DNA-Dependent Protein Kinase Inhibitors PI-103 and Samotolisib Augment CRISPR/Cas9 Knock-in Efficiency in Human T Cells

Cytotherapy, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

---

In-depth analysis of the safety of CAR-T cell therapy for solid tumors

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: Feb. 24, 2025

In recent years, the rapid progress in oncology, immunology, and molecular biology has dramatically advanced cancer immunotherapy, particularly CAR-T cell therapy. This innovative approach involves engineering a patient's T cells to express receptors that specifically target tumor antigens, enhancing their ability identify eliminate cells. However, effectiveness of therapy solid tumors is often hampered by challenging microenvironment (TME). The complex TME includes dense stroma obstructs infiltration, abnormal blood vessel structures leading hypoxia, an acidic pH, all which hinder function. Additionally, presence immunosuppressive factors reduces efficacy cells, making successful targeting more difficult. safety gained interest, especially shown considerable various cancers, with notable results multiple myeloma hepatocellular carcinoma, among others. Nonetheless, associated several adverse reactions primarily driven heightened levels proinflammatory cytokines. These include cytokine release syndrome (CRS), neurotoxicity (CANS), organ toxicity, serious complications. CRS, characterized systemic inflammation due release, can escalate severe dysfunction. It typically occurs within first week post-infusion, correlating expansion presents fever hypotension. Meanwhile, CANS encompasses neurological issues ranging from mild symptoms seizures, possibly exacerbated CRS. Organ toxicity also arise therapy, potential damage affecting gastrointestinal tract, kidneys, liver, lungs, tied shared antigens found both healthy tissues. Moreover, long-term effects like cytokine-associated hematotoxicity (CAHT) secondary malignancies represent significant concerns could affect quality life post-treatment. challenges treating underscore need for ongoing research. Strategies improve efficacy, minimize reactions, enhance patient are critical. Future explorations designing better navigate TME, identifying specific antigen profiles off-target damage, developing adjunct therapies mitigate cytokine-related toxicity. Continued monitoring will be paramount improving outcomes maintaining life. Overall, while holds great promise, it must administered careful consideration side rigorous management strategies ensure treatment efficacy.

Language: Английский

---

Safe CAR-T: shedding light on CAR-related T-cell malignancies

EMBO Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 28, 2025

As of September 30, 2023, the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database has received 12 reports secondary T-cell malignancies since first BCMA-/CD19-targeted autologous CAR-T therapies was approved in 2017 (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). Consequently, FDA released a statement on November 28, announcing their ongoing investigation into identified risk malignancy, which been associated with severe outcomes such as hospitalization death. On April 18, 2024, mandated inclusion boxed warning for following treatment BCMA-/CD19-directed cell immunotherapies. In this commentary, we have thoroughly elucidated possible mechanisms underlying theoretical tumorigenesis induced by current viral vectors. Furthermore, primarily proposed safer genetic engineering strategies cells, underscored necessity introducing more sensitive reliable safety evaluation indicators, T receptor (TCR) diversity integration site analysis.

Language: Английский

---

Current landscape of vector safety and genotoxicity after hematopoietic stem or immune cell gene therapy

Leukemia, Journal Year: 2025, Volume and Issue: unknown

Published: April 8, 2025

Abstract Malignant transformation of gene modified haematopoietic stem cells caused anxiety following adverse events in early clinical trials using gamma-retroviral vectors (γRV) to correct (HSC) monogenic immune disorders. Adoption HIV-derived lentiviral (LV) with SIN (self-inactivating) configurations greatly reduced risks and subsequently hundreds patients have been dosed HSC therapy for blood, metabolic conditions. Nevertheless, as experience builds, it’s now well recognised that vector integration can drive clonal expansions these may carry long term safety risks. Documented cases haematological malignancy after SIN-LV recently emerged, particular where heterologous retroviral promoters were employed there are concerns around certain insulator elements other possible contributors expansions. Similarly, tens thousands subjects received engineered T cell products, longstanding dogma mature cannot be transformed is being questioned, reports a small number malignant wider secondary malignancies some groups patients. We summarize current information revisit genotoxicity ex-vivo modification cells.

Language: Английский

---

Less frequent complications following CAR T-cell therapies: hemophagocytic lymphohistiocytosis, graft-versus-host disease, thrombotic microangiopathy, coagulation disorders and secondary malignancies: best practice recommendations from the EBMT Practice Harmonization and Guidelines Committee

Bone Marrow Transplantation, Journal Year: 2025, Volume and Issue: unknown

Published: April 9, 2025

Language: Английский

---

Chimeric antigen receptor NK cells for breast cancer immunotherapy

Cancer Treatment Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102943 - 102943

Published: April 1, 2025

Language: Английский

---