预约演示

更新于：2025-03-20

Folinic Acid

亚叶酸

更新于：2025-03-20

概要

基本信息

药物类型

小分子化药

别名

(5-formyl-5,6,7,8-tetrahydropteroyl)glutamate、10-Formyl-7,8-dihydrofolic acid、5-Formyl-5,6,7,8-tetrahydrofolic acid

+ [12]

靶点

TYMS

作用方式

抑制剂

作用机制

TYMS抑制剂(胸苷酸合成酶抑制剂)

治疗领域

肿瘤消化系统疾病

在研适应症

结直肠癌

非在研适应症-

原研机构-

在研机构-

非在研机构-

最高研发阶段批准上市

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构/序列

分子式C20H23N7O7

InChIKeyVVIAGPKUTFNRDU-ABLWVSNPSA-N

CAS号58-05-9

关联

516

项与亚叶酸相关的临床试验

NCT06783491

/ Not yet recruiting临床3期IIT

Efficacy of the Use of Neoadjuvant With/without Hyperthermic Intraperitoneal Chemotherapy in the Treatment of Locally Advanced Colon Cancer: a Phase III Multi-arm, Randomized and Controlled Clinical Trial (FOXHIPECT4)

The main objective of this randomized and controlled trial is to determine whether the use of a proactive strategy, systemic neoadjuvant treatment (FOLFOX) with or without hyperthermic intraperitoneal chemoterapy (HIPEC) with mitomycin C followed by postoperative systemic adjuvant treatment, increases disease-free survival at 36 months in patients with locally advanced colon cancer compared to standard treatment. Therefore, a phase III, randomized, academic, multicenter, controlled trial will be conducted. Patients with locally advanced colon adenocarcinoma (cT4, cT3 with invasion >5mm) Nx and no metastases will be included. Control group (n=361) will receive standard treatment (surgery and adjuvant chemotherapy FOLFOX x 12 based); Experimental group 1 (n=361) = Neoadjuvant chemotherapy (FOLFOX x6) + surgery (associating HIPEC) and FOLFOX x 6; Experimental group 2 (n=361): Neoadjuvant chemotherapy (FOLFOX x6) + surgery and FOLFOX x 6. Randomization will be 1:1:1, stratified and centralized. The primary outcome will be disease-free survival at 36 months. Secondary outcomes will be tumor regression rate, ctDNA negativization, peritoneal relapse rate at 36 months, pattern of relapse, toxicity, morbidity and overall survival. Considering the results obtained with these two independent strategies (FOLFOX and HIPEC), a new trial is justified in order to provide strong evidence for this proactive treatment. The aim is to combine both to obtain a better benefit, which opens the direct possibility of increasing the current percentage of disease-free survival. The results of this study will have important scientific and social impact, since is aimed at improving the outcomes of one subpopulation of patients with locally advanced colon cancer whose current treatment, is not enough to avoid the recurrence of disease.

开始日期2025-06-01

申办/合作机构

Maimonides Institute for Biomedical Research of Cordoba

NCT06820463

/ Recruiting临床2期

A Phase 2, Open-Label, Randomized, Master Protocol Study to Evaluate Safety and Efficacy of Multiple Treatment Combinations With Telisotuzumab Adizutecan in Subjects With Metastatic Colorectal Cancer

CRC is the third most common type of cancer diagnosed worldwide with developed countries at highest risk. The purpose of this study is to assess adverse events and change in disease activity when telisotuzumab adizutecan is given in combination with oxaliplatin, fluorouracil (5FU), leucovorin (LV) (FOLFOX), and bevacizumab or panitumumab.
Telisotuzumab adizutecan is an investigational drug being developed for the treatment of mCRC. Fluorouracil and leucovorin are drugs approved for the treatment of mCRC. This study will be divided into two stages, with the first stage treating participants with increasing doses of telisotuzumab adizutecan with FOLFOX and bevacizumab or 5FU/LV and panitumumab until the dose reached is tolerable and expected to be efficacious. Participants will then be randomized into 3 groups called treatment arms where one group will receive one of two optimized doses of telisotuzumab adizutecan from the dose escalation phase with FOLFOX and bevacizumab or 5FU/LV and panitumumab, or a comparator of FOLFOX and bevacizumab or panitumumab. Approximately 390 adult participants with mCRC will be enrolled in the study in 100 sites worldwide.
In the dose escalation stage participants will be treated with increasing intravenous (IV) doses of telisotuzumab adizutecan with FOLFOX and bevacizumab or 5FU/LV and panitumumab until the dose reached is tolerable and expected to be efficacious. In the dose optimization stage participants will be receive FOLFOX or receive 5FU/LV, but with one of two optimized doses of telisotuzumab adizutecan, or a comparator of FOLFOX and bevacizumab/pantitumumab. The study will run for a duration of approximately 6 years.
There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, questionnaires and side effects.

开始日期2025-03-26

申办/合作机构

AbbVie, Inc.

