Tag: Clinical Trial

LungVax vaccine uses DNA technology to prevent lung cancer

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Developed by scientists from the University of Oxford, the Francis Crick Institute and University College London, the LungVax vaccine uses technology similar to the highly successful Oxford/AstraZeneca COVID-19 vaccine.

The team will receive funding for the study over the next 2 years to support lab research and initial manufacturing of 3,000 doses of the vaccine at the Oxford Clinical BioManufacturing Facility.

Lung cancer cells look different from normal cells due to having “red flag” proteins called neoantigens. Neoantigens appear on the surface of the cell because of cancer-causing mutations within the cell’s DNA.

The LungVax vaccine will carry a strand of DNA which trains the immune system to recognize these neoantigens on abnormal lung cells. The LungVax vaccine will then activate the immune system to kill these cells and stop lung cancer.

In this study, the scientists are developing this vaccine in the lab to show that it successfully triggers an immune response. If this work is successful, the vaccine will move straight into a clinical trial. If the subsequent early trial delivers promising results, the vaccine could then be scaled up to bigger trials for people at high risk of lung cancer. This could include people aged 55-74 who are current smokers, or have previously smoked, and currently qualify for targeted lung health checks in some parts of the UK.

There are around 48,500 cases of lung cancer every year in the UK. 72% of lung cancers are caused by smoking, which is the biggest preventable cause of cancer worldwide.

Kidani Professor of Immuno-oncology at the University of Oxford and research lead for the LungVax project, Professor Tim Elliott, said:

“Cancer is a disease of our own bodies and it’s hard for the immune system to distinguish between what’s normal and what’s cancer. Getting the immune system to recognize and attack cancer is one of the biggest challenges in cancer research today.

“This research could deliver an off-the-shelf vaccine based on Oxford’s vaccine technology, which proved itself in the COVID-19 pandemic. If we can replicate the kind of success seen in trials during the pandemic, we could save the lives of tens of thousands of people every year in the UK alone.”

When given to people with cancer at its earliest stages, anti-cancer treatments are more likely to be successful.

We are developing a vaccine to stop the formation of lung cancer in people at high risk. This is an important step forward in preventing this devastating disease.”

Professor Sarah Blagden, Professor of Experimental Oncology at the University of Oxford and founder of the LungVax project

Professor Mariam Jamal-Hanjani of University College London and the Francis Crick Institute, who will be leading the LungVax clinical trial, said:

“Fewer than 10% of people with lung cancer survive their disease for 10 years or more. That must change. This research complements existing efforts through lung health checks to detect lung cancer earlier in people who are at greatest risk.

“We think the vaccine could cover around 90% of all lung cancers, based on our computer models and previous research, and this funding will allow us to take the vital first steps towards trials in patients.

“LungVax will not replace stopping smoking as the best way to reduce your risk of lung cancer. But it could offer a viable route to preventing some of the earliest stage cancers from emerging in the first place.”

Chief Executive of Cancer Research UK, Michelle Mitchell, said:

“The science that successfully steered the world out of the pandemic could soon be guiding us toward a future where people can live longer, better lives free from the fear of cancer.

“Projects like LungVax are a really important step forward into an exciting future, where cancer is much more preventable. We’re in a golden age of research and this is one of many projects which we hope will transform lung cancer survival.”

President of CRIS Cancer Foundation, Lola Manterola, said:

“We are at a crucial moment in the history of cancer research and treatment. For the first time, technology and knowledge of the immune system are allowing us to take the first steps towards preventing cancer.

“This groundbreaking study represents a firm step in that direction, and we at CRIS consider it essential to support it.”

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March 22, 2024
Investigational gene therapy shows promise for rare childhood neurodegenerative disease

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An investigational gene therapy for a rare neurodegenerative disease that begins in early childhood, known as giant axonal neuropathy (GAN), was well tolerated and showed signs of therapeutic benefit in a clinical trial led by the National Institutes of Health (NIH). Currently, there is no treatment for GAN and the disease is usually fatal by 30 years of age. Fourteen children with GAN, ages 6 to 14 years, were treated with gene transfer therapy at the NIH Clinical Center and then followed for about six years to assess safety. Results of the early-stage clinical trial appear in the New England Journal of Medicine.

The gene therapy uses a modified virus to deliver functional copies of the defective GAN gene to nerve cells in the body. It is the first time a gene therapy has been administered directly into the spinal fluid, allowing it to target the motor and sensory neurons affected in GAN. At some dose levels, the treatment appeared to slow the rate of motor function decline. The findings also suggest regeneration of sensory nerves may be possible in some patients. The trial results are an early indication that the therapy may have favorable safety and tolerability and could help people with the rapidly progressive disease.

One striking finding in the study was that the sensory nerves, which are affected earliest in GAN, started ‘waking up’ again in some of the patients. I think it marks the first time it has been shown that a sensory nerve affected in a genetic degenerative disease can actually be rescued with a gene therapy such as this.”

Carsten G. Bonnemann, M.D., senior author and chief of the Neuromuscular and Neurogenetic Disorders of Childhood Section at the National Institute of Neurological Disorders and Stroke (NINDS)

Participants in this “first-in-human” trial, which began in 2015, received a single dose of the gene therapy, called scAAV9/JeT-GAN, through an injection into the fluid surrounding the spine. The first two patients received the lowest dose of the gene transfer, which was increased in subsequent patients. Four dose levels were tested over the course of the trial, which were estimated based on results from studies in animal models. Only one serious adverse event – a fever – was potentially linked to the gene therapy. The treatment resulted in 129 related adverse events of lesser seriousness, including headache, back pain, irregular heart rhythms, and inflammation in spinal fluid that was treated with corticosteroids. Two patients who were older and received the lowest-dose therapy died during the study period due to events related to their underlying disease.

