According to a new study, lower doses of approved immunotherapy for malignant melanoma can give better results against tumours, while reducing side effects. This is reported by researchers at Karolinska Institutet in the Journal of the National Cancer Institute.
“The results are highly interesting in oncology, as we show that a lower dose of an immunotherapy drug, in addition to causing significantly fewer side effects, actually gives better results against tumours and longer survival,” says last author Hildur Helgadottir, a researcher at the Department of Oncology-Pathology at Karolinska Institutet, who led the study.
The traditional dose of nivolumab and ipilimumab is the one that is approved and established. Due to the extensive side effects, Sweden has increasingly begun to use a treatment regimen with a lower dose of ipilimumab, which is both gentler and cheaper. Ipilimumab is the most expensive part of this immunotherapy and causes the most side effects.
“In Sweden, we have greater freedom to choose doses for patients, while in many other countries, due to reimbursement policies, they are restricted by the doses approved by the drug authorities,” says Hildur Helgadottir.
Lower dose is more effective
The study included nearly 400 patients with advanced, inoperable malignant melanoma, the most serious form of skin cancer. The study shows that the regimen with the lower dose of ipilimumab is more effective, with a higher proportion of patients responding to treatment, 49%, compared to the traditional dose, 37%.
Progression-free survival, the time the patient lives without the disease worsening, was a median of nine months for the lower dose, compared to three months for the traditional dose. Overall survival was also longer, 42 months compared to 14 months.
Serious side effects were seen in 31% of patients in the low-dose group, compared to 51% in the traditional group.
“The new immunotherapies are very valuable and effective, but at the same time they can cause serious side effects that are sometimes life-threatening or chronic. Our results suggest that this lower dosage may enable more patients to continue the treatment for a longer time, which is likely to contribute to the improved results and longer survival,” says Hildur Helgadottir.
There were some differences between the two treatment groups, but even after adjusting for several factors such as age and tumour stage, the better outcome for the lower dose of ipilimumab remained. The study is a retrospective observational study and therefore it is not possible to definitively establish a causal relationship.
Breast cancer cells. Image by National Cancer Institute
Triple-negative breast cancer is one of the most aggressive cancers. The name tells the story: It lacks the three main targets that make other types of breast cancers more treatable with powerful therapies.
UCLA researchers have developed a novel therapy that could fundamentally change the treatment plan for this deadly disease. In a study published in the Journal of Hematology & Oncology, the team details how this new type of immunotherapy, called CAR-NKT cell therapy, could attack tumors from multiple fronts while dismantling their protective shields.
“Patients with triple-negative breast cancer have been waiting far too long for better treatment options,” said senior author Lili Yang, a professor of microbiology, immunology and molecular genetics and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “To finally have a therapy that shows superior cancer-fighting ability – and to be just one step away from clinical testing – is incredibly exciting.”
The therapy uses engineered immune cells called CAR-NKT cells, which can be mass-produced from donated blood stem cells and stored ready-to-use. This off-the-shelf approach offers an immediately available treatment option at a fraction of the cost of current personalized cell therapies, which can soar into the hundreds of thousands of dollars.
A triple threat against a triple-negative cancer
CAR-T cell therapies have transformed treatment for certain blood cancers by turning patients’ own immune cells into precision weapons. However, these therapies have struggled against solid tumours like breast cancer, which employ sophisticated defence mechanisms and constantly evolve to evade treatment.
To tackle these hurdles, the UCLA team’s cell therapy harnesses a rare but powerful type of immune cell called invariant natural killer T cell, or NKT cell. When equipped with a chimeric antigen receptor, or CAR, targeting mesothelin (a protein found on triple-negative breast cancer cells) these potent tumour-fighting cells gain the ability to recognise and destroy cancer through three distinct mechanisms.
The first mechanism uses the engineered CAR to target mesothelin, which is associated with more aggressive, metastatic disease. The second leverages the cells’ natural killer receptors that recognize more than 20 molecular markers, making it nearly impossible for tumours to evade all of them. The third employs the cells’ unique T cell receptor to reshape the tumour microenvironment by eliminating immunosuppressive cells.