NCT05870800

/ Recruiting临床2期IIT

Phase II Open-label Trial of Neoadjuvant Immunotherapy (Atezolizumab) in Combination With CAPOX for Resectable Non-metastatic Proficient Mismatch Repair (pMMR) Colon CancER: NICER Study

This is a Phase II open-label trial of neoadjuvant immunochemotherapy with Atezolizumab and CAPOX followed by surgery and potentially adjuvant chemotherapy for patients with localized resectable pMMR adenocarcinoma of the colon with a target accrual of 28 patients. The investigators will explore if appropriately timed neoadjuvant CAPOX with anti-PD-L1 mAb (Atezolizumab) can be administered safely and feasibly, and that this combination will lead to improved clinical response associated with enhanced numbers of immune cells in surgically resected colon tumors. Patients will receive 4 cycles of atezolizumab in combination with 4 cycles of CAPOX (atezolizumab will be administered prior to chemotherapy) before standard of care surgical resection. Following surgery, patients still considered to be at high-risk of recurrence (per SOC guidelines) will receive further adjuvant chemotherapy (mFOLFOX6 or CAPOX), based on the discretion of the treating oncologist/investigator. Circulating tumor DNA (ctDNA) dynamic change status will be analyzed through collection of blood samples throughout different stages of the patient's neoadjuvant treatment regimen (baseline, pre-neoadjuvant therapy, mid-neoadjuvant, post-neoadjuvant therapy, and during postoperative period) as a marker of early read on efficacy.
The end of the study for each patient enrolled will be at the 6 month postoperative visit.
On Study Protocol: Patients will be followed up for an efficacy follow-up phase during the first 6 months after surgery (week 2 & months 3, 6 visits). All assessments beyond the 6 month visit will be performed under standard of care surveillance office visits.
Off Study Protocol: Thereafter they will enter a survival follow-up phase per standard of care protocols. Patients will be seen every 6 months starting at month 12 until month 36. All collection of research-specific assessments including whole blood, stool collection and quality of life questionnaires will be optional beyond the 6 month postop visit (months 12-36).

开始日期2025-02-01

申办/合作机构

Baylor College of Medicine

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100 项与亚叶酸相关的临床结果

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100 项与亚叶酸相关的转化医学

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100 项与亚叶酸相关的专利（医药）

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9,679

项与亚叶酸相关的文献（医药）

2025-04-01·Talanta

Magnetic separation-assisted DNAzyme walker-based nanosensor for point-of-care therapeutic drug monitoring of methotrexate

Article

作者: Liu, Xiaoting ; Shao, Wenqing ; Zhou, Yi

Methotrexate (MTX) is a widely used antimetabolite drug, mainly used in the treatment of a variety of cancer. Given the low therapeutic index and significant individual variability of MTX, it was critical to perform therapeutic drug monitoring (TDM) to minimize the side effects. Here, we designed a rapid and sensitive fluorescence/colorimetric assay for the detection of MTX in diluted human serum. After the aptamer binds specifically to MTX, the Walking strand cleaves the Hairpin strand and releases a large amount of fluorescent signal, and the color of the gold nanoparticles changes after the addition of sodium chloride. The change of color could be visualized by eyes to achieve point-of-care TDM of MTX. The quantitative detection of MTX concentration is carried out through the collection of fluorescent signals or absorptions. The fluorescence method can detect MTX in the range of 0.05-1000 μM with the detection limit of 0.0243 μM, meanwhile, the colorimetric method can detect MTX in the range of 0.01-100 μM with the detection limit of 0.0097 μM. The magnetic separation-assisted DNAzyme walker-based nanosensor exhibited good sensitivity, selectivity and stability for detecting MTX in serum and achieve point-of-care methods of TDM of MTX and the nanocarriers has demonstrated significant potential for clinical application.

2025-03-01·Journal of Gastroenterology

Efficacy of liposomal irinotecan + 5-FU/LV vs. S-1 in gemcitabine-refractory metastatic pancreatic cancer: a real-world study using inverse probability of treatment weighting

Article

作者: Suzuki, Yuko ; Shibata, Ryusuke ; Asagi, Akinori ; Okuyama, Hiroyuki ; Kawamoto, Yasuyuki ; Naganuma, Atsushi ; Kobayashi, Satoshi ; Nagano, Hiroaki ; Ikeda, Masafumi ; Suzuki, Rei ; Nakachi, Kohei ; Ueno, Masayuki ; Terashima, Takeshi ; Shioji, Kazuhiko ; Kitano, Yohei ; Sakamoto, Yasunari ; Hosokawa, Ayumu ; Ohba, Akihiro ; Negoro, Yuji ; Murohisa, Gou ; Shimizu, Satoshi ; Tsumura, Hidetaka ; Ashida, Reiko ; Umemoto, Kumiko ; Ohyama, Hiroshi ; Doi, Toshifumi ; Kawaguchi, Shinya ; Kimura, Nana ; Nebiki, Hiroko ; Imaoka, Hiroshi ; Kawata, Kazuhito ; Tsuji, Kunihiro ; Kobayashi, Noritoshi ; Morizane, Chigusa ; Ueno, Makoto ; Okano, Naohiro ; Furuse, Junji