In addition to safety, Dr. Bonnemann and his colleagues also assessed motor function scores and tests of nerve function among the study participants. With increasing dose levels, they found the probability of any slowing of motor decline was 44%, 92%, 99%, and 90%, respectively. As GAN progresses, electrical measures of sensory nerves decline and eventually disappear. With gene therapy, 6 of 14 patients regained sensory nerve response after treatment-;electrical measures increased, stopped declining, or became measurable after being absent.

Mutations to the GAN gene result in an inability to break down intermediate filaments, which are cellular structures that make up the framework of nerve cell extensions called axons. Axons are essential for transmission of signals between brain cells. The disease name refers to the enlarged and bloated appearance of the axon under the microscope. As GAN progresses, the axons of motor and sensory nerves break down, resulting in difficulty with movement and sensation because nerve cells cannot communicate with each other.

The first symptoms of GAN are often a clumsy and unsteady gait, becoming evident as early as 2 or 3 years of age. The disease progresses so that by age 8 or 9, patients typically require the use of a wheelchair, followed by increasingly limited use of the arms and little to no use of their legs. In the later stages, people with GAN often require breathing assistance and a feeding tube.

This trial could also benefit gene therapy for other diseases. Researchers testing other gene therapies have already adopted direct administration into the spinal fluid, which requires lower doses compared to usual delivery into the bloodstream by vein. Injecting into the spinal fluid also reduces the likelihood of an immune response, which enables patients who have developed immunity to adeno-associated virus (AAV), the common virus used as the gene delivery system in the therapy, to potentially receive treatment. Previously, children carrying antibodies to AAV from natural exposure to the virus would have been excluded from gene therapy because of their immune reaction.

Scientists will continue evaluating the scAAV9/JeT-GAN therapy to refine the treatment. Next, investigators plan to test whether the GAN gene transfer is more effective when given to younger children or those in an earlier stage of the disease. The next phase of the trial will help to further determine its safety and efficacy.

The study was supported by NINDS and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, Hannah’s Hope Fund, Taysha Gene Therapies Inc., Bamboo Therapeutics/Pfizer Inc., Child Neurology Society, and the American Society of Gene and Cell Therapy. Hannah’s Hope Fund was integral in the development of the therapy, which was then advanced through collaborative efforts involving academia, industry, and government organizations.

Source:

NIH/National Institute of Neurological Disorders and Stroke

Journal reference:

Bharucha-Goebel, D. X., et al. (2024) Intrathecal Gene Therapy for Giant Axonal Neuropathy. New England Journal of Medicine. doi.org/10.1056/NEJMoa2307952.

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March 21, 2024
Genetic test can identify how patients with triple negative early-stage breast cancer will respond to immunotherapy

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Researchers have developed a genetic test that can identify how patients with triple negative early-stage breast cancer will respond to immunotherapy drugs. This means that patients who are unlikely to respond to these drugs can avoid the adverse side effects associated with them and can be treated with other therapies.

Professor Laura van ‘t Veer told the 14^th European Breast Cancer Conference that the latest results from the I-SPY2 trial suggest that the current standard of care for patients with triple negative breast cancer should be reconsidered.

“Immunotherapy drugs can have very severe, irreversible adverse side effects, as observed in the I-SPY2 trial. The findings I’m presenting today should provoke a discussion about whether giving immunotherapy drugs to all patients with triple negative disease, which has recently become the standard of care in most countries, is the right strategy. Our research shows that it should be adapted so as to select only those patients who are very likely to benefit from this treatment. Patients who are unlikely to respond could then receive alternative therapies,” said Prof. van ‘t Veer, who is a Professor of Laboratory Medicine, Co-leader of the Breast Oncology Program and Director of Applied Genomics at the Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, USA.

The I-SPY2 trial was established in 2010 to find ways to screen new anti-cancer drugs and match them to specific biological markers in patients with breast cancer at high risk of early recurrence. Researchers developed an immune classifier, called ImPrint, composed of 53 genes, which can be used in the clinic to predict the likelihood of a patient responding to immunotherapies by looking at the biology of the patient’s tumor. It classifies tissue from patient biopsies into ‘likely responder’ or ‘likely non-responder’ to immunotherapy.

Today, Prof. van ‘t Veer presented the results for an updated version of the classifier, ImPrintTN, refined to provide more accurate predictions for patients with triple-negative breast cancer – the type of breast cancer in which the cancer cells are not fuelled by either estrogen, progesterone or the HER2 protein.

“Previously, we showed that gene expression signatures representing the active components of the immune system can predict the response to pembrolizumab – an immune-oncology drug that targets PD1, which is a protein on the surfaces of cells that plays a role in the immune system. Both patients with triple negative disease and also patients with hormone receptor positive breast cancer, who had not yet received treatment and whose tumours had this active immune biology, showed a significant, up to three times higher, pathologic complete response rate when treated with pembrolizumab,” she said.

A pathologic complete response (pCR) is when the cancer shrinks and even disappears after drug treatment.