“We’re not just targeting one molecular marker on cancer cells — we’re identifying dozens of them simultaneously,” said first author Yanruide (Charlie) Li, a postdoctoral scholar in the UCLA Broad Stem Cell Research Center Training Program. “It’s like attacking a fortress from every direction at once. The cancer simply can’t adapt fast enough to escape.”
When the research team tested the novel therapy on tumour samples from patients with late-stage metastatic breast cancer, the CAR-NKT cells successfully killed cancer cells in every single sample tested, while also eliminating the immunosuppressive cells that tumours recruit as protective escorts.
Engineering universal accessibility
Beyond its multipronged cancer-fighting capabilities, the CAR-NKT platform addresses critical barriers that have limited cell therapy access: manufacturing complexity and cost.
Current cellular immunotherapies require collecting each patient’s immune cells, shipping them to specialised laboratories for genetic modification, then returning the customized product into the patient weeks later — a process that can cost six figures and create dangerous delays for patients with aggressive cancers.
Yang’s team takes a fundamentally different approach. Because NKT cells naturally work with any immune system, they can be mass-produced from donated blood stem cells using a scalable system. A single donation could generate enough cells for thousands of treatments, reducing costs to approximately $5,000 per dose.
One product to tackle multiple cancers
The therapy’s promise extends beyond triple-negative breast cancer. Since mesothelin is also highly expressed in ovarian, pancreatic and lung cancers, the same cell product could potentially treat multiple cancer types that remain difficult to address with current immunotherapies.
With all preclinical studies complete for both triple-negative breast cancer and ovarian cancer, the team is preparing to submit applications to the Food and Drug Administration to begin clinical trials.
“We’ve walked 99 steps to get here,” Yang said. “We’re missing just one final step to begin clinical testing and demonstrate what this promising therapy can really do for patients.”
Patients with cancer who received mRNA-based COVID vaccines within 100 days of starting immune checkpoint therapy were twice as likely to be alive three years after beginning treatment, according to a new study led by researchers at The University of Texas MD Anderson Cancer Center.
“This study demonstrates that commercially available mRNA COVID vaccines can train patients’ immune systems to eliminate cancer,” Grippin said. “When combined with immune checkpoint inhibitors, these vaccines produce powerful antitumour immune responses that are associated with massive improvements in survival for patients with cancer.”
How was this association discovered?
The discovery that mRNA vaccines were powerful immune activators came from research conducted by Grippin during his graduate work at the University of Florida in the lab of Elias Sayour, MD, PhD. While developing personalised mRNA-based cancer vaccines for brain tumours, Grippin and Sayour found that mRNA vaccines trained immune systems to eliminate cancer cells, even when the mRNA didn’t target tumours directly.
This finding led to the hypothesis that other types of mRNA vaccines might have the same effect, and the approval and use of mRNA-based COVID vaccines created an opportunity to test this hypothesis. Lin and Grippin initiated a major effort to retrospectively study if MD Anderson patients who received mRNA COVID vaccines lived longer than those who did not receive these vaccines.
How do mRNA COVID vaccines impact immunotherapy responses in cancer?
To better understand the mechanisms at work that can help explain the clinical data, the Lin and Sayour labs at both institutions studied preclinical models. They discovered that mRNA vaccines work like an alarm, putting the body’s immune system on high alert to recognise and attack cancer cells.
In response, the cancer cells start making the immune checkpoint protein PD-L1, which works as a defence mechanism against immune cells. Fortunately, several immune checkpoint inhibitors are designed to block PD-L1, creating a perfect environment for these treatments to unleash the immune system against cancer.
These preclinical observations held up in clinical studies as well. The investigators found similar mechanisms, including immune activation in healthy volunteers and increased PD-L1 expression on tumours in patients who received COVID mRNA vaccines.
While the mechanisms are not yet fully understood, this study suggests COVID mRNA vaccines are powerful tools to reprogram immune responses against cancer.
What are the major implications of this discovery?
“The really exciting part of our work is that it points to the possibility that widely available, low-cost vaccines have the potential to dramatically improve the effectiveness of certain immune therapies,” Grippin said. “We are hopeful that mRNA vaccines could not only improve outcomes for patients being treated with immunotherapies but also bring the benefits of these therapies to patients with treatment-resistant disease.”
A multi-centre, randomised Phase III trial currently is being designed to validate these findings and investigate whether COVID mRNA vaccines should be part of the standard of care for patients receiving immune checkpoint inhibition.