AbstractBackgroundS-1 monotherapy had previously been widely used as a second-line treatment for pancreatic cancer (PC) after gemcitabine-based chemotherapy mainly in Japan. Based on the results of the NAPOLI-1 trial, the recommended second-line therapy is now liposomal irinotecan plus fluorouracil/folinic acid (nal-IRI + 5-FU/LV). However, there have been no studies comparing nal-IRI + 5-FU/LV therapy with S-1 monotherapy.MethodsThe main objective of this study was to compare overall survival (OS) in patients treated with nal-IRI + 5-FU/LV and those treated with S-1 monotherapy as second-line treatments, using the inverse probability of treatment weighting (IPTW) method. This study was conducted in 31 institutions participating in Japan Oncology Network in Hepatobiliary and Pancreas. To minimize potential biases due to the retrospective design, IPTW analysis was performed with multiple imputation, and imputed IPTW-adjusted hazard ratios and corresponding 95% confidence intervals (CIs) were estimated using a Cox proportional hazards model and combined into pooled estimates.ResultsA total of 463 metastatic PC patients were enrolled in this study (257 in the S-1 monotherapy group and 206 in the nal-IRI + 5-FU/LV group). The median OS was 7.50 months (95% CI 4.18–12.69 months) in the nal-IRI + 5-FU/LV group and 5.72 months (95% CI 2.76–10.79 months) in the S-1 monotherapy group. In the IPTW-adjusted Cox proportional hazards model, nal-IRI + 5-FU/LV was associated with a significant OS benefit (pooled IPTW-adjusted hazard ratio, 0.779; 95% CI 0.399—0.941; p = 0.025).ConclusionThese findings support the use of nal-IRI + 5-FU/LV as standard second-line treatment for PC patients after gemcitabine-based chemotherapy.

2025-03-01·Journal of Palliative Medicine

Quality of Life in Patients with Locally Advanced Pancreatic Cancer During Stereotactic Radiotherapy Combined with Heat-Killed Mycobacterium Obuense Vaccination

Article

作者: Moskie, Miranda ; Schafthuizen, Laura ; van ‘t Land, Freek R. ; Dijk, Monique van ; van Eijck, Casper H.J. ; van Rosmalen, Joost

Background: New treatment options for patients with locally advanced pancreatic cancer (LAPC) have proven to be safe but, in addition, may have an effect on the patient's quality of life. Objectives: To evaluate the effect of stereotactic body radiotherapy (SBRT) combined with intradermal heat-killed mycobacterium obuense (IMM-101) vaccination on health-related quality of life (HRQoL), pain, and sleep, in patients with LAPC. Design: Prospective cohort study. Setting/Participants: In total, 42 Dutch patients with LAPC were included after completion of at least four cycles of (m) leucovorin calcium (folinic acid), fluorouracil, irinotecan hydrochloride, and oxaliplatin (FOLFIRINOX). Measurements: Quality of life was assessed with the EORTC QLQ-C30. Patients completed the Richard Campbell Sleep Questionnaire (RCSQ) for five consecutive nights and wore simultaneously a GENEActiv tri-axial accelerometer, which registered sleep duration and sleep efficiency. The Numeric Rating Scale was used to assess pain intensity during treatment. Data were collected at the baseline visit [i.e., at inclusion in the study after (m)FOLFIRINOX treatment] and at week 8 (i.e., 6 weeks after start date of SBRT and after four IMM-101 vaccinations). Results: Univariable linear mixed model analysis revealed significant improvement for EORTC QLQ-C30 items "cognitive functioning" and "emotional functioning." Outcomes on RCSQ subscales and "RCSQ total score" did not significantly change. In the multivariable model, with "Global HRQoL scale" and "RCSQ total score" as outcomes, we did not find a significant change during treatment. Conclusion: In this prospective cohort study, we found that SBRT combined with IMM-101, in patients with LAPC, is well tolerated and does not negatively affect HRQoL, sleep quality, and pain.