She continued: “This classifier had a good performance across triple negative and hormone receptor positive breast cancers combined, and had very high positive predictive value for hormone receptor positive breast cancers, meaning that it identified those cancers that would likely respond to an immunotherapy.”

“However, we noticed that the performance of ImPrint for triple negative breast cancers, where immune oncology drugs are now standard of care, was not yet good enough to identify patients in whom a ‘likely response’ to immunotherapy was so low that harm from serious side-effects would be higher than the benefit.

“This new work now presents an update of the ImPrint classifier specifically for triple negative breast cancers, ImPrintTN. We found that it can predict patients who are unlikely to respond to immunotherapy, so that the harms from the treatment are greater than the benefit. This means it would be acceptable for them to forgo an immunotherapy drug in order to avoid the risk of these sometimes life-long irreversible adverse effects.”

Out of 150 patients receiving immunotherapy in four arms of the trial and 128 patients in the control arm, receiving taxane and anthracycline chemotherapy, ImPrintTN identified 66% patients with triple negative breast cancer as being likely to respond to immunotherapy.

Patients in the immunotherapy arms had been divided equally into two sets: a training and a test set, and the sets were also balanced so as to have an equal number of ‘responders’ and ‘non-responders’.

In the independent test set, pCR rates were 71% compared to 22% in patients identified as unlikely to respond. When all five arms were combined (the test and the training sets), pCR rates were 74% in patients identified as likely to respond and 16% in those that ImPrintTN classified as unlikely to respond. This improves on the previous version of ImPrint where pCR rates were 38% among patients that it identified as unlikely to respond.

In the control arm of the trial where patients had been treated with standard of care chemotherapies only, pCR rates were 30% among patients identified by ImPrint as ‘responders’ and 15% among ‘non-responders’.

“The likelihood of an immunotherapy drug response for triple negative cancers that are ImPrint-positive, remains very high at 74%, while among patients that ImPrintTN identified as likely ‘non-responders’ the pCR rates for immunotherapy are now very low at 16% – low enough for the harm from immunotherapy drugs to outbalance the benefit in these patients,” said Prof. van ‘t Veer. “This is a clinically important improvement and suggests that ImPrintTN may help to inform prioritisation of immunotherapies versus other treatments for patients with triple negative breast cancer in order to best balance likely benefit versus the risk of serious and irreversible adverse effects. There is a subgroup of patients where the harm of these drugs outweighs the therapeutic benefit.

“Once ImPrintTN has been validated further, immunotherapy drugs should only be given to patients with triple negative or HR positive disease who have a high likelihood of benefitting.”

Professor Michail Ignatiadis from the Institut Jules Bordet in Brussels, Belgium, is Chair of the 14th European Breast Cancer Conference and was not involved in the research.

It is increasingly appreciated that the ‘one size fits all’ approach is not optimal for the systemic treatment of patients with early triple negative breast cancer. The identification of biomarkers to identify patients that do not need neoadjuvant immunotherapy is an unmet medical need. The results presented today show that ImPrintTN is a promising such biomarker that, if further validated, can spare many women the short and long-term toxicity of these drugs.”

Professor Michail Ignatiadis, Institut Jules Bordet in Brussels, Belgium

Source:

European Organisation for Research and Treatment of Cancer

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March 20, 2024
Pembrolizumab enhances breast cancer treatment regardless of age or menopausal status

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New data from the KEYNOTE-756 phase 3 clinical trial show that adding the immunotherapy drug, pembrolizumab, to chemotherapy before and after surgery for breast cancer leads to better outcomes for patients regardless of their age or menopausal status.

The findings, presented at the 14^th European Breast Cancer Conference (EBCC 14) today (Wednesday), add to information available on the effect of pembrolizumab in patients with early-stage breast cancer that is at high risk of recurring or spreading further, and that is oestrogen receptor positive (ER positive) and HER2 negative.

KEYNOTE-756 is an international trial, which has been running for eight years. It randomised 1278 patients to receive pembrolizumab or placebo in addition to neoadjuvant chemotherapy (given before surgery) followed by adjuvant (given after surgery) pembrolizumab or placebo in combination with an endocrine therapy. The patients had invasive ductal carcinoma (IDC), meaning the cancer had started to spread out of the milk ducts into the surrounding breast tissues.

Professor Javier Cortés, Director of the International Breast Cancer Centre in Barcelona, Spain, said: “We have already reported that there was a statistically significant increase in the pathological complete response rate in patients receiving pembrolizumab compared to those receiving the placebo. The pathological complete response rate, meaning that no cancer cells remained in the breast or lymph nodes, was 24.3% in patients treated with pembrolizumab compared to 15.6% in patients treated with the placebo.

“Now we can show that these pCR rates occurred regardless of the patients’ age or menopausal status. In patients younger than 50 years old, the pCR rate was 23.8% in those on pembrolizumab (76 out of 319 patients) compared to 16.9% (55 out of 326) for those receiving placebo, and was 24.7% (78 of 316 patients) versus 14.2% (45 of 317) respectively in those aged 50 or older. In pre-menopausal women, the pCR rate was 23.4% (83 out of 354 patients) versus 16.1% (57 out of 353) respectively, and in post-menopausal women, it was 24.8% (69 out of 278 patients) versus 14.6% (42 out of 287), respectively.