What are the key data from this study on mRNA COVID vaccines and immunotherapy outcomes?
This study included multiple cohorts of several cancer types, evaluating patients who had received an mRNA vaccine within 100 days of starting immunotherapy treatment.
In the first group, 180 patients with advanced non-small cell lung cancer who received a vaccine had a median survival of 37.33 months, compared to 20.6 months in 704 patients who did not receive a vaccine. In a cohort of patients with metastatic melanoma, median survival was 26.67 months in 167 patients who did not receive a vaccine, but it had not yet been reached in 43 patients receiving a vaccine – suggesting a significant improvement.
Importantly, these survival improvements were most pronounced in patients with immunologically “cold” tumors, which would not be expected to respond well to immunotherapy. These patients, who have very low PD-L1 expression on their tumours, experienced a nearly five-fold improvement in three-year overall survival with receipt of a COVID vaccine.
Findings were consistent even when considering independent factors, such as vaccine manufacturer, number of doses, and when patients received treatment at MD Anderson.
A new study, published in Nature, underscores the importance of investigating interactions between cancer and the nervous system – a field known as cancer neuroscience. The results suggest that targeting the signalling pathways involved can reverse this inflammation and improve treatment responses.
“These findings uncover novel mechanisms by which the immune system and nerves within the tumour microenvironment interact, revealing actionable targets that could transform the way we approach resistance to immunotherapy in patients with cancer,” said co-corresponding author Moran Amit, MD, PhD, professor of Head and Neck Surgery. “This marks a significant advance in our understanding of tumour-neuro-immune dynamics, highlighting the importance of investigating the interplay of cancer and neuroscience in meaningful ways that can directly impact clinical practice.”
Tumours can sometimes infiltrate the space around nerves and nervous system fibres that are in close proximity, a process known as perineural invasion, which leads to poor prognosis and treatment escalation in various cancer types. Yet little is known about how this invasion affects or interacts with the immune system.
Collaborating with the immunotherapy platform, part of the James P. Allison Institute, the team analysed trial samples using advanced genetic, bioinformatic and spatial techniques. The researchers revealed that cancer cells break down the protective myelin sheaths that cover nerve fibres, and that the injured nerves promote their own healing and regeneration through an inflammatory response.
Unfortunately, this inflammatory response gets caught in a chronic feedback loop as tumors continue to grow, repeatedly damaging nerves which then recruit and exhaust the immune system, ushering in an immunosuppressive tumor microenvironment that leads to treatment resistance. The study showed that targeting the cancer-induced nerve injury pathway at different points can reverse this resistance and improve treatment response.
Importantly, the authors point out that this reduced neuronal health is directly associated with perineural invasion and cancer-induced nerve injury, rather than a general cancer-induced effect, highlighting the importance of studying cancer-nerve interactions that can potentially contribute to cancer progression.
As part of MD Anderson’s Cancer Neuroscience Program, researchers are investigating scientific themes – such as neurobiology, tumours of the brain and spine, neurotoxicities and neurobehavioural health – to understand how the nervous system and cancer interact and how this affects patients throughout their cancer journey.
Next step is testing ‘holy grail’ therapy’s safety and effectiveness in patients
Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash
A new, highly potent class of immunotherapeutics with unique Velcro-like binding properties can kill diverse cancer types without harming normal tissue, University of California, Irvine cancer researchers have demonstrated.
A team led by Michael Demetriou, MD, PhD, reported that by targeting cancer-associated complex carbohydrate chains called glycans with binding proteins, they could penetrate the protective shields of tumor cells and trigger their death without toxicity to surrounding tissue.
Their biologically engineered immunotherapies – glycan-dependent T cell recruiter (GlyTR, pronounced ‘glitter’) compounds, GlyTR1 and GlyTR 2 – proved safe and effective in models for a spectrum of cancers, including those of the breast, colon, lung, ovaries, pancreas and prostate, the researchers reported in the journal Cell.
“It’s the holy grail – one treatment to kill virtually all cancers,” said Demetriou, a professor of neurology, microbiology and molecular genetics at the UC Irvine School of Medicine and the paper’s corresponding author. “GlyTR’s velcro-like sugar-binding technology addresses the two major issues limiting current cancer immunotherapies: distinguishing cancer from normal tissue and cancer’s ability to suppress the immune system.”