102

项与亚叶酸相关的新闻（医药）

2025-02-21

·ioncology

年度盘点丨李恩孝教授：继往开来——2024年胰腺癌领域重磅研究进展

点击蓝字关注我们年度盘点微专辑扫描二维码可查看更多内容编者按春风十里，春景初盛。回首2024年，胰腺癌领域的研究百花齐放，成果斐然。新年伊始，《肿瘤瞭望消化时讯》特邀西安交通大学第一附属医院李恩孝教授为我们梳理过去一年胰腺癌领域的诊疗进展，并展望未来的发展方向。李恩孝教授西安交通大学第一附属医院肿瘤内科学科带头人主任医师，教授，医学博士，博士研究生导师陕西省抗癌协会肿瘤生物治疗专业委员会主委 CSCO理事 CSCO胆道肿瘤专委会副主委、胰腺癌专业委员会委员、 GP-NET专委会常委、中西医结合专委会常委国家卫健委能力建设和继续教育肿瘤学专委会委员中国康复医学会肿瘤康复专委会常委中国老年医学学会肿瘤学分会副会长 CACA肿瘤分子靶向治疗专业委员会，NET专业委员会常委中国研究型医院协会精准医学与肿瘤MDT专业委员会副主委中国医疗保健国际交流促进会消化肿瘤综合诊疗学分会, NET专委会副主委《现代肿瘤医学》《中国肿瘤临床与康复》编委胰腺癌具有高致死率、起病隐匿、进展迅速和预后极差的特点。目前，胰腺癌的5年生存率仅为7%~10%。据GLOBOCAN 2022年的统计数据显示，我国胰腺癌的发病率排名第十，死亡病例为11万，死亡率位居肿瘤相关死亡原因第六位[1]。尽管胰腺癌的基础转化研究和临床研究面临严峻挑战，但多项研究为这一“癌王”的治疗带来了新的希望。指南领航，优化精准治疗策略 2024年美国国家综合癌症网络（NCCN）胰腺癌指南2025.V1版重磅发布[2]，重点更新了精准治疗策略、一线治疗方案及局晚期/转移性疾病的治疗推荐。指南特别强调了使用二代测序（NGS）检测临床上可操作的和/或新出现的突变，以加强靶向治疗的应用。其中包括基因融合（ALK、NRG1、NTRK、ROS1，FGFR2和RET）、基因突变（BRAF、BRCA、KRAS和PALB2）、基因扩增（HER2）、微卫星不稳定性（MSI）、错配修复缺陷（dMMR）及肿瘤突变负荷（TMB）。通过全面的基因组分析，可为患者提供更精准的个体化治疗方案，预测治疗效果并评估预后。多点开花，基于化疗排兵布阵新辅助治疗新辅助治疗在胰腺癌治疗中的地位日益凸显。如何制定有效的治疗方案，以实现肿瘤降期、提高R0切除率、建立药敏平台并改善患者预后，一直是临床探索的重点。 2024 ASCO GI大会公布的Ⅱ期NEO-Nal-IRI研究结果显示[3]，NALIRIFOX方案（伊立替康脂质体+奥沙利铂+5-氟尿嘧啶/亚叶酸钙）用于可切除及临界可切除胰腺癌患者新辅助治疗的客观缓解率（ORR）为45%，疾病控制率（DCR）为73%，R0切除率为90%，且安全性可控。这一结果为胰腺癌的新辅助治疗奠定了良好的基础。一线治疗一线治疗是胰腺癌患者长期生存的关键。2023 ASCO GI大会公布的Ⅲ期NAPOLI-3研究结果显示[4]，NALIRIFOX（伊立替康脂质体+奥沙利铂+5-氟尿嘧啶/亚叶酸钙）对比Gem+NabP（白蛋白紫杉醇+吉西他滨）在无进展生存期（PFS）和总生存期（OS）方面均显示出显著获益。2024 ASCO大会进一步公布了随访29.5个月后的数据[5]，NALIRIFOX组的OS获益持续优于Gem+NabP组，两组12个月和18个月的OS率分别为45.6% vs. 39.6%和26.6% vs. 20.0%（图1）。此外，在临床试验中，NALIRIFOX组腹泻不良发生率较低，且患者耐受性良好。图1. OS获益结果一线治疗中老年胰腺癌患者约占三分之一，但其治疗方案一直缺乏高质量的循证医学证据。2024 ASCO大会公布的Ⅱ期GIANT研究评估了吉西他滨+白蛋白紫杉醇（AG）+5-FU对比亚叶酸钙联合脂质体伊立替康（nal-IRI+5-FU/LV）一线治疗老年转移性胰腺肿瘤的疗效。结果显示[6]，两组患者的OS和PFS获益均无显著差异，且安全性相当。这一研究为老年胰腺癌患者的一线治疗提供了重要参考。二线治疗一线治疗失败后，胰腺癌患者的二线治疗选择有限。目前，多项基于伊立替康脂质体的二线治疗方案正在探索中。 2024 ESMO大会公布的一项Ⅱ期研究显示[7]，伊立替康脂质体联合替吉奥（S-1）用于一线含吉西他滨化疗失败的患者，中位OS为10.3个月，中位PFS为5.7个月，ORR为20.4%，DCR为79.6%，且安全性可控，表现显著的临床获益，同时S-1作为一种口服氟尿嘧啶类药物，可以替代静脉滴注，减轻患者的住院负担和不便。 2024 ESMO大会公布的另一项Ⅰ/Ⅱ期研究进一步比较了伊立替康脂质体联合S-1与联合5-FU/LV二线治疗吉西他滨化疗后的晚期胰腺癌患者的疗效。结果显示[8]，S-1组对比5-FU/LV组在OS方面具有获益趋势，且不良反应发生率更低。因此，当前伊立替康脂质体联合氟尿嘧啶/亚叶酸方案仍是最佳选择，其他联合方案仍需进一步探索。曙光初现，靶向治疗迎来“破局” 目前，胰腺癌最主要的四个驱动基因突变包括KRAS、TP53、SMAD4和CDKN2A已被证实在众多胰腺癌患者中存在突变。长期以来，KRAS一直被认为是不可成药靶点。但近年来越来越多的靶向药物及方案在胰腺癌临床研究显示出希望。 KRAS 2024 ASCO GI大会公布了KRAS G12C抑制剂glecirasib在胰腺癌和其他实体肿瘤患者中的初步活性和安全性结果。数据显示[9]，在28例胰腺癌患者中，ORR为46.4%，DCR为96.4%，中位DOR为4.1个月，中位PFS为5.5个月。安全性方面，患者耐受性良好，不良事件可控，未出现因治疗相关不良事件导致的死亡或治疗终止。针对KRAS G12D突变的药物研究也取得了初步成果。2023 ESMO大会公布了KRAS G12D抑制剂HRS-4642的Ⅰ期临床研究数据，其中1例胰腺癌患者获益显著[10]。此外，后续，Ⅰ/Ⅰb期RMC-9805-001研究结果显示[11]，新型口服KRAS G12D选择性共价抑制剂RMC-9805在KRAS G12D突变胰腺癌患者的后线治疗中ORR为30%，DCR为80%（图2）。尽管这些结果来自早期临床研究，但未来对其后续研究结果充满期待。图2. RMC-9805-001研究结果 RAS 同样，针对泛RAS抑制剂的研究也显示出潜力。Ⅰb期临床研究数据显示[12]，泛RAS抑制剂RMC-6236单药二线治疗KRAS G12X或任何RAS突变胰腺癌患者中位PFS分别为8.5个月和7.6个月，中位OS均为14.5个月，且安全性良好。目前，RMC-6236的Ⅲ期研究正在筹备中，未来值得期待。 HER2 HER2靶向ADC药物在胰腺癌领域的研究也备受关注。