决定异体 CAR T 细胞排斥与扩增的细胞和分子机制
Cellular and molecular mechanisms determining allogeneic CAR T cell rejection and expansion.
我们评估了11例接受单一批次cemacabtagene ansegedleucel(cema-cel)治疗的大B细胞淋巴瘤患者,cemacabtagene ansegedleucel是一种异体抗CD19 CAR T产品。
英文原题:Developments in pancreatic cancer emerging therapies, diagnostic methods, and epidemiology.
尽管在分子机制理解方面有所进步,治疗上也有所创新,但总生存期仍然极差:不足 9% 的患者生存超过 5 年。
胰腺癌仍是致死率最高的恶性肿瘤之一,其特征包括诊断时已至晚期、生物学行为侵袭性强及对传统治疗耐药显著。尽管对分子机制的认识和治疗技术有所进步,总生存率仍极低:不足9%的患者生存超过5年。由于化疗耐药、快速转移和有效免疫治疗选择有限,预计到2030年胰腺癌(PC)将成为美国癌症相关死亡的第二大原因。本综述介绍该领域当前进展,包括流行病学、危险因素、诊断工具和新兴生物标志物。近期基因和分子谱分析为认识胰腺癌提供了重要信息,已鉴定出KRAS、TP53、CDKN2A和SMAD4等在疾病驱动中发挥重要作用的关键基因突变。这些发现推动了针对相关突变的新型靶向治疗探索。与此同时,纳入循环肿瘤细胞、循环肿瘤DNA和外泌体的液体活检技术取得进展,在早期诊断、监测治疗应答和检测微小残留病方面前景显著,有望彻底改变PC管理。晚期PC治疗选择仍极其有限,手术是唯一潜在治愈方法,但仅10%–15%的患者在诊断时可能接受切除。研究者正在探索新方法,帮助更多患者获得手术资格,包括术前化疗和放疗以缩小肿瘤。FOLFIRINOX(含5-氟尿嘧啶、亚叶酸、伊立替康和奥沙利铂)等新化疗方案改善了部分患者的结局,但仍可能引起显著副作用。免疫疗法虽已革新其他癌症的治疗,但由于PC免疫抑制性肿瘤微环境,其治疗PC的成功有限。研究者正在探索将免疫检查点抑制剂与化疗、放疗及靶向周围组织的药物联合,以增强机体免疫应答。采用CAR-T细胞和TIL等过继细胞疗法进行个体化治疗也令人兴奋,早期试验显示潜在疗效。研究者还尝试应对PC致密的促结缔组织增生间质。迄今,实验室研究显示,能够对抗耐药或改变肿瘤环境、阻止周围组织改变并改善药物递送的新药具有一定潜力。研究者也在开发纳米颗粒药物递送系统,以提高化疗药物生物利用度和靶向递送。
Pancreatic cancer is still one of the deadliest malignancies, characterised by late-stage diagnosis, aggressive biology, and considerable resistance to conventional treatments. Despite improvements in understanding the molecular mechanisms and innovations in treatment, the overall survival remains abysmal: fewer than 9 % of patients survive beyond 5 years. By 2030, PC is predicted to become the second leading cause of cancer-related deaths in the U.S. owing to chemoresistance, rapid metastatic spread, and limited effective immunotherapeutic choices. This review highlights current progress in this field, including epidemiology, risk factors, diagnostic tools, and emerging biomarkers. Recent progress in genetic and molecular profiling has provided important information about pancreatic cancer. It has identified key mutations in genes like KRAS, TP53, CDKN2A, and SMAD4 that play a major role in driving the disease. Such revelations have provided the impetus to explore novel targeted therapies against these mutations. Furthermore, the advances in liquid biopsies incorporating circulating tumour cells, circulating tumour DNA, and exosomes hold substantial promise for early diagnosis, treatment response monitoring, and detection of minimal residual disease-any of which could radically transform PC management. While very limited options for the treatment of advanced-stage PC remain, the only potential curative treatment is surgery, yet only 10-15 % of patients are diagnosed with potentially resectable disease. Researchers are looking into new methods to help more patients qualify for surgery. This involves using chemotherapy and radiotherapy to reduce the size of the tumor before the operation. New chemotherapy treatments like FOLFIRINOX (which includes 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin) have improved results for some patients, but they can still cause significant side effects. Immunotherapy, though revolutionary in other cancers, has had limited success in PC due to the tumour's immunosuppressive microenvironment. Researchers are looking into using immune checkpoint inhibitors together with chemotherapy, radiation, and drugs that target the surrounding tissue to improve the body's immune response. There is also considerable excitement surrounding personalised approaches with adoptive cell therapies such as CAR-T cells and TILs, which are trialled with early evidence of potential efficacy. Attempts are also being made to address the dense desmoplastic stroma of the tumour that characterises PC. Drugs that can fight resistance or new medicines that might affect the tumor environment, stop changes in surrounding tissues, and improve how drugs are delivered have shown some potential in laboratory tests so far. Nanoparticle-based drug delivery systems are also being developed to improve the bioavailability and targeted delivery of chemotherapy.
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