The researchers were awarded a Cancer Moonshot Initiative grant from the National Cancer Institute in 2018 for this study.
Landmark research
The study’s publication, the culmination of a decade of research, is a watershed moment and source of pride for UC Irvine and the UCI Health Chao Family Comprehensive Cancer Center.
“This landmark study is a paradigm shift with the very real potential to change how we treat cancer patients,” said Marian Waterman, PhD, former deputy director of research at the cancer centre and champion of the project since Demetriou and his then-postdoctoral fellow, Raymond W. Zhou, the study’s first author, began working on the concept in 2015.
Added Richard A. Van Etten, MD, PhD, director of the cancer centre and also an early supporter of the GlyTR project, “This novel technology may, for the first time, allow the widespread application of targeted T-cell therapy to solid tumours, which is the ‘holy grail’ in the immuno-oncology field.”
Current treatments, such as chimeric antigen receptor (CAR) T therapy, use the body’s white blood cells to attack cancer. They have largely worked only for blood cancers, such as leukaemia. The GlyTR technology also proved effective in targeting leukaemia, the study shows.
Unorthodox approach
While many cancer researchers have sought protein biomarkers for specific cancers, Demetriou and Zhou aimed at a more abundant target, the unique coating of glycans that surround cancer cells but are found in very low density in normal cells.
These complex sugar chains are the most widespread cancer antigens known, but were generally ignored by researchers because they are inert to the immune system.
To solve this problem, Demetriou and Zhou engineered the GlyTR compounds to attach themselves, Velcro-like, to glycan-dense cancer cells while ignoring low-glycan-density normal cells. Once attached, the GlyTR compounds identify the cancer cells as targets for killing by the body’s immune system.
In contrast, current cancer immunotherapies attack cells based on specific proteins regardless of their glycan density and thereby fail to distinguish tumour cells from healthy tissue.
A second impediment to developing broadly active cancer immunotherapies is the shield glycans form around solid tumours.
By targeting glycans and blanketing the tumour cells with the Velcro-like compounds, the GlyTR technology overcomes both obstacles.
Human trials
The next step will be testing the therapy’s safety and effectiveness in humans. Clinical grade GlyTR1 protein manufacturing is already being developed at the NCI Experimental Therapeutics program labs in Maryland, Demetriou said.
That will enable the launch of a phase 1 clinical trial, which could begin within about two years. It will test the therapy in patients with a range of metastatic solid cancers. The highest glycan density is typically seen in patients with refractory/metastatic disease, a population that also has the greatest unmet need for treatment.
New research has shown why preserving lymph nodes, often removed near tumours to prevent cancer spread, could improve patient outcomes and make immunotherapies more effective.
A team of researchers, led by the Peter Doherty Institute for Infection and Immunity (Doherty Institute), explored the cellular and molecular interactions revealing how lymph nodes play a crucial role in the fight against chronic infection and cancer.
The research, published across two papers in Nature Immunology (references and links below), showed that lymph nodes provide the right environment for stem-like T cells, an important type of immune cell, to survive, multiply and produce killer cells that can fight cancer or viruses. In other immune organs, such as the spleen, these cells don’t develop or proliferate as effectively, making lymph nodes essential for a strong immune response and successful immunotherapy.
The University of Melbourne’s Professor Axel Kallies, Laboratory Head at the Doherty Institute and senior author of both papers, said the findings have important implications for cancer therapy.
“Lymph nodes aren’t just passive waiting rooms for immune cells, they actively train and educate T cells, and send them off to do their job,” said Professor Kallies.
“Our research suggests that removing lymph nodes during cancer surgery, a common practice to prevent tumour spread, may inadvertently reduce the effectiveness of treatments, such as checkpoint blockade and CAR T cell therapies. Preserving lymph nodes could strengthen immune responses and increase the effectiveness of immunotherapy.”
This work may also help explain why some patients respond better to immunotherapy than others. The state and function of lymph nodes influence how well the immune system can produce cancer-fighting T cells, directly impacting the success of immunotherapy.
The University of Melbourne’s Dr Carlson Tsui, Postdoctoral Researcher at the Doherty Institute and first author of one of the papers, said the findings could help to develop new strategies to make immunotherapy more effective.