“We also found that adding pembrolizumab to neoadjuvant chemotherapy did not delay the time to surgery. The average time to surgery in both groups of patients was about a month. The average time after surgery to the start of adjuvant treatment was 1.2 months in both groups.”

The study found there were similar rates of breast-conserving surgery and mastectomy in both groups. Among the patients who had breast-conserving surgery, 41.3% (262 patients) received pembrolizumab and 43.7% (281 patients) received placebo. Among those who had a mastectomy, 55.3% (351 patients) were treated with pembrolizumab and 54.4% (350 patients) had the placebo.”

Tissue collected at the time of surgery was analysed to see if any cancer cells remained after the neoadjuvant treatment, known as residual cancer burden (RCB). Neoadjuvant pembrolizumab resulted in a lower RCB for more patients, regardless of how well the immunotherapy had blocked a protein called PD-L1, which also drives some breast cancers.

Pathology reports found that 35% of patients (222 patients) treated with pembrolizumab had no or very small amounts of cancer cells remaining (RCB 0-1) versus 23.6% of patients (152) receiving placebo. A moderate amount of RCB (RCB-2) was found in 40.8% of patients treated with pembrolizumab versus 45.3% (259 versus 291 patients), and extensive RCB (RCB-3) was found in 20.5% versus 28.9% of patients respectively (130 versus 186 patients).

When the researchers looked at the effect of pembrolizumab according to whether patients had cancer that was ER positive in less than 10% of cells or in 10% or more, they found that 64.7% of patients (22 out of 34) with less than 10%, who were treated with pembrolizumab, had an RCB status of 0-1, compared to 37.2% of patients treated with placebo (16 out of 43). In patients with 10% or more ER positive cells, 33.3% compared to 22.7% had an RCB 0-1 status (200 out of 601 patients versus 136 out of 600 patients respectively).

Dr Fatima Cardoso, Director of the Breast Unit of the Champalimaud Clinical Centre, Lisbon, Portugal, is the principal investigator for the trial. Speaking before EBCC 14, she said: “Keynote 756 trial showed that the addition of pembrolizumab to neoadjuvant chemotherapy significantly increased pathological response at the time of surgery, and this was true regardless of PD-L1 levels and estrogen receptor positivity. However, we saw a bigger benefit with higher PD-L1 levels and in ER-low tumors.

“Keynote-756 is also the only trial that is powered to analyze the impact of immunotherapy in long-term outcomes for this subtype of breast cancer.”

Adverse events from the treatments were unchanged from previous reports from the trial and were consistent with what is known already about each regimen.

The trial continues to follow the patients, and information is being collected on survival rates and whether there are any recurrences of cancer or other related symptoms.

Professor Michail Ignatiadis from the Institut Jules Bordet in Brussels, Belgium, is Chair of the 14th European Breast Cancer Conference and was not involved in the research.

We have heard more data from the KEYNOTE-756 trial about which ER positive / HER2 negative patient subgroups benefit most from pembrolizumab in terms of pathological complete response. Longer follow-up is needed in order to see whether the improvement in pCR rates will result in more patients living for longer without their disease recurring, and we look forward to these data in due course.”

Professor Michail Ignatiadis, Institut Jules Bordet in Brussels, Belgium

Source:

European Organisation for Research and Treatment of Cancer

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March 20, 2024
Tracking circulating tumor DNA could indicate gastroesophageal cancer treatment response

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Monitoring levels of DNA shed by tumors and circulating in the bloodstream could help doctors accurately assess how gastroesophageal cancers are responding to treatment, and potentially predict future prognosis, suggests a new study led by researchers at the Johns Hopkins Kimmel Cancer Center and its Bloomberg~Kimmel Institute for Cancer Immunotherapy.

The study tracked minimal residual disease (the amount of cancer left following treatment) by analyzing circulating tumor DNA (ctDNA), showing how these “liquid biopsies” can provide valuable insights into treatment outcomes over time. Absence of ctDNA was seen occurring together with specific activation of T cells that are part of the immune system’s defense to recognize and fight cancer.

“We found that the elimination of ctDNA was a good indicator of patients’ cancer-free survival,” says Valsamo “Elsa” Anagnostou, M.D., Ph.D., senior co-author of the study and associate professor of oncology and director of the thoracic oncology biorepository at Johns Hopkins.

Anagnostou is also leader of Precision Oncology Analytics, co-leader of the Johns Hopkins Molecular Tumor Board and co-director of the Lung Cancer Precision Medicine Center of Excellence at Johns Hopkins. “We were gratified to see tumor shrinkage at a molecular level together with the immune system flaring up and clearing the tumor,” she says.

The findings, reported in a paper published March 19 in Nature Medicine, emerged from a clinical trial examining the safety and efficacy of two immunotherapy drugs -; nivolumab and relatlimab -;as part of pre-operative treatment for patients with operable esophageal and gastroesophageal junction cancer.

Patients with gastroesophageal cancer who have successfully completed the standard treatment of chemoradiotherapy followed by surgery unfortunately often see a resurgence of the disease. Therefore, researchers are looking for new immunotherapy approaches, as well as more accurate ways to assess tumors’ response to treatment.

Immunotherapy has not yet been broadly effective for patients with gastroesophageal cancer. By testing new treatments in patients prior to surgery, we can make these powerful observations linking treatment-induced molecular changes with survival outcomes, thus accelerating the development of different immunotherapy approaches for our patients.”