2024 ASCO大会公布的Ⅱ期DESTINY-PanTumor02研究显示[13]，胰腺癌患者的ORR为4.0%，中位PFS为3.2个月，这表明T-DXd在HER2表达的胰腺癌患者中显示出一定的抗肿瘤活性，但因纳入人群有限，特别是在IHC 3+组中，所以其疗效仍需进一步验证。 CLDN18.2 CLDN18.2是潜在的胰腺癌治疗靶点。2024 ASCO大会公布了一项Ⅰ期临床研究中抗CLDN18.2/CD3双特异性抗体IBI389在晚期胰腺癌患者中的安全性和有效性初步结果[14]。数据显示，在27例胰腺癌患者中，ORR为29.6%，DCR为70.4%，且安全性可控。这一结果为CLDN18.2靶点在胰腺癌中的应用提供了新的方向。此外，另一款针对CLDN18.2靶点的ADC药物ATG-022也正在临床研究中[15]，目前尚未有后续数据公布。创新引领，解锁免疫治疗新策略 2024年The Lancet Oncology首次公布Ⅰ/Ⅱa期LOKON001研究第1组的结果显示[16]，溶瘤腺病毒LOAd703+白蛋白结合型紫杉醇+吉西他滨用于既往治疗或未接受过治疗的不可切除或转移性胰腺癌患者，ORR为44%。不良反应多为1~2级，整体安全性良好。这一研究为溶瘤病毒联合化疗的临床应用提供了初步证据。 2024年Nature Medicine发表的一项Ⅰ期研究评估了新型淋巴结靶向性mKRAS特异性两亲疫苗ELI-002 2P在胰腺癌和结直肠癌患者中的安全性、耐受性、推荐的Ⅱ期剂量（RP2D）以及初步的抗肿瘤活性[17]。数据显示，中位无复发生存期（RFS）为16.3个月（图3），中位OS为16.3个月（图4）。研究结果证明了ELI-002 2P疫苗在治疗KRAS突变型肿瘤中的安全性和免疫原性，且可有效缓解结直肠癌和胰腺癌患者的肿瘤复发，增加患者生存率。这些结果为KRAS突变肿瘤的免疫治疗提供了新的策略，并为未来的Ⅱ期研究奠定了基础。图3. RFS获益结果图4. OS获益结果攻坚克难，齐心探索结硕果胰腺癌术后复发率高达70%以上，如何早期发现复发并采取干预措施是临床上的重大挑战。对此李恩孝教授所在团队通过基于循环肿瘤DNA（ctDNA）的微小残留病灶（MRD）检测对胰腺癌患者展开了前瞻性研究，通过ctDNA动态监测用于患者术前和术后的风险分层和指导疾病监测及辅助治疗决策。同时，李恩孝教授所在团队针对局部晚期胰腺癌患者开展了一项Ⅱ期临床研究，旨在探索索凡替尼联合AG方案用于此类患者转化治疗的疗效和安全性。目前，初步研究结果已在2024美国胰腺大会和欧洲胰腺大会等国际会议上以壁报形式发表。数据显示，截至2024年12月共纳入25例患者，其中24例可评估患者的ORR为45%，DCR为87.5%，83%患者实现了肿瘤退缩。在完成术前治疗的20例患者中65%达到切除标准，40%实现了R0切除，安全性总体可控。目前，PFS和OS等长期指标仍在随访中，研究结果值得期待。任重道远，未来曙光在前胰腺癌的治疗仍然面临诸多挑战，但近年来在靶向治疗、免疫治疗和细胞治疗等领域的研究进展为我们带来了新的希望。未来可从以下几个方面进一步突破：第一，通过基础研究深入探索包括NTRK、ROS1、SMAD4、BRCA、BRAF、KRAS等关键驱动基因的可成药性是关键。第二，探索联合治疗策略是提升疗效的重要方向。需进一步优化基于细胞毒性药物的联合治疗方案，如索凡替尼联合AG方案在转化治疗中已显示出潜力。第三，免疫治疗仍然是未来研究的重要方向。其中溶瘤病毒和癌症疫苗等新策略可为克服“免疫荒漠”胰腺癌提供新的思路。胰腺癌的治疗之路任重道远，期待未来更多研究成果的涌现，为患者带来新的希望。参考文献（上下滑动可查看） [1] Siegel RL, Miller KD, Fuchs HE, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. [2] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), Pancreatic Adenocarcinoma, Version 1.2025, November 20, 2024. [3] Thomas J. Georgel, et al. ASCO GI 2024. Poster 655. [4] Wainberg ZA, et al. Lancet. 2023;402(10409):1272-81. [5] 2024 ASCO. Abstract 4136. [6] 2024 ASCO. Abstract 4003. [7] Hiroshi Imaoka, et al. 2024 ESMO 1521P. [8] Anne M. Gehrels, et al. 2024 ESMO LBA63 [9] 2024 ASCO GI.Abstract：604. [10] 2023 ESMO. Abstract LBA33. [11] Revolution Medicines Presents Initial Data from RMC-9805 Monotherapy Study in Patients with Advanced Pancreatic Ductal Adenocarcinoma. Retrieved October 25, 2024 from https://ir.revmed.com/news-releases/news-release-details/revolution-medicines-presents-initial-data-rmc-9805-monotherapy. [12]https://www.globenewswire.com/en/news-release/2024/10/23/2967583/0/en/Revolution-Medicines-Presents-Updated-Data-from-RMC-6236-Monotherapy-Study-in-Patients-with-Advanced-Pancreatic-Ductal-Adenocarcinoma.html. [13] Meric-Bernstam F, et al.J Clin Oncol. 2024;42(1):47-58. [14] Musher, Benjamin L et al. The Lancet Oncology. 2024; 25(4):488 - 500. [15] Pant S, et al. Nat Med. 2024;30(2):531-542. [16] 2024 ASCO. Abstract 4011. [17] 2024 ASCO. Abstract 2526. （来源：肿瘤瞭望消化时讯）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