“Our research identifies molecular signals that are involved in the regulation of stem-like cells and in their capacity to produce effective killer cells. These findings could guide the development and refinement of immune-based treatments for cancer and chronic infection,” said Dr Tsui.
“Furthermore, our research shows that rather than only focusing on the tumour itself, therapies should also be designed to preserve and enhance lymph node function. By targeting these critical immune hubs, we could boost the body’s natural ability to fight cancer, increase the effectiveness of existing immunotherapies and help more patients respond to treatment.”
Together, the two peer-reviewed papers provide a deeper understanding of how lymph nodes shape immune responses. While they are based on work with animal models, they will guide future treatment strategies for chronic infection and cancer treatment.
Professor Shahneen Sandhu, Research Lead for the Melanoma Medical Oncology Service at the Peter MacCallum Cancer Centre, commented on the clinical implications of this work.
“While this research was done in the laboratory with pre-clinical models, we’re excited to study these findings in clinical samples from patients receiving immune checkpoint inhibitors, as part of an ongoing Melanoma Research Victoria collaboration with Professor Kallies,” Professor Sandhu said.
“Combining clinical and preclinical studies will help us translate these discoveries from bench to bedside and back, ultimately improving outcomes for cancer patients.”
Tsui C, Heyden L, et al. Lymph nodes fuel KLF2-dependent effector CD8+ T cell differentiation during chronic infection and checkpoint blockade. Nature Immunology (2025). DOI: https://doi.org/10.1038/s41590-025-02276-7
Wijesinghe SKM, Rausch L, et al. Lymph-node-derived stem-like but not tumor-tissue-resident CD8+ T cells fuel anticancer immunity. Nature Immunology (2025). DOI: https://doi.org/10.1038/s41590-025-02219-2
A two-drug combination for treating advanced kidney cancer had sustained and durable clinical benefit in more than five years of follow-up, according to a study published August 1 in Nature Medicine.
The study reports final clinical data and biomarker analyses from the Phase 3 KEYNOTE-426 trial, which compared the drug combination pembrolizumab plus axitinib versus the single drug sunitinib for patients with previously untreated advanced clear cell renal cell carcinoma, the most common type of kidney cancer.
“KEYNOTE-426 was the first trial to combine a PD-1 inhibitor immunotherapy (pembrolizumab) with a VEGF receptor inhibitor antiangiogenic drug (axitinib) in the first-line setting for advanced renal cell carcinoma. It therefore has the longest follow-up duration among the various trials comparing these types of drug combinations,” said Brian Rini, MD, a medical oncologist at Vanderbilt-Ingram Cancer Center, Professor of Medicine and the study’s lead and corresponding author.
Immunotherapy drugs like pembrolizumab stimulate the immune system to kill tumour cells. VEGF receptor inhibitors like axitinib and sunitinib block angiogenesis — the development of blood vessels that tumours need to grow and spread. Pembrolizumab plus axitinib and other immunotherapy-antiangiogenic drug combinations are now standard first-line treatments for advanced kidney cancer.
“Before the development of antiangiogenic drugs and immunotherapies, advanced renal cell carcinoma had a very poor prognosis. These drug combinations have dramatically improved treatment options and outcomes for patients,” said Rini.
The first interim analysis of outcomes from KEYNOTE-426, published Feb. 16, 2019, in the New England Journal of Medicine, demonstrated that trial participants treated with pembrolizumab plus axitinib had longer overall and progression-free survival, and higher objective response rates compared to those taking sunitinib. The median follow-up was 12.8 months.
Now, with a median follow-up of 67.2 months, the current analysis confirms and extends the interim analysis and provides valuable information about biomarkers that could help guide treatment decisions.
The study in Nature Medicine reports that pembrolizumab plus axitinib had longer overall survival (47.2 months versus 40.8 months for sunitinib) and longer progression-free survival (15.7 months versus 11.1 months for sunitinib). The objective response rate was 60.6% for pembrolizumab plus axitinib and 39.6% for sunitinib.
The researchers reported a variety of associations between the expression of biomarkers and outcomes (overall survival, progression-free survival, objective response rate). The biomarkers they evaluated included an 18-gene T-cell-inflamed expression profile, angiogenesis signature, and PD-1 ligand expression.
