?? This week's edition of Xpeer's Medical News!

This week’s edition comes with groundbreaking research in the microbiota field and the potential implications of long-term ADHD medication. Moreover, in case you missed it, we are breaking down the most recent FDA warning concerning CAR-T immunotherapies:

1?? FDA Investigating T-Cell Malignancy Risk in CAR-T Immunotherapy

The FDA is currently investigating a concerning risk of T-cell malignancies following immunotherapy with autologous CAR-T cells targeting BCMA or CD19. Incidences of T-cell malignancies have been observed in patients treated with various agents, which include FDA-approved:

• Idecabtagene vicleucel
• Lisocabtagene maraleucel
• Ciltacabtagene autoleucel
• Tisagenlecleucel
• Brexucabtagene autoleucel
• Axicabtagene ciloleucel

? Here's what you need to know:

• Understanding the Potential Risk:

While the overall benefits of approved BCMA-directed and CD19-directed CAR T cell immunotherapies continue to outweigh potential risks (incidence stands at 0.07%, with 12 cases out of more than 20.000 patients), the FDA is currently investigating this adverse effect. The identified risk of T cell malignancy could lead to severe outcomes, including hospitalization and death. This potential risk of developing secondary malignancies was long known since CAR-T cells are engineered using integrating vectors (lentiviral or retroviral) which integrate into the core DNA of lymphocytes almost randomly. Thus, potential insertions could deregulate oncogenes.

• Approach for safety

To mitigate this risk and swiftly halt the malignant proliferation of T-cells, CAR-Ts with "suicide genes" are under development. These genes, inserted into CAR-T cells, can be activated to selectively eliminate these cells in case of adverse effects. Non-viral gene editing methods are also being explored to minimize risks. To comprehensively assess long-term safety and the risk of secondary malignancies post-treatment, mandatory observational safety studies over 15 years are underway.

2?? Maternal microbiota communicates with the fetus through microbiota-derived extracellular vesicles

In a recent study published in the Microbiome journal, researchers Kaisanlahti and collaborators unravel the dynamics of gut microbial communities within the fetal environment. To investigate the presence of bacterial extracellular vesicles during healthy pregnancies and whether these can reach the fetus, they uncovered that extracellular vesicles from the maternal microbiota act as messengers linking the maternal microbiota and the fetus. This communication may play a crucial role in preparing the fetal immune system for the colonization of the gut after birth.

? Here are their key discoveries:

• Bacterial extracellular vesicles were identified in the amniotic fluid of healthy pregnant women. These vesicles closely resembled those found in the mother's gut bacteria. In mice, researchers observed that extracellular vesicles originating from the maternal gut microbiota made their way into the space surrounding the developing fetus. ? Dynamic changes in microbial composition over time were observed, highlighting the temporal variability inherent in the gut microbiome. The study explores how external factors, such as diet and environmental exposures, play a pivotal role in shaping the gut microbiome landscape.
• The research sheds light on the vast diversity within the gut microbiome, showcasing the presence of numerous bacterial species with unique roles and functions. Most intriguingly, the researchers identified individualized microbial fingerprints, emphasizing the uniqueness of each person's gut microbiome.
• Understanding the dynamics of the gut microbiome opens doors to personalized health interventions. Tailoring treatments based on an individual's unique microbial profile could revolutionize approaches to digestive disorders, metabolic conditions, and overall well-being.

3?? Long-term ADHD Medication Use associated with increased cardiovascular disease

In a recent investigation featured on JAMA Psychiatry, researchers have delved into the realm of Attention-Deficit/Hyperactivity Disorder (ADHD) treatment and its potential association with cardiovascular diseases. Previous meta-analyses of randomized clinical trials indicated increased heart rate and blood pressure associated with ADHD medications. This comprehensive study, focusing on the long-term impact of ADHD medications, involved 278,027 individuals aged 6 to 64 with ADHD. The findings emphasize the need for prolonged monitoring of cardiovascular health in individuals with ADHD undergoing medication.

? Key findings:

• The incidence rate of cardiovascular disease was determined to be 7.34 per 1000 person-years. The research, examining 10,388 cases with CVD and 51,672 matched controls, revealed elevated rates of CVD in those with ADHD. The cases were identified based on recorded diagnoses of various CVD types, including ischemic heart diseases, cerebrovascular diseases, hypertension, heart failure, arrhythmias, thromboembolic disease, arterial disease, and other forms of heart disease. ? This found that the stimulant methylphenidate posed a 20% increased risk of CVD for 3 to 5-year users and 19% for over 5-year users.
• Lisdexamfetamine showed a 23% elevated CVD risk for 2 to 3 years and 17% for over 3 years. Non-stimulant atomoxetine exhibited a significant association with CVD only during the first year of use, showing a 7% increased risk.
• ADHD, characterized by inattentiveness, impulsivity, and hyperactivity, is commonly treated with stimulants, impacting neurotransmitter levels. Atomoxetine, a non-stimulant, acts on norepinephrine reuptake. While effective for some, its success rate is lower compared to stimulants. Non-stimulants, sometimes tricyclic antidepressants, are associated with heart arrhythmias and off-target side effects.

In case you missed them

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Sources and read more:

1. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous
2. Source: Kaisanlahti, A., Turunen, J., Byts, N., Samoylenko, A., Bart, G., Virtanen, N., ... & Reunanen, J. (2023). Maternal microbiota communicates with the fetus through microbiota-derived extracellular vesicles. Microbiome, https://microbiomejournal.biomedcentral.com/articles/10.1186/s40168-023-01694-9
3. Zhang, L., Li, L., Andell, P., Garcia-Argibay, M., Quinn, P. D., D’Onofrio, B. M., ... & Chang, Z. (2023). Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases. JAMA psychiatry. (https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2811812)
4. Cortese, S., & Fava, C. (2023). Long-Term Cardiovascular Effects of Medications for Attention-Deficit/Hyperactivity Disorder—Balancing Benefits and Risks of Treatment. JAMA psychiatry. (https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2811813)

| By: Blanca de Alarcón (2023)