens and the presence of immune cells within or around the tumour receive greater benefit from immunotherapy. This makes sense because each mutation has the potential to be recognised as non-self by the immune system, increasing the probability of immune cells already positioned around the tumour to recognise and target the cancer,” said Brian Lehmann, PhD, Research Associate Professor of Medicine and lead correlative scientist on the study.

“One surprising finding was the trend toward greater benefit for patients with higher body mass indexes and patients with uncontrolled blood glucose at prediabetic and diabetic levels while on the study. Both obesity and diabetes are linked to systemic inflammation, and the increased benefit may be attributed to higher adipose tissue composition in the breast and augmented by metabolic syndrome conditions such as Type 2 diabetes. Further studies are necessary to validate these findings and delineate the effects of blood glucose and obesity on immunotherapy,”

The combination therapy was generally well-tolerated, and toxic effects were consistent with previous reports for atezolizumab. The most common drug complications on the combination arm of the clinical trial were low blood platelet counts, anaemia, lymphocytopenia, nausea, fatigue and increased liver enzymes. The participants identified as 69% white, 19% African American, 10% unknown and 1% Asian.

Source: Vanderbilt University Medical Center

Categories : Cancer UrogenitalTags : Leave a comment

New Treatment Combination could Prevent Cystectomy in Invasive Bladder Cancer

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Photo by cottonbro studio

Mount Sinai investigators have developed a new approach for treating invasive bladder cancer without the need for surgical removal of the bladder, they report in their study published in Nature Medicine. At present, cystectomy (removal of the bladder) is currently a standard approach when cancer has invaded the muscle layer of the bladder.

In a phase 2 clinical trial that was the first of its kind, doctors found that some patients could be treated with a combination of chemotherapy and immunotherapy without the need to remove their bladder. Radical cystectomy can be curative in muscle-invasive bladder cancer, but the procedure is a life-changing operation due to the need for urinary diversion and is associated with a 90 day mortality risk of up to 6–8%.

“Treatment for muscle-invasive bladder cancer is in need of major improvements from both a quality-of-life and an effectiveness standpoint,” said Matthew Galsky, MD, Co-Director of the Center of Excellence for Bladder Cancer at The Tisch Cancer Institute, a part of the Tisch Cancer Center at Mount Sinai. “If additional research confirms our findings, this may lead to a new paradigm in the treatment of muscle-invasive bladder cancer.”

The 76 patients received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Approximately 43% (33 patients) achieved a complete response (no detectable cancer) when treated with this combination of chemotherapy and immunotherapy. Patients with a clinical complete response were offered the opportunity to proceed with additional immunotherapy, without surgical removal of the bladder. Among patients opting to proceed without surgical removal of the bladder, about 70% had no evidence of recurrent cancer after two years.

The most common adverse events were fatigue, anaemia, neutropenia and nausea. Somatic alterations in pre-specified genes or increased tumour mutational burden did not improve the positive predictive value of complete response.

Based on the results of this trial, two follow-up studies were launched to build on this approach; one is ongoing, and another will open in the next six months.

Source: The Mount Sinai Hospital / Mount Sinai School of Medicine

Categories : Cancer PaediatricsTags : Leave a comment

Neuroblastomas: ‘New’ Immune System Responds Better to Therapy

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Credit: National Cancer Institute

Cancer researchers have shown that immunotherapy after stem cell transplantation effectively combats neuroblastomas in children. Crucially, stem cells from a parent provide children with a new immune system that responds much better to immunotherapies. These results of an early clinical trial were published in the Journal of Clinical Oncology.

Tumours of the nervous system, neuroblastomas are associated with an unfavourable prognosis if the tumour is classified as a high-risk type. and particularly poor for patients in the relapsed stage. In this study by scientists at St. Anna Children’s Cancer Research Institute and the Eberhard Karls University of Tübingen, immunotherapy following stem cell transplantation is now associated with long-term survival in a substantial proportion of the patients. Compared to an earlier study the survival rate was increased.

“After the transplantation of stem cells from a parent, the patients are equipped with a new immune system. This enables a better immune response to the subsequent immunotherapy and clearly improves the outcome,” explains Prof Ruth Ladenstein, MD, co-first author.

Five-year survival exceeds 50%

“After a median follow-up of about eight years, we see that more than half of the study patients live five years or longer with their disease,” Prof Ladenstein reports (5-year overall survival: 53%). In comparison, the 5-year overall survival in an earlier study, in which stem cell transplantation was not followed by immunotherapy, was only 23%. Those patients who showed a complete or partial response to prior treatment had significantly better survival.

“In summary, immunotherapy with dinutuximab beta following transplantation of stem cells from matched family donors resulted in remarkable outcomes when patients had at least a partial response to prior treatment,” says Prof Ladenstein. “In our study, there were no unexpected side effects and the frequency of graft-versus-host-disease was low.”