“There is an unmet need for biomarkers that are predictive of patient outcomes following treatment with available first-line therapies for advanced renal cell carcinoma,” Rini said. “Although our analysis showed potential clinical utility of some RNA signatures in identifying patients who are likely to benefit the most from each treatment, further prospective clinical studies are needed.”
Pembrolizumab plus axitinib is a first-line treatment option for patients with advanced renal cell carcinoma regardless of biomarker subtypes, he noted.
A new study led by Keck Medicine of USC researchers may have uncovered an effective combination therapy for glioblastoma, a brain tumour diagnosis with few available effective treatments. According to the National Brain Tumor Society, the average survival for patients diagnosed with glioblastoma is eight months.
The study, which was published in the journal Med, finds that using Tumour Treating Fields therapy (TTFields), which delivers targeted waves of electric fields directly into tumours to stop their growth and signal the body’s immune system to attack cancerous tumour cells, may extend survival among patients with glioblastoma, when combined with immunotherapy (pembrolizumab) and chemotherapy (temozolomide).
TTFields disrupt tumour growth using low-intensity, alternating electric fields that push and pull key structures inside tumour cells in continually shifting directions, making it difficult for the cells to multiply. Preventing tumour growth gives patients a better chance of successfully fighting the cancer. When used to treat glioblastoma, TTFields are delivered through a set of mesh electrodes that are strategically positioned on the scalp, generating fields at a precise frequency and intensity focused on the tumour. Patients wear the electrodes for approximately 18 hours a day.
Researchers observed that TTFields attract more tumour-fighting T cells, which are white blood cells that identify and attack cancer cells, into and around the glioblastoma. When followed by immunotherapy, these T cells stay active longer and are replaced by even stronger, more effective tumour-fighting T cells.
“By using TTFields with immunotherapy, we prime the body to mount an attack on the cancer, which enables the immunotherapy to have a meaningful effect in ways that it could not before,” said David Tran, MD, PhD, chief of neuro-oncology with Keck Medicine, co-director of the USC Brain Tumor Center and corresponding author of the study. “Our findings suggest that TTFields may be the key to unlocking the value of immunotherapy in treating glioblastoma.”
TTFields are often combined with chemotherapy in cancer treatment. However, even with aggressive treatment, the prognosis for glioblastoma remains poor. Immunotherapy, while successful in many other cancer types, has also not proved effective for glioblastoma when used on its own.
However, in this study, adding immunotherapy to TTFields and chemotherapy was associated with a 70% increase in overall survival. Notably, patients with larger, unresected (not surgically removed) tumours showed an even stronger immune response to TTFields and lived even longer. This suggests that, when it comes to kick-starting the body’s immune response against the cancer, having a larger tumour may provide more targets for the therapy to work against.
Using alternating electric fields to unlock immunotherapy
Pembrolizumab, the immunotherapy used in this study, is an immune checkpoint inhibitor (ICI), which enhances the body’s natural ability to fight cancers by improving T cells’ ability to identify and attack cancer cells.
However, there are typically few T cells in and around glioblastomas because these tumours originate in the brain and are shielded from the body’s natural immune response by the blood-brain barrier. This barrier safeguards the brain by tightly regulating which cells and substances enter from the bloodstream. Sometimes, this barrier even blocks T cells and other therapies that could help kill brain tumours.
This immunosuppressive environment inside and around the glioblastoma is what makes common cancer therapies like pembrolizumab and chemotherapy significantly less effective in treating it. Tran theorised the best way to get around this issue was to start an immune reaction directly inside the tumour itself, an approach known as in situ immunisation, using TTFields.
This study demonstrates that combining TTFields with immunotherapy triggers a potent immune response within the tumour – one that ICIs can then amplify to bolster the body’s own defence against cancer.
“Think of it like a team sport – immunotherapy sends players in to attack the tumour (the offence), while TTFields weaken the tumour’s ability to fight back (the defence). And just like in team sports, the best defence is a good offence,” said Tran, who is also a member of the USC Norris Comprehensive Cancer Center.