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2025-02-20

·今日头条

Nature：RNA疫苗“神操作”：在胰腺癌患者体内培养“长寿战士”CD8 T细胞，抗癌效果惊艳

点击蓝字关注我们【导读】癌症疫苗面临的一个基本挑战，是如何产生对肿瘤抗原具有特异性的长效功能性T细胞。在这项研究中，团队发现针对体细胞突变衍生的新抗原的mRNA脂质体疫苗，可以解决胰腺导管腺癌（PDAC）的这一难题。 2025年2月19日，美国纪念斯隆凯特琳癌症中心的研究团队在期刊《Nature》上发表了题为“RNA neoantigen vaccines prime long-lived CD8 T cells in pancreatic cancer”的研究论文。这项研究展示了mRNA新抗原疫苗在PDAC中诱导强、特异性、功能性和持久T细胞反应的潜力，为癌症疫苗的广泛测试和应用提供了支持。 https://www.nature.com/articles/s41586-024-08508-4 01 研究背景团队之前报道过1项研究者发起的辅助序贯抗PD-L1（atezolizumab，单次疫苗接种前剂量）的1期试验的早期临床和免疫学结果，然后是8次静脉内初免剂量的个体化尿苷mRNA新抗原疫苗（自基因头孢莫新生；包含多达20种主要组织相容性复合体I类（MHCI）和II类（MHCII）限制性新抗原，针对主要体细胞客体突变在atezolizumab后3周给药）， mFOLFIRINOX （12个周期）和单次疫苗加强剂量在19名手术切除的PDAC患者中（安全性可评估队列包括16名接种疫苗的患者和3名接受atezolizumab治疗的患者）。在中位随访1.5年时，在16名接种疫苗的患者（生物标志物可评估队列）中，有8名患者自基因头孢梅兰诱导了与延迟PDAC复发相关的高强度、多功能新抗原特异性CD8效应 T细胞。 02 疫苗可诱导长寿命T细胞克隆通过对所有8位应答者进行从接种前到接种后约4年的CloneTrack（26个时间点的131个样本中的547万个克隆、995万个细胞），团队发现疫苗在接种后诱导了79个T细胞克隆（“CloneTrack 克隆”），所有患者中都有多个克隆，而7位接受了增强剂量的应答者中没有新的增强诱导克隆。通过绘制所有25个ELISpot阳性疫苗新抗原的同源克隆图，团队发现8名应答者中有7人的79个CloneTrack克隆中有29个（37%）是ELISpot阳性疫苗新抗原特异性CD8 T细胞（其余50个CloneTrack克隆是ELISpo 阳性疫苗新抗原特异性CD8 T细胞），其中5个应答者的15个克隆通过TCR克隆和最小新表位图绘制，证实了对疫苗新抗原的特异性。虽然CloneTrack克隆在疫苗剂量数量不同的情况下达到峰值，但77%的CloneTrack克隆在6个或更少的启动剂量下达到扩增峰值，个别克隆扩增约100倍或更多，达到占所有外周T细胞0.2%的中位峰值百分比。因此，在PDAC患者中，自体血清cevumeran诱导剂量（而非增强剂量）可诱导高数量级的T细胞克隆。 mRNA疫苗诱导具有多年新寿命的T细胞。 03 总结 1. 克服宿主耐受性：研究表明，通过使用基于尿苷的未修饰mRNA-lipoplex疫苗（autogene cevumeran），针对体细胞突变衍生的新抗原，可以在疾病负担最小的患者中产生强、特异性、功能性和耐用的T细胞反应，从而克服宿主耐受性。 2. 疫苗诱导的T细胞特性：疫苗诱导的CD8 T细胞具有多年甚至数十年的寿命，表现出强大的新抗原特异性和多功能性，并且能够浸润复发的胰腺导管腺癌（PDAC）肿瘤。这些T细胞在稳态下持续存在，模拟了PDAC中可能的“自然”免疫控制。 3. 疫苗的长期免疫效果：疫苗诱导的免疫反应跨越了PDAC复发窗口，可能在最高易感期内提供保护。疫苗诱导的T细胞克隆在记忆期不会获得耗竭特征，并且可能具有循环功能。 4. 疫苗的广泛适用性：由于新抗原是肿瘤发生的基本副产品，针对新抗原的疫苗理论上可以适用于几乎所有癌症，特别是那些突变负荷较低、对免疫检查点抑制剂不敏感的“冷肿瘤”，如胃肠道癌症。 5. 疫苗的潜在机制和挑战：疫苗诱导的T细胞可能通过克隆逃逸机制产生耐药性，因此，有效的癌症疫苗可能需要初始多价疫苗，随后进行新抗原重采样和适应性疫苗接种以应对克隆逃逸。 6. 未来研究方向：需要进行更多的实验验证和全球随机试验（如IMCODE 003；NCT05968326）来进一步验证这些发现，并探索mRNA新抗原疫苗作为辅助癌症疗法的广泛潜力。参考资料： 1.Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023). 2.Neoptolemos, J. P. et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. JAMA 304, 1073–1081 (2010). 【关于投稿】转化医学网（360zhyx.com）是转化医学核心门户，旨在推动基础研究、临床诊疗和产业的发展，核心内容涵盖组学、检验、免疫、肿瘤、心血管、糖尿病等。如您有最新的研究内容发表，欢迎联系我们进行免费报道（公众号菜单栏-在线客服联系），我们的理念：内容创造价值，转化铸就未来！转化医学网（360zhyx.com）发布的文章旨在介绍前沿医学研究进展，不能作为治疗方案使用；如需获得健康指导，请至正规医院就诊。热门推荐活动点击免费报名 🕓 全国｜2024年12月-2025年03月 ▶ 中国转化医学产业大会 🕓 上海｜2025年02月28日-03月01日 ▶ 第四届长三角单细胞组学技术应用论坛暨空间组学前沿论坛点击对应文字查看详情