Vincent Lam, M.D., senior study co-author, director of the Esophageal Cancer Research Program and an assistant professor of oncology at Johns Hopkins

The trial included 32 patients with operable esophageal or gastroesophageal junction cancer, who received nivolumab either alone or in combination with relatlimab prior to and during their standard treatment of chemotherapy and radiation. The drugs tested are both immune checkpoint inhibitors, which prevent cancer cells from dampening the body’s anti-cancer immune response. Researchers used liquid biopsies -; tests that monitor trace levels of tumor DNA shed into the bloodstream -;at different timepoints during treatment. They also measured levels of tumor-recognizing T cells and other components of tumor-specific immune responses.

About 40% of those in the nivolumab arm and 21.4% in the combination arm had a pathological complete response, meaning there was no evidence of cancer at the time of surgery. Over half of patients in both arms had a major pathological response, meaning less than 10% of cancer cells were remaining at the time of surgery.

“Historically, about two-thirds of patients treated with standard chemoradiation prior to surgery are alive after two years,” Lam says. “In our study, some 72.5% of participants had no signs of cancer and 82.6% were still living after two years. Notably, patients with undetectable ctDNA at different timepoints following immunotherapy had significantly longer cancer-free survival.”

The findings “open the door for more personalized treatment,” says lead study author Ronan Kelly, M.D., M.B.A., chief of oncology at Baylor Scott & White Health – North Texas. Kelly was at Johns Hopkins at the time of the study. “We can either de-escalate or intensify the treatment for patients who have gone through the standard protocol,” he says. “If we see ctDNA is still there, and they don’t have robust T cell response, these are the patients who may benefit most from additional treatment.”

The study adds to a growing collection of evidence showing the value of molecular readouts like ctDNA to assess response to therapy and guide future treatment plans. For example, another recent study from Anagnostou’s lab, along with a ctDNA-adaptive clinical trial led by Johns Hopkins investigators, showed that ctDNA clearance can predict the success of immunotherapy treatment in patients with advanced lung cancer.

“You can imagine that liquid biopsies may be used to capture and monitor cancer spread in the body and determine tumor regression across all types of cancers and therapies. There’s ever-growing evidence to support the use of ctDNA in the full range of the cancer care continuum,” says Anagnostou. “We think it’s the future.”

Additional study co-authors were Blair Landon, Dipika Singh, Jenna Canzoniero, Archana Balan, Russell Hales, K Ranh Voong, Richard Battafarano, Stephen Yang, Stephen Broderick, Jinny Ha, Kristen Marrone, Gavin Pereira, Nisha Rao, Aryan Borole, Katerina Karaindrou, Zineb Belcaid, James White, Suqi Ke, Eun Ji Shin, Elizabeth Thompson, Kellie Smith, Chen Hu and Josephine Feliciano of Johns Hopkins. Experts from the Allegheny Health Network Cancer Institute also contributed to the work.

The study was supported by Bristol Myers Squibb. Translational work was supported in part by the National Institutes of Health (grants CA121113, R37 CA251447), the Cancer Research Institute, Torrey Coast Foundation GEMINI CLIP Award, the Bloomberg~Kimmel Institute for Cancer Immunotherapy, the ECOG-ACRIN Thoracic Malignancies Integrated Translational Science Center grant, the Mark Foundation for Cancer Research, and the Conquer Cancer Foundation of ASCO Career Development Award.

Source:

Journal reference:

Kelly, R. J., et al. (2024). Neoadjuvant nivolumab or nivolumab plus LAG-3 inhibitor relatlimab in resectable esophageal/gastroesophageal junction cancer: a phase Ib trial and ctDNA analyses. Nature Medicine. doi.org/10.1038/s41591-024-02877-z.

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March 20, 2024
Breast Cancer Now funds researchers to investigate targeted radiotherapy for metastatic breast cancer in the brain

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Researchers are trialing a new type of targeted radiotherapy to treat secondary breast cancer tumors in the brain, thanks to new funding from Breast Cancer Now.

Image Credit: Breast Cancer Now

Secondary (or metastatic) breast cancer is when breast cancer spreads to other parts of the body. While it’s incurable, the disease can be treated, but treatments are limited when the cancer has spread to the brain.

The most common treatment is whole-brain radiotherapy, which can cause serious side effects such as hair loss, nausea, vomiting, and fatigue, because healthy brain tissue receives the same dose of radiotherapy as the cancer.

Breast Cancer Now has awarded £173,414 to Dr Matt Williams and his team at Imperial College London, who will investigate whether a type of targeted radiotherapy, called DE-iPTV VMAT, could be a more effective treatment for secondary breast cancer patients.

This type of radiotherapy targets secondary breast cancer tumors in the brain while minimizing damage to healthy tissues, which should cause fewer side effects for patients than whole-brain radiotherapy.

Everyone taking part in the clinical trial will receive this new type of radiotherapy so the researchers can assess its impact and how it affects patients’ quality of life.

The team will also collect and analyze blood samples to see if it’s possible to tell who might benefit the most from this treatment.

In addition, Dr Williams will be using national cancer data to develop a fuller picture of people whose breast cancer has spread to the brain, analyzing patients’ survival rates and use of health care services.

Currently, there is no official record of the number of people living with secondary breast cancer or of their experience with the disease. Developing a broader understanding of these patients would help scientists develop kinder, cost-effective treatments and improve women’s quality of life.