Study methodology and results
The study analysed data from 2-THE-TOP, a Phase 2 clinical trial, which enrolled 31 newly diagnosed glioblastoma patients who had completed chemoradiation therapy. Of those, 26 received TTFields combined with both chemotherapy and immunotherapy. Seven of these 26 patients had inoperable tumours due to their locations – an especially high-risk subgroup with the worst prognosis and few treatment options.
Patients in the trial were given six to 12 monthly treatments of chemotherapy alongside TTFields for up to 24 months. The number and duration of treatments were determined by patients’ response to treatment. The immunotherapy was given every three weeks, starting with the second dose of chemotherapy, for up to 24 months.
Patients who used the device alongside chemotherapy and immunotherapy lived approximately 10 months longer than patients who had used the device with chemotherapy alone in the past. Moreover, those with large, inoperable tumours lived approximately 13 months longer and showed much stronger immune activation compared to patients who underwent surgical removal of their tumours.
“Further studies are needed to determine the optimal role of surgery in this setting, but these findings may offer hope, particularly for glioblastoma patients who do not have surgery as an option,” said Tran.
The researchers are now moving ahead to a Phase 3 trial.
Elated at graduating with a doctoral degree is Dr Aviwe Ntsethe. Credit: University of KwaZulu-Natal
Dr Aviwe Ntsethe’s curiosity in the Medical field deepened when he started exploring the complexities of human physiology and the crucial role of the immune system in cancer, leading to him graduating with a PhD.
Growing up in the small town of Bizana in the Eastern Cape, Ntsethe attended Ntabezulu High School, where his passion for Medical Science took root. Despite facing significant challenges, including limited funding opportunities for his studies, he remained determined to advance in the discipline.
Throughout his PhD journey at UKZN, Ntsethe had to juggle multiple jobs to support himself and his studies while conducting his research. He worked at Netcare Education and the KwaZulu-Natal College of Emergency Care, and later took up a position as a contractual laboratory technician in the Department of Physiology at UKZN. It was with the guidance of his PhD supervisor, Professor Bongani Nkambule, that he learned critical work ethics and advanced laboratory techniques. The co-supervision of Professor Phiwayinkosi Dludla further enriched his research experience and contributed to his academic growth.
Ntsethe’s thesis focused on investigating B cell function and immune checkpoint expression in patients with Chronic Lymphocytic Leukaemia (CLL). The study found that patients with CLL had higher levels of immune checkpoint proteins in their B cell subsets, which play a crucial role in regulating the immune system.
Furthermore, using monoclonal antibodies that target these immune checkpoints, he found these patients could potentially benefit from immunotherapy. Specifically, immunotherapy may improve the function of B cells, key players in fighting infections and cancers, thereby offering new hope for better outcomes in patients with CLL.
He has published three papers from this study. ‘I am excited and proud when I reflect on my achievement of completing this significant journey which was both challenging and rewarding, pushing me to expand my knowledge and skills in ways I never imagined.’
Now, a lecturer at Nelson Mandela University, Ntsethe is committed to mentoring the next generation of Medical scientists. He continues to use the invaluable knowledge and experience he gained during his PhD studies to inspire students and cultivate their passions in research and health sciences. Looking ahead, Ntsethe hopes to expand his research, focusing on immune system interactions in chronic diseases while also encouraging students from diverse backgrounds to pursue careers in Medical Science.
Outside academia, Ntsethe enjoys travelling, staying physically active through workouts, playing chess and indulging in coding or programming.
Killer T cells about to destroy a cancer cell. Credit: NIH
After treatment with CAR-T cells, immune cells engineered to attack cancer, patients sometimes tell their doctors they feel like they have “brain fog,” or forgetfulness and difficulty concentrating.
A new Stanford Medicine-led study shows that CAR-T cell therapy causes mild cognitive impairments, independent of other cancer treatments, and that this happens via the same cellular mechanism as cognitive impairment from two other causes: chemotherapy and respiratory infections such as flu and COVID-19. The study, conducted mostly in mice, which was published in Cell, also identifies strategies for reversing the problem.
Medications that ameliorate brain fog will enable better recovery from cancer immunotherapies, the researchers said.
“CAR-T cell therapy is enormously promising,” said senior author, Michelle Monje, MD, PhD, professor in paediatric neuro-oncology. “We need to understand all its possible long-term effects, including this newly recognised syndrome of immunotherapy-related cognitive impairment, so we can develop therapeutic approaches to fix it.”