疫苗信使RNA临床1期临床结果

2025-02-04

·drugs

Dual-Targeted Therapies Plus Chemo Improve Objective Response Rate in BRAF V600E Metastatic CRC

TUESDAY, Feb. 4, 2025 -- For patients with BRAF V600E-mutant metastatic colorectal cancer (mCRC), encorafenib + cetuximab (EC) plus standard chemotherapy (modified folinic acid [or levofolinate], fluorouracil , and oxaliplatin regimen [mFOLFOX6]) is associated with an improved objective response rate compared with standard of care (SOC), according to a study published online Jan. 25 in Nature Medicine . The research was published to coincide with the American Society of Clinical Oncology annual Gastrointestinal Cancers Symposium, held from Jan. 23 to 25 in San Francisco. Scott Kopetz, M.D., Ph.D., from the University of Texas MD Anderson Cancer Center in Houston, and colleagues examined EC+mFOLFOX6 versus SOC in patients with previously untreated BRAF V600E mCRC in the phase 3 BREAKWATER study. At data cutoff, data were not mature for the dual primary end point of progression-free survival. However, the researchers found that BREAKWATER met the other dual primary end point of objective response rate, demonstrating a significant and clinically relevant improvement (60.9 versus 40.0 percent for EC+mFOLFOX6 versus SOC; odds ratio, 2.443). The median duration of response was 13.9 and 11.1 months, respectively. The hazard ratio was 0.47 at this first interim analysis of overall survival. The safety profiles were consistent with those known for each agent; serious adverse event rates were 37.7 and 34.6 percent in the EC+mFOLFOX6 and SOC groups, respectively. "These encouraging data support this regimen to potentially become the new SOC in BRAF V600E-mutant mCRC; prespecified analyses of mature progression-free survival and overall survival data are planned," the authors write. Several authors disclosed ties to biopharmaceutical companies, including Pfizer, which sponsored BREAKWATER; support was also received from other pharmaceutical companies. Abstract/Full Text More Information Whatever your topic of interest, subscribe to our newsletters to get the best of Drugs.com in your inbox.

ASCO会议临床结果临床3期

100 项与亚叶酸相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D07986	亚叶酸	L01XX	DB00650