The team at Imperial hope that using this data and the results from the initial study will help them plan a larger clinical trial to test the benefits of targeted radiotherapy treatment more thoroughly.

Dr Matt Williams, Consultant Clinical Oncologist at Imperial College Healthcare NHS Trust said: “We’ve developed a way to deliver radiotherapy that increases the dose that the tumors in the brain receive, while reducing the dose to the rest of the brain.

“This targeted approach should be more effective in treating people with secondary breast cancer in the brain than whole-brain radiotherapy and have fewer side effects. But we need to see if it’s practical and works for patients.”

Over 1,000 people with breast cancer receive radiotherapy for tumors in the brain each year in the UK. Most of them could benefit from a targeted radiotherapy that reduces the radiation to healthy brain tissue, which could improve the quality of life for people affected by the disease. With an estimated 61,000 people living with incurable secondary breast cancer in the UK, we hope our research could lead to more treatment options that give people more time to live their lives to the fullest.”

Dr Simon Vincent, Director of Research, Support and Influencing, Breast Cancer Now

Scott Henniker from Birchington in Kent lost his wife, Hayley, to secondary breast cancer in 2020. Hayley was diagnosed with HER2-positive breast cancer in 2014 and despite responding well to treatment, was given the devastating news that the breast cancer had spread to her brain in 2018.

Scott says: “Hayley had an operation to remove the tumor in her brain and recovered well. She was always so positive, and you would not have known she was unwell. However, the cancer came back and for a time was kept under control by radiotherapy, but Hayley started to decline significantly from March 2020, and she sadly passed away in the August with our two kids and I beside her.”

Scott is passionate about supporting research to find more targeted treatments to treat secondary breast cancer in the brain.

Scott says: “Hayley received localized and whole brain radiotherapy and experienced all kinds of challenging side effects. We watched her gradually become a completely different person to the one we knew and loved which was heartbreaking for our family. I support any research that is looking for more targeted and effective treatments for breast cancer that has spread to the brain, so that less people lose loved ones to this dreadful disease.”

Breast Cancer Now is the research and support charity here for anyone affected by breast cancer. Call their free helpline on 0808 800 6000 to speak to their expert nurses or find out more and donate at breastcancernow.org

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March 18, 2024
Viroclinics-DDL rebrands to Cerba Research

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Viroclinics-DDL (referred to herein as Cerba Research, the Netherlands) a world leading vaccine and antiviral specialty laboratory providing research and clinical trial solutions rooted in virology, proudly announces changing its name to Cerba Research as of the 1st of April 2024. This branding step was an expected move after the Viroclinics-DDL teams had joined Cerba Research in 2022, now operating as one company well positioned in the entire value chain of research and clinical trials.

Viroclinics-DDL, with its three specialty laboratory and office locations in the Netherlands, and an extensive partner laboratory network worldwide, has been part of the Cerba Research group since early 2022. By fully entering into the Cerba Research brand now, the company underscores its collective focus and dedication to the advancement of clinical research together.

The name change of Viroclinics-DDL to Cerba Research marks a natural step forward in the company’s mission to accelerate the development of life-saving therapies and improve patient outcomes; uniquely positioning Cerba Research to offer a broader portfolio of research and clinical trial solutions spanning virology, oncology, cell & gene therapy, and beyond.

The Netherlands business unit combines the strengths and capabilities of existing specialty laboratory services with Cerba Research’s unique global footprint which includes Africa, USA, Europe, Asia Pacific, and Australia to provide end-to-end support throughout the drug development lifecycle across the globe; from pre-clinical research and biomarker discovery to clinical trial management and epidemiological studies.

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March 18, 2024
Innovative Levodopa infusion pump trial shows promise for reducing Parkinson’s symptoms

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An international, multisite phase 3 trial co-led by a University of Cincinnati researcher found Parkinson’s disease medication delivered through an infusion pump is safe and effective at reducing symptoms for longer periods of time.

These results, published March 15 in the Lancet Neurology journal, could lead to additional treatment options for patients with the condition.

Parkinson’s symptoms such as tremors, slowness and stiffness are caused by low levels of dopamine in the body. For decades, doctors have treated Parkinson’s by giving patients levodopa, the inactive substance in the brain that once converted makes dopamine.

“Levodopa is a replacement strategy. We all make levodopa, but Parkinson’s patients make less of it,” said Espay, co-principal investigator of the trial, James J. and Joan A. Gardner Family Center for Parkinson’s Disease Research Endowed Chair in UC’s Department of Neurology and Rehabilitation Medicine and a physician at the UC Gardner Neuroscience Institute.

Espay said oral levodopa is effective and typically helps people regain normal motor function, but its benefits tend to last less than a few hours after a few years, requiring increases in doses or its frequency.

Levodopa is most commonly administered orally, but this trial tested continuous, 24-hour levodopa delivery through a subcutaneous infusion pump. A total of 381 patients with Parkinson’s disease in 16 countries enrolled in the trial and were randomized to receive levodopa through the infusion pump or through traditional oral medication.

The researchers found levodopa delivered through the infusion pump was safe and led to almost two hours of day (1.72) of additional “on time,” or the time when the medication is working and symptoms are lessened, compared to taking levodopa orally.

Espay said the results of this trial pave the way for this specific infusion pump delivery system to be approved by the Food and Drug Administration and other countries’ respective governing bodies.

