Medical Bulletin 16/ September/ 2024 - Video

Interim data from the Phase I dose escalation part of the mRNA cancer immunotherapy (mRNA-4359), show promise in patients with advanced solid cancers.

Results from the Phase I trial were presented at the European Society of Medical Oncology conference in Barcelona.

The investigational mRNA cancer immunotherapy is targeted for patients with lung cancer, melanoma and other solid tumours. Nineteen patients with advanced stage cancers received between one and nine doses of the immunotherapy treatment. Scientists have found the immunotherapy created an immune response against cancer and was well tolerated, with adverse events including fatigue, injection site pain and fever.

Eight out of sixteen patients who could have their responses evaluated were able to demonstrate their tumour size did not grow and no new tumours appeared.

Data also showed the mRNA immunotherapy could activate the immune system in many patients, generating immune cells in the blood that could recognise the two proteins of interest (PD-L1 and IDO1). Researchers were able to show in some patients that the immunotherapy can increase levels of important immune cells that can kill cancer cells as well as reduced levels of other immune cells that can prevent the immune system from fighting cancer.

The UK’s Chief Investigator of the trial Dr Debashis Sarker, a Clinical Reader in Experimental Oncology at King’s College London and a consultant in medical oncology at Guy’s and St Thomas’ NHS Foundation Trust, said: “This study evaluating an mRNA cancer immunotherapy is an important first step in hopefully developing a new treatment for patients with advanced cancers.

“We have shown that the therapy is well tolerated without serious side effects and can stimulate the body’s immune system in a way that could help to treat cancer more effectively. However, as this study has only involved a small number of patients to date, it’s too early to say how effective this could be for people with advanced stage cancer.”

Reference: mRNA cancer immunotherapy Phase I trial presented on Saturday, 14th September at the European Society of Medical Oncology conference in Barcelona. https://www.kcl.ac.uk/news/mrna-cancer-vaccine-potential-advanced-stage-cancer-patients-in-phase-1-trial

As society ages, the number of patients with heart failure is rapidly increasing. A group from the Nagoya University Graduate School of Medicine in Japan has found an enzyme protein kinase N (PKN) that regulates heart fibrosis. The enzyme catalyses the conversion of heart fibroblasts to myofibroblasts, which threatens the integrity of the heart. Deleting this enzyme reduced cardiac dysfunction, indicating the potential of anti-PKN treatments as a promising therapeutic for protecting patients against heart failure. The study was published in Nature Communications.

The enzyme protein kinase N (PKN) has been implicated in a signaling cascade that causes heart fibroblast activation. A group of researchers in the Department of Cardiology at the Nagoya University Graduate School of Medicine suspected the involvement of protein kinase N (PKN) in the changes of fibroblasts to myofibroblasts seen in fibrosis. jl

In mammal cells, there are three forms of protein kinase N (PKN): protein kinase N 1, 2, and 3. Using RNA-sequencing data, they identified protein kinase N 1 and 2 in heart fibroblasts. The study used mice raised without protein kinase N 1 and 2. It found that although heart function remained unaffected, there was a notable decrease in actin and collagen expression in the myocardial infarction and heart failure model. These proteins are essential components responsible for the tissue buildup observed in fibrosis. They also found that mice with suppressed protein kinase N 1 and 2 did not show conversion of fibroblasts to myofibroblasts.

“Although our study was done in a mouse model, protein kinase N (PKN) expression has been demonstrated in human heart fibroblasts, so similar results are expected in human trials,” said Dr. Satoya Yoshida, who co-led the study. “In fact, almost all heart diseases are closely related to heart fibrosis. I believe our findings contribute to improving the prognosis of many heart diseases, especially heart failure.”

Reference: Yoshida, S., Yoshida, T., Inukai, K. et al. Protein kinase N promotes cardiac fibrosis in heart failure by fibroblast-to-myofibroblast conversion. Nat Commun 15, 7638 (2024). https://doi.org/10.1038/s41467-024-52068-0

A Cleveland Clinic study identified key factors that can impact the long-term weight loss of patients with obesity who were prescribed injectable semaglutide or liraglutide (glucagon-like peptide-1 receptor agonists, or GLP-1 RA medications) for the treatment of type 2 diabetes or obesity. The study was published in JAMA Network Open.

“In patients with obesity who were prescribed semaglutide or liraglutide, we found that long-term weight reduction varied significantly based on the medication’s active agent, treatment indication, dosage and persistence with the medication,” said Hamlet Gasoyan, Ph.D., lead author of the study and a researcher with Cleveland Clinic’s Center for Value-Based Care Research.

This retrospective cohort study included 3,389 adult patients with obesity who initiated treatment with injectable semaglutide or liraglutide between July 1, 2015, and June 30, 2022. Follow-up ended in July 2023.

At the start of the study, the median baseline body mass index among study participants was 38.5; 82.2% had type 2 diabetes as treatment indication. Among the patients, 68.5% were white, 20.3% were Black, and 7.0% were Hispanic. More than half of the participants were female (54.7%). Most of the patients received treatment for type 2 diabetes. Overall, 39.6% were prescribed semaglutide for type 2 diabetes, 42.6% liraglutide for type 2 diabetes, 11.1% semaglutide for obesity, and 6.7% liraglutide for obesity.

Results show that one year after the initial prescription’s fill, weight change was associated with the following factors:

The medication’s active agent. On average, weight change was -5.1% with semaglutide versus -2.2% with liraglutide.

The dosage. Patients experienced -3.5% mean weight change with low maintenance dose versus -6.6% with high dose.

Treatment indication. Patients who received the medications for type 2 diabetes experienced -3.2% in mean weight change compared to -5.9% for obesity treatment.

Persistence with medication. On average, patients who were persistent with the medication at one year experienced -5.5% weight change versus -2.8% among patients who had 90-275 medication coverage days within the first year and -1.8% among those with less than 90 covered days.

Overall, 37.4% of patients receiving semaglutide for obesity achieved 10% or more body weight reduction compared to 16.6% of patients receiving semaglutide for type 2 diabetes. In comparison, 14.5% of those receiving liraglutide for obesity achieved 10% or more body weight reduction versus 9.3% of those receiving liraglutide for type 2 diabetes.

Among patients who persisted with their medication one year after their initial prescriptions, the proportion who achieved 10% or more weight reduction was 61% with semaglutide for obesity, 23.1% with semaglutide for type 2 diabetes, 28.6% with liraglutide for obesity, and 12.3% with liraglutide for type 2 diabetes.

Based on the study’s multivariable analysis that accounted for relevant socio-demographic and clinical variables, the following factors were associated with higher odds of achieving 10% or more weight reduction one year after the initial prescriptions:

Patients who received semaglutide versus liraglutide

A high maintenance dose of the medication versus low

Obesity as a treatment indication versus type 2 diabetes

Patients who persisted with the medication within the first year or had between 90-275 days of medication coverage versus less than 90 days of medication coverage

Patients who had higher initial BMI

Patients who were female versus male

“Our findings could help inform patients and providers regarding some of the key factors that are associated with the probability of achieving sustained weight loss of a magnitude large enough to provide clinically significant health benefits,” said Dr. Gasoyan. “Having real-world data could help manage expectations regarding weight reduction with GLP-1 RA medications and reinforce that persistence is key to achieve meaningful results.”

Reference: Gasoyan H, Pfoh ER, Schulte R, Le P, Butsch WS, Rothberg MB. One-Year Weight Reduction With Semaglutide or Liraglutide in Clinical Practice. JAMA Netw Open. 2024;7(9):e2433326. doi:10.1001/jamanetworkopen.2024.33326