研发状态

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适应症	国家/地区	公司	日期
结直肠癌	-	-	-

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临床结果

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03504397 (SPOTLIGHT \| SPOTLIGHT study, CTgov)	临床3期	胃食管交界处癌	565	folinic acid+zolbetuximab+oxaliplatin+fluorouracil	(鏇製壓製鏇衊觸壓範壓) = 衊憲鏇憲製鬱構廠繭餘網鑰製範築窪顧壓夢積 (壓觸壓糧願憲鹽鹹衊鏇, 選選鏇夢鹽醖顧遞鹹艱 ~ 積鏇餘構願鏇廠蓋餘選) 更多	-	2025-02-26
NCT03259035 (CCTG CO.28 \| NEO \| CO.28, CTgov)	临床2期	直肠癌	58	folinic acid+oxaliplatin+capecitabine+fluorouracil	夢淵憲範獵淵艱觸鬱鹽(鹽鏇齋鬱選廠艱窪鏇膚) = 網製廠選築鹽淵簾襯憲簾鑰獵廠積遞衊選簾壓 (淵窪窪餘壓顧壓蓋網壓, 夢窪顧築廠顧憲繭鹹鏇 ~ 製範鏇窪構鏇艱糧衊構) 更多	-	2024-10-10
JPRN-UMIN000048143 (JON 2109-P, ESMO2024) 人工标引	临床3期	胰腺癌二线	446	S-1 monotherapy	(衊餘築襯積獵餘襯製網) = 艱醖積願網衊願鏇願觸鹹範鹹遞鹹獵齋醖遞選 (鑰襯選鏇願積簾憲餘餘 ) 更多	积极	2024-09-16
JPRN-UMIN000048143 (JON 2109-P, ESMO2024) 人工标引	临床3期	胰腺癌二线	446	Nanoliposomal irinotecan plus 5-fluorouracil/leucovorin regimen	(衊餘築襯積獵餘襯製網) = 積積觸獵齋廠蓋鑰窪齋鹹範鹹遞鹹獵齋醖遞選 (鑰襯選鏇願積簾憲餘餘 ) 更多	积极	2024-09-16
NCT02842580 (HIGH-LIGHT, CTgov)	临床2期	转移性结直肠癌	21	acide folinique+Bevacizumab+irinotecan+Oxaliplatin+capécitabine+5FU (Standard Arm (Escalation Strategy - Arm A))	(餘淵網繭鏇鬱製窪獵鹹) = 簾網鑰糧繭簾艱觸觸糧夢憲繭繭鏇衊繭網鹹鹽 (鏇範繭選窪夢衊積鏇夢, 築顧衊鬱鑰衊憲顧鹽壓 ~ 醖簾糧廠積淵範襯壓襯) 更多	-	2024-07-10
NCT02842580 (HIGH-LIGHT, CTgov)	临床2期	转移性结直肠癌	21	acide folinique+Bevacizumab+irinotecan+Oxaliplatin+capécitabine+5FU (Experimental Arm (De-escalation Strategy -Arm B))	(餘淵網繭鏇鬱製窪獵鹹) = 糧糧醖襯獵選鏇鬱簾餘夢憲繭繭鏇衊繭網鹹鹽 (鏇範繭選窪夢衊積鏇夢, 壓積夢構簾膚衊遞窪簾 ~ 鹽遞構構廠積蓋鹽遞鬱) 更多	-	2024-07-10
NCT02352337 (PRODIGE 35-PANOPTIMOX \| PANOPTIMOX, CTgov)	临床2期	转移性胰腺癌	276	Leucovorin Calcium+irinotecan+oxaliplatin+Irinotecan hydrochloride+FLUOROURACIL (FOLFIRINOX)	鏇構簾夢網淵糧齋餘膚(顧築膚餘壓構獵襯鏇選) = 壓糧鹽餘選艱範鏇簾製壓網鏇築製醖淵顧願觸 (築鏇構顧蓋鹽簾築夢鏇, 遞衊範繭繭觸窪窪窪築 ~ 窪顧選壓構製觸觸醖衊) 更多	-	2024-07-10
NCT02352337 (PRODIGE 35-PANOPTIMOX \| PANOPTIMOX, CTgov)	临床2期	转移性胰腺癌	276	LV+irinotecan+oxaliplatin+Irinotecan hydrochloride+FLUOROURACIL (FOLFIRINOX + LV5FU2 in Maintenance)	鏇構簾夢網淵糧齋餘膚(顧築膚餘壓構獵襯鏇選) = 壓鑰鹽鬱襯壓遞範廠鹹壓網鏇築製醖淵顧願觸 (築鏇構顧蓋鹽簾築夢鏇, 衊鏇簾選淵蓋餘築構淵 ~ 顧範廠選構繭窪製鹽顧) 更多	-	2024-07-10
NAPOLEON-2 (ESMO_GI2024) 人工标引	N/A	胰腺癌二线	87	Nano-liposomal irinotecan, fluorouracil, and folinic acid (NFF)	(繭壓構淵壓夢範鏇構襯) = 壓網鏇遞淵壓遞齋鑰艱積衊糧製築淵衊鹹遞衊 (範築夢蓋淵構遞鹽餘憲, 6.4 ~ 9.4) 更多	积极	2024-06-27
NCT01515787 (PROSPECT, CTgov)	临床2/3期	局部晚期直肠癌	1,194	surgery+leucovorin+Oxaliplatin+5-fluorouracil+capecitabine (Group 1)	壓衊簾淵選壓積壓醖鏇(範糧淵齋蓋網襯獵顧膚) = 膚鹹構襯鏇鏇構窪糧鑰構糧築鹹觸膚鬱餘選願 (壓鑰壓獵淵醖醖艱願鹹, 窪製襯簾願壓遞選廠製 ~ 齋蓋壓構糧糧鏇齋餘鬱) 更多	-	2024-02-02
NCT01515787 (PROSPECT, CTgov)	临床2/3期	局部晚期直肠癌	1,194	surgery+leucovorin+Oxaliplatin+5-fluorouracil+capecitabine (Group 2)	壓衊簾淵選壓積壓醖鏇(範糧淵齋蓋網襯獵顧膚) = 積繭構鑰衊築淵鬱積壓構糧築鹹觸膚鬱餘選願 (壓鑰壓獵淵醖醖艱願鹹, 醖餘範衊醖衊鑰壓簾夢 ~ 願鹹夢壓鏇夢觸膚獵齋) 更多	-	2024-02-02
ASCO_GI2024 人工标引	N/A	局部晚期胃癌新辅助	38	Fluorouracil+ leucovorin+ oxaliplatin + docetaxel	(觸鹹積餘願製選衊艱積) = 蓋鑰製淵獵簾膚窪衊壓鹹蓋築願憲製鬱齋網簾 (鬱獵製鹹淵鹽觸餘壓齋, 1.0 ~ 28) 更多	不佳	2024-01-18
NCT02839343 (Alliance A021501, ASCO_GI2024) 人工标引	临床2期	胰腺癌新辅助	51	oxaliplatin+ irinotecan+ leucovorin + 5-FU +surgery	(齋襯衊憲糧衊獵窪鹽網) = 築蓋膚齋製鑰鹽醖餘膚顧築繭製鑰鏇獵醖廠蓋 (構繭窪積艱廠鹽壓衊齋 ) 更多	积极	2024-01-18
ESMO 12023 \| ESMO 22023 人工标引	N/A	转移性胰腺癌	129	pegylated liposomal irinotecan + 5-fluorouracil + leucovorin	(鏇觸鏇製艱觸鹽鏇蓋鬱) = 鏇餘鏇糧構觸襯築糧蓋夢鹽夢糧獵艱繭膚網鹹 (繭蓋衊鑰夢繭艱壓選顧, 47.4 ~ 68.7) 更多	积极	2023-10-23