Once approved, this will become an important treatment strategy to consider for patients with Parkinson’s disease experiencing motor fluctuations not adequately controlled with medication. Future studies will need to determine the durability of the long-term benefits and whether any safety issues could emerge, as well as how it might compare with deep brain stimulation.”

Prof Alberto J Espay, James J and Joan A Gardner Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati

Two additional subcutaneous delivery systems are also expected to be approved this year, Espay said, and researchers are continuing to study how to improve levodopa formulations and delivery to optimize its effect for patients.

“Levodopa delivery systems are expected to continue to improve over time,” he said. “This is a thriving area of research for the benefits of our patients.”

Source:

Journal reference:

Espay, A. J., et al. (2024). Safety and efficacy of continuous subcutaneous levodopa–carbidopa infusion (ND0612) for Parkinson’s disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial. The Lancet Neurology. doi.org/10.1016/s1474-4422(24)00052-8

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March 15, 2024
Innovative CAR T cell therapy targets two proteins to combat aggressive brain tumor growth

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In a recent report published in Nature Medicine, researchers presented the initial results of recurrent glioblastoma (rGBM) patients treated with intrathecally administered, autologous, bivalent chimeric antigen receptor (CAR) T cells targeting epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2) in a phase 1 clinical trial.

Study: Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Image Credit: Gorodenkoff/Shutterstock.com

Background

Recurrent GBM is an aggressive, treatment-resistant brain cancer with no conventional therapeutic options after chemoradiotherapy. The median overall survival (OS) is less than one year, indicating that effective treatment is an urgent unmet medical need in oncology.

Despite limited therapy options, chimeric antigen receptor T cells that target GBM-specific antigens have demonstrated tolerable safety but poor effectiveness in adults.

Tumor antigen heterogeneity, intrinsic T cell malfunction, and immunosuppressive tumor microenvironments are all examples of resistance mechanisms.

About the report

In the present report, researchers describe CART-EGFR-IL13Rα2 cell efficacy and safety in treating rGBM patients recruited in an ongoing, open-label, phase 1 trial.

The researchers included six adults presenting with multifocal and progressive wild-type glioblastoma recurring after radiotherapy, excluding those who received bevacizumab within three months before trial initiation and those with localized central nervous system tumors.

They used pre-treatment immunofluorescence analysis to detect EGFR and IL13Rα2 in brain samples. The data cutoff date was February 2, 2024, with a median follow-up of 2.5 months.

Three patients received 1 × 107 cells (dose level 1), while the others received 2.5 × 107 cells (dose level 2) 17–35 days following surgery between June 14, 2023, and January 2, 2024. The primary objectives were safety, maximum tolerated dosage, dose-limiting toxicity (DLT), and adverse events.

Secondary objectives included the proportion of treated patients, manufacturing failures, objective response rate (ORR), response length, overall survival (OS), and progression-free survival (PFS).

The team obtained brain magnetic resonance imaging (MRI) images 24 to 48 hours after CAR T therapy, four weeks later, and monthly afterward.

They collected cerebrospinal fluid (CSF) at baseline and on day one, day four, day seven, day 10, day 14, day 21, and day 28 for pharmacokinetic evaluation by quantitative polymerase chain reaction (qPCR).

They rated cytokine release syndrome (CRS) according to the American Society for Transplantation and Cellular Therapy (ASTCT) guidelines and neurotoxicity using the immune effector-associated neurotoxicity syndrome (ICANS) criteria.

They assessed treatment response using the Modified Response Assessment in Neuro-Oncology (mRANO) standards.

Results

The use of CART-EGFR-IL13Rα2 cells in cancer patients was associated with early-onset neurotoxicity, perhaps ICANS. All six patients showed reduced tumor size and enhancement, but none satisfied the ORR criteria. The researchers identified CAR T cell abundance and cytokine release in all patients and all developed neurotoxicity.

Patient 1 was diagnosed with grade 2 neurotoxicity following CAR treatment, resulting in disorientation, nausea, and aphasia. Anakinra and dexamethasone improved his neurological condition.

The researchers surgically removed a tumor nodule, revealing therapy-related alterations and uncommon glial cells. After two months, the disease progressed, for which the patient received bevacizumab and continues to remain alive with an eight-month OS.

Patient 2 had rapid tumor development and facial paralysis, which indicated grade 3 neurotoxicity. The team administered anakinra and dexamethasone as treatments. On day two, the tumor mass decreased without intervention, showing pseudo-progression. The patient developed hydrocephalus symptoms, denied shunting, and died five months after receiving CAR T cell therapy.

Patient 3, presenting with deteriorating leptomeningeal illness and decreased performance, developed grade 3 neurotoxicity and received anakinra and dexamethasone treatment.

Despite fluctuations in orientation and alertness, the patient recovered on day four, reverted to his pre-treatment neurological baseline within a week, and continues to have stable disease.

Patient 4 experienced significant neurotoxicity and received dexamethasone, anakinra, and tocilizumab, resulting in a better mental state and a restoration to the pre-treatment neurological baseline. Patient 4’s enhancement foci and periventricular nodules were decreased at treatment level 2.0 and remained stable.

Patient 5 developed multifocal tumor progression and grade 2 CAR neurotoxicity, which improved to grade 1 on the third day. He developed increased weariness, physical weakness, and anorexia. The tumor burden decreased dramatically following a doubling of dexamethasone dosage.