Restoring natural killer cell potency

Dinutuximab beta is a monoclonal antibody that binds to a molecule, GD2, on the surface of tumour cells, marking them for destruction by natural killer cells. But prior chemotherapies may impair natural killer cells. “Therefore, a transplantation of intact natural killer cells from matched family donors seems reasonable before immunotherapy is administered. The transplanted, new natural killer cells are now able to target the tumour cells more efficiently – by means of an antibody-dependent reaction,” explains Prof Ladenstein.

According to the authors, further studies are needed to determine the individual components of the therapeutic approaches. Recently, conventional chemotherapy has also been combined with immunotherapy early in the treatment strategy, resulting in similarly improved response rates. The hope is that a renewed immune system through a healthy parent in combination with the described transplantation procedure could further increase survival rates: “Our approach could thus result in stronger and longer lasting tumour control. A randomised study would be necessary to scientifically substantiate the additional potential benefit of a new immune system in the context of relapse therapy,” Prof Ladenstein adds.

Source: St. Anna Children’s Cancer Research Institute

Categories : Cancer NeurologyTags : Leave a comment

In A First, Immunotherapy for Glioblastoma Successfully Tested in Mice

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Photo by Kanashi ZD on Unsplash

Immunotherapy has dramatically improved survival against many cancers but efforts to use it against glioblastomas have to date proven fruitless. Now, Salk scientists have found the immunotherapy treatment anti-CTLA-4 leads to considerably greater survival of mice with glioblastoma. Furthermore, they discovered that this therapy was dependent on immune cells called CD4+ T cells infiltrating the brain and triggering the tumour-destructive activities of other immune cells called microglia, which permanently reside in the brain.

The findings, published in the journal Immunity, show the benefit of harnessing the body’s own immune cells to fight brain cancer and could lead to more effective immunotherapies for treating brain cancer in humans.

Glioblastoma, the most common and deadly form of brain cancer, grows rapidly to invade and destroy healthy brain tissue. The tumour sends out cancerous tendrils into the brain that make surgical tumour removal extremely difficult or impossible.

“There are currently no effective treatments for glioblastoma – a diagnosis today is basically a death sentence,” says Professor Susan Kaech, senior author and director of the NOMIS Center for Immunobiology and Microbial Pathogenesis. “We’re extremely excited to find an immunotherapy regimen that uses the mouse’s own immune cells to fight the brain cancer and leads to considerable shrinkage, and in some cases elimination, of the tumour.”

For some tumours, immunotherapy can be used, in which the body’s own immune cells to seek and destroy cancer cells, leading to strong, lasting anti-cancer responses for many patients. Kaech sought new ways of harnessing the immune system to develop more safe and durable treatments for brain cancer.

Her team found three cancer-fighting tools that have been somewhat overlooked in brain cancer research that may cooperate and effectively attack glioblastoma: an immunotherapy drug called anti-CTLA-4 and specialized immune cells called CD4+ T cells and microglia.

Anti-CTLA-4 immunotherapy works by blocking cells from making the CTLA-4 protein, which, if not blocked, inhibits T cell activity. It was the first immunotherapy drug designed to stimulate our immune system to fight cancer, but it was quickly followed by another, anti-PD-1, that was less toxic and became more widely used. Whether anti-CTLA-4 is an effective treatment for glioblastoma remains unknown since anti-PD-1 took precedence in clinical trials. Unfortunately, anti-PD-1 was found to be ineffective in multiple clinical trials for glioblastoma – a failure that inspired Kaech to see whether anti-CTLA-4 would be any different.

As for the specialized immune cells, CD4+ T cells are often overlooked in cancer research in favour of a similar immune cell, the CD8+ T cell, because CD8+ T cells are known to directly kill cancer cells. Microglia live in the brain full time, where they patrol for invaders and respond to damage – whether they play any role in tumour death was not clear. When treated with anti-CLA-4, mice with glioblastoma had longer lifespans than those receiving anti-PD-1.

Upon investigation, they found that after anti-CTLA-4 treatment, CD4+ T cells secreted a protein called interferon gamma that caused the tumour to throw up “stress flags” while simultaneously alerting microglia to start eating up those stressed tumour cells. As they gobbled up the tumour cells, the microglia would present scraps of tumour on their surface to keep the CD4+ T cells attentive and producing more interferon gamma, creating a cycle that lasts until the tumour is destroyed.

“Our study demonstrates the promise of anti-CTLA-4 and outlines a novel process where CD4+ T cells and other brain-resident immune cells team up to kill cancerous cells,” says co-first author Dan Chen, a postdoctoral researcher in Kaech’s lab.

To understand the role of microglia in this cycle, the researchers collaborated with co-author and Salk Professor Greg Lemke. For decades, Lemke has investigated critical molecules, called TAM receptors, used by microglia to send and receive crucial messages. The researchers found that TAM receptors told microglia to gobble up cancer cells in this novel cycle.

“We were stunned by this novel codependency between microglia and CD4+ T cells,” says co-first author Siva Karthik Varanasi, a postdoctoral researcher in Kaech’s lab. “We are already excited about so many new biological questions and therapeutic solutions that could radically change treatment for deadly cancers like glioblastoma.”

Connecting the pieces of this cancer-killing puzzle brings researchers closer than ever to understanding and treating glioblastoma.