The study’s lead authors are Anna Geraghty, PhD, senior staff scientist in the Monje lab, and MD/PhD student Lehi Acosta-Alvarez.
Cognitive impairment after CAR-T cell therapy is typically mild; patients are not developing dementia, for instance. But it is frustrating and may not resolve on its own, Monje said. In mice, her team reversed the impairment using compounds similar to existing medications or medications in clinical development – meaning a treatment could be available relatively quickly, she said.
“We’re deeply interested in how cancer therapies affect cognition because it affects patients’ quality of life,” Monje said. “And this is especially important for kids because their brains are still developing.”
Investigating brain fog
CAR-T cell therapy was approved in the US for acute lymphoblastic leukaemia in 2017. The treatment involves removing some of the patient’s own immune cells, known as T cells, and engineering them to attack targets on cancer cells. The modified T cells are returned to the patient’s body, where they recognise and destroy cancer.
In addition to leukaemia, CAR-T cells are now used to treat other blood cancers, including multiple myeloma and some kinds of lymphoma, and they are being tested in clinical trials for various solid tumours. Monje and her colleagues have an ongoing trial of CAR-T cells for deadly brain stem and spinal cord tumours in children, which is beginning to show success.
Although patients report brain fog after CAR-T cell therapy, studies to measure how much cognitive impairment the therapy causes are only just emerging.
The research team wanted to get a comprehensive understanding of the situations in which CAR-T cell therapy might cause cognitive impairment. They studied mice that had tumours induced in the brain, blood, skin and bone. The researchers wanted to understand the influence on cognition of CAR-T cell treatment in combination with the tumours’ location (originating in, spreading to or staying outside the brain), as well as the degree to which the engineered cells evoked additional, accompanying immune responses. Before and after CAR-T cell treatment, the researchers used standard cognitive tests on the mice, measuring how mice responded to a novel object and navigated a simple maze.
CAR-T therapy caused mild cognitive impairment in mice with cancers originating in, metastasizing to and located completely outside the brain. The only mice tested that did not develop cognitive impairment after CAR-T treatment were those that had bone cancer that causes minimal additional inflammation beyond the cancer-fighting activity of the CAR-T cells.
“This is the first study to demonstrate that immunotherapy on its own is sufficient to cause lasting cognitive symptoms,” Monje said. “It’s also the first paper to uncover the mechanisms. We found the exact same pathophysiology we’ve seen in brain fog syndromes that occur after chemotherapy, radiation, and mild respiratory COVID-19 or influenza.”
The researchers demonstrated that the brain’s immune cells, called microglia, are key players in the problem. First, the microglia become activated by the body’s immune response. The activated, “annoyed” microglia produce inflammatory immune molecules known as cytokines and chemokines, which in turn have widespread effects throughout the brain. They are particularly harmful for oligodendrocytes, the brain cells responsible for making myelin, the fatty substance that insulates nerve fibres and helps nerves transmit signals more efficiently. Reduction in the nerves’ insulation translates into cognitive impairment.
Examining tissue samples
The scientists also analysed samples of brain tissue from human subjects who participated in the team’s ongoing clinical trial of CAR-T cells for spinal cord and brain stem tumours. Using post-mortem tissue samples, the researchers confirmed that microglia and oligodendrocytes appear dysregulated in the same way the team had observed in mice after CAR-T therapy.
In mice, the research team tested strategies to resolve the cognitive problems. They gave a compound that depleted microglia in the brains of the mice for a two-week period. After that transient depletion, the microglia returned in the brain in a normal, non-reactive state. The mice were no longer cognitively impaired.
The researchers also gave the mice a medication that enters the brain and interferes with signals from damaging chemokines, blocking a specific receptor for these molecules.
“That alone rescued cognition,” Monje said, adding that the researchers are now exploring how to safely translate the two strategies – transiently depleting microglia or interrupting chemokine signals – in people who have had CAR-T cell therapy.
“This research further illustrates that there is a unifying principle underpinning brain fog syndromes,” said Monje, a member of the Stanford Cancer Institute. “And this particular study is so exciting because not only have we identified the cells central to this pathophysiology, we’ve found a molecular target we can investigate to treat it.”