However, the patient returned with more lethargy, fatigue, and inadequate oral intake. On day 28, raising the steroid dosage reduced the severity of multifocal irregular enhancement.

Following a CAR T cellular injection, Patient 6 had tumor development in the left midbrain and severe right-sided hemiparesis. He experienced deteriorating aphasia and increased right-sided weakness, resulting in total hemiplegia.

Despite treatment with dexamethasone and anakinra, extensive hemiparesis remained. He got bevacizumab intravenously as part of his therapy.

The first-in-human data demonstrates the safety and bioactivity of CART-EGFR-IL13Rα2 treatment in individuals with multifocal, treatment-resistant rGBM.

The therapy decreased tumor size and enhancement but resulted in early-onset acute neurotoxicity, controllable at both dosages. The findings require confirmation with larger sample sizes and longer follow-ups.

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March 15, 2024
Novel dual-target CAR T cell therapy shows promise in treating recurrent glioblastoma

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Targeting two brain tumor-associated proteins-; rather than one-; with CAR T cell therapy shows promise as a strategy for reducing solid tumor growth in patients with recurrent glioblastoma (GBM), an aggressive form of brain cancer, according to early results from the first six patients treated in an ongoing Phase I clinical trial led by researchers from the Perelman School of Medicine at the University of Pennsylvania and Penn Medicine’s Abramson Cancer Center. The findings, published today in Nature Medicine, suggest that this “dual-target” approach is an encouraging step toward developing effective, long-lasting therapies for solid tumors like GBM.

This is the first time CAR T cell therapy with two targets, rather than just one, has been administered to patients with glioblastoma. Our results suggest that this is a step in the right direction, and this method, when delivered through a patient’s spinal fluid, could be the key to developing therapies that outsmart the complicated defense systems of GBM.”

Stephen Bagley, MD, MSCE, assistant professor of Hematology-Oncology, and Neurosurgery, and principal investigator in the clinical trial

GBM is the most common-;and most aggressive-;type of cancerous brain tumor in adults. Individuals with GBM usually expect to live 12-18 months following their diagnosis. Despite decades of research, there is no known cure for GBM, and approved treatments-;such as surgery, radiation, and chemotherapy-;have limited effect in prolonging an individual’s life expectancy. However, even after aggressive treatment, GBM returns in most patients, which is known as recurrent GBM. The median survival rate for recurrent GBM is less than one year.

CAR T cell therapy uses a patient’s own immune system to fight cancer; a patient’s T cells-;the white blood cells that find and fight illness and infection in the body-;are removed, re-programmed to recognize proteins, or antigens, characteristic of a specific type of cancer, and then returned to the body, where they seek out and destroy these cancer cells. CAR T cell therapy is FDA approved to fight a number of blood cancers, like leukemia, but researchers have struggled to engineer cells to successfully seek out and kill solid tumors, which make up the vast majority of cancer types, including GBM.

“The challenge with GBM and other solid tumors is tumor heterogeneity, meaning not all cells within a GBM tumor are the same or have the same antigen that a CAR T cell is engineered to attack, and every person’s GBM is unique to them, so a treatment that works for one patient might not be as effective for another,” said Bagley. “What’s more, GBM tumors can evade a patient’s immune system, and block immune cells-;both engineered CAR T cells, and a patient’s own immune cells-;that might otherwise fight the tumor. Our challenge is getting our treatment around the tumor’s defenses so we can kill it.”

In this trial, researchers used a technology developed in the lab of Donald M. O’Rourke, MD, the John Templeton, Jr., MD Professor in Neurosurgery and director of the Glioblastoma Translational Center of Excellence at the Abramson Cancer Center, and scientific advisor to the trial. This technique delivers CAR T cells targeting two proteins commonly found in brain tumors: epidermal growth factor receptor (EGFR), which is estimated to be present in 60 percent of all GBMs, and interleukin-13 receptor alpha 2 (IL13Rα2), which is expressed in over 75 percent of GBMs. While CAR T cell therapy for blood cancers is typically delivered through an IV, researchers administered these dual-target CAR T cells intrathecally, through an injection into the cerebrospinal fluid, so that the engineered cells could reach the tumors more directly in the brain.

MRI scans 24 to 48 hours after dual-target CAR T cells targeting EGFR and IL13Rα2 that were administered revealed reduced tumor sizes in all six patients, and these reductions have been sustained out to several months later in a subset of patients.

“We are energized by these results, and are eager to continue our trial, which will give us a better understanding of how this dual-target CAR T cell therapy affects a wider range of individuals with recurrent GBM,” said

O’Rourke. “This cancer is unique in each individual, so a wider range of patients will help us determine the optimal dose, better understand effects like neurotoxicity, and more firmly establish efficacy.”

A major concern with CAR T cell therapy, especially when delivered to the brain, is neurotoxicity, which occurs when a toxic substance alters the activity of the nervous system, and can disrupt or kill brain cells, called neurons. The researchers report that in all six patients treated with CAR T cell therapy in this trial, neurotoxicity was substantial but manageable.

Source:

University of Pennsylvania School of Medicine

Journal reference:

Bagley, S. J., et al. (2024). Intrathecal bivalent CAR T cells targeting EGFR and IL13Rα2 in recurrent glioblastoma: phase 1 trial interim results. Nature Medicine. doi.org/10.1038/s41591-024-02893-z.

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March 13, 2024