“We can now reimagine glioblastoma treatment by trying to turn the local microglia that surround brain tumours into tumour killers,” says Kaech. “Developing a partnership between CD4+ T cells and microglia is creating a new type of productive immune response that we have not previously known about.”

Next, the researchers will examine whether this cancer-killing cell cycle is present in human glioblastoma cases. Additionally, they aim to look at other animal models with differing glioblastoma subtypes, expanding their understanding of the disease and optimal treatments.

Source: Salk Institute

Categories : Ageing CancerTags : Leave a comment

Losing the Y Chromosome to Age Drives Bladder Cancers but Improves Immunotherapy

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Chromosomes. Credit: NIH

As men age, some of their cells lose their Y chromosome and this loss hampers the body’s ability to fight cancer, according to new research from Cedars-Sinai Cancer. The study, published in Nature, found that loss of the Y chromosome helps cancer cells evade the immune system, resulting in aggressive bladder cancer. Somehow, this also renders the disease more responsive to immune checkpoint inhibitors.

Based on their research, investigators are developing a test for loss of the Y chromosome in tumours with the goal of helping clinicians tailor immune checkpoint inhibitor treatment for male patients with bladder cancer.

“This study for the first time makes a connection that has never been made before between loss of the Y chromosome and the immune system’s response to cancer,” said corresponding author Dan Theodorescu, MD, PhD, who initiated the research. “We discovered that loss of the Y chromosome allows bladder cancer cells to elude the immune system and grow very aggressively.”

Lead collaborators on the study also included Johanna Schafer, a postdoctoral fellow, and Zihai Li, MD, PhD, medical oncologist and immunologist, both at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute.

In men, loss of the Y chromosome has been observed in several cancer types, including 10%–40% of bladder cancers. Loss of the Y chromosome also has been associated with heart disease and Alzheimer’s disease.

The Y chromosome contains the blueprints for certain genes. Based on the way these genes are expressed in normal cells in the bladder lining, investigators developed a scoring system to measure loss of the Y chromosome in cancers.  

The investigators then reviewed data on two groups of men. One group had muscle invasive bladder cancer and had their bladders removed, but were not treated with an immune checkpoint inhibitor. The other group participated in a clinical trial and were treated with an immune checkpoint inhibitor. They found that patients with loss of the Y chromosome had poorer prognosis in the first group and much better overall survival rates in the latter.

To determine why this happens, investigators next compared growth rates of bladder cancer cells from laboratory mice.

Cancer cells were grown in vitro and not exposed to immune cells. The researchers also grew the diseased cells in mice that were missing T-cells. In both cases, tumours with and without the Y chromosome grew at the same rate.

In mice with intact immune systems, tumours lacking the Y chromosome grew at a much faster rate than did tumours with the intact Y chromosome.

“The fact that we only see a difference in growth rate when the immune system is in play is the key to the ‘loss-of-Y’ effect in bladder cancer,” Theodorescu said. “These results imply that when cells lose the Y chromosome, they exhaust T-cells. And without T-cells to fight the cancer, the tumor grows aggressively.”

Based on their results derived from human patients and laboratory mice, Theodorescu and his team also concluded that tumours missing the Y chromosome, while more aggressive, were also more vulnerable and responsive to immune checkpoint inhibitors. This therapy, one of the two mainstay bladder cancer treatments available to patients today, reverses T-cell exhaustion and allows the body’s immune system to fight the cancer.

“Fortunately, this aggressive cancer has an Achilles’ heel, in that it is more sensitive than cancers with an intact Y chromosome to immune checkpoint inhibitors,” said co-first author Hany Abdel-Hafiz, PhD, associate professor at Cedars-Sinai Cancer.

Preliminary data not yet published shows that loss of the Y chromosome also renders prostate cancers more aggressive, Theodorescu said.

“Our investigators postulate that loss of the Y chromosome is an adaptive strategy that tumour cells have developed to evade the immune system and survive in multiple organs,” said Shlomo Melmed, MB, ChB, dean of the Medical Faculty at Cedars-Sinai. “This exciting advance adds to our basic understanding of cancer biology and could have far-reaching implications for cancer treatment going forward.”

Further work is needed to help investigators understand the genetic connection between loss of the Y chromosome and T-cell exhaustion.

“If we could understand those mechanics, we could prevent T-cell exhaustion,” Theodorescu said. “T-cell exhaustion can be partially reversed with checkpoint inhibitors, but if we could stop it from happening in the first place, there is much potential to improve outcomes for patients.”

While women do not have a Y chromosome, Theodorescu said these findings could have implications for them as well. The Y chromosome contains a set of related genes, called paralogue genes, on the X chromosome, and these might play a role in both women and in men. Additional research is needed to determine what that role might be.

“Awareness of the significance of Y chromosome loss will stimulate discussions about the importance of considering sex as a variable in all scientific research in human biology,” Theodorescu said. “The fundamental new knowledge we provide here may explain why certain cancers are worse in either men or women, and how best to treat them. It also illustrates that the Y chromosome does more than determine human biologic sex.”

Source: Cedars-Sinai Medical Center