12个月患者总生存率超90%的抗癌联合疗法；治疗慢性HBV感染的表观遗传沉默剂进入临床…… | 一周盘点
▎药明康德内容团队编辑
本期看点
1. Cue Biopharma公司公布了其两款新型生物制品的积极临床数据，其中接受CUE-101联用PD-1抑制剂pembrolizumab一线治疗的HPV阳性复发性/转移性头颈部鳞状细胞癌（R/M HNSCC）患者12个月时的总生存率为91.3%。
2. 胸苷酸合成酶抑制剂NUC-3373联用pembrolizumab在一项临床研究中使1名尿路上皮膀胱癌患者的靶病灶缩小了100%。
3. 用于治疗慢性乙肝病毒（HBV）感染的表观遗传沉默剂TUNE-401在新西兰获批进入1b期临床试验。
药明康德内容团队整理
CUE-101、CUE-102：公布1期临床试验的新数据
Cue Biopharma公司公布其CUE-101治疗头颈癌和CUE-102治疗WT1阳性癌症的1期临床试验的积极新数据。CUE-101是该公司开发的一款基于白细胞介素-2（IL-2）的T细胞诱导剂，旨在选择性调节和激活HPV阳性T细胞，以提高疗效，同时减少传统免疫疗法的副作用。CUE-102是一种由两个呈递WT1肽的人白细胞抗原（HLA）分子、四个亲和力减弱的IL-2分子和一个效应减弱的人免疫球蛋白G（IgG1）Fc结构域组成的新型生物制品，被开发作为单一疗法治疗WT1阳性复发/转移性癌症患者。
截至2024年9月11日的数据，接受CUE-101联用PD-1抑制剂pembrolizumab一线治疗的HPV阳性R/M HNSCC患者的客观缓解率（ORR）为46%，疾病控制率（DCR）为75%，12个月时的总生存率为91.3%，中位总生存期（OS）为21.8个月。在历史研究KEYNOTE-048中，pembrolizumab单药治疗的ORR为19%，12个月时的总生存率为51%，中位OS为12.3个月。在本研究中，1例患者达到完全缓解（CR），10例患者达到部分缓解（PR），以及7例患者获得了超过12周的持久疾病稳定（SD）。接受该一线联合治疗的PD-L1低表达患者的ORR为50%。
截至2024年10月29日的数据，接受CUE-102单药治疗的晚期胰腺癌患者的DCR为67%，其中包括肿瘤负荷减少40%的未确认的PR。有证据表明，WT1特异性CD8阳性T细胞受到了选择性刺激和扩增，而非特异性CD8阳性T细胞的总数没有明显增加。
NUC-3373：公布1b/2期联合治疗临床试验数据
NuCana公司公布了其正在进行的1b/2期模块化研究的初步数据，模块1研究评估了NUC-3373联用PD-1抑制剂pembrolizumab治疗晚期实体瘤患者的疗效，模块2研究评估了NUC-3373联用多西他赛治疗肺癌患者的疗效。NUC-3373是一种胸苷酸合成酶抑制剂，由核苷类似物5-氟尿嘧啶衍生而来，可导致DNA损伤。
模块1包括12名患有各种实体瘤、已用尽所有其他治疗方案的患者，其中9例患者曾接受过PD-1/PD-L1抑制剂的治疗。接受NUC-3373联用pembrolizumab治疗后，患者实现了显著的肿瘤体积缩小，PFS得到延长。2名患者获得了确认的PR，4例患者达到SD。在疗效可评估人群中，ORR为22%，DCR为67%。其中，1例尿路上皮膀胱癌患者接受联合治疗后靶病灶缩小了100%（非靶病灶依然存在），1例BRAF突变转移性皮肤黑色素瘤患者的靶病灶缩小了81%。此外，NUC-3373联合pembrolizumab的耐受性普遍良好。
模块2包括4名非小细胞肺癌（NSCLC）或胸膜间皮瘤患者，这些患者在既往含化疗方案中出现疾病进展或无法耐受。患者在接受NUC-3373联用多西他赛治疗后PFS得到延长，2例患者实现了长期的SD。
TUNE-401：在新西兰获批启动1b期临床试验
Tune Therapeutics公司宣布，该公司已获得新西兰药品和医疗器械安全局（Medsafe）的临床试验申请（CTA） ，将推进其用于治疗慢性HBV感染的表观遗传沉默剂TUNE-401进入1b期临床试验。
TUNE-401是一款潜在"first-in-class"的表观遗传沉默剂，利用Tune Therapeutics的多功能、模块化TEMPO平台所开发。TUNE-401通过脂质纳米颗粒（LNP）将编码活性、HBV靶向的RNA直接递送至肝细胞。在这些细胞内，所递送的RNA被翻译为表观沉默蛋白，靶向整合入宿主细胞的乙肝病毒DNA（intDNA）和共价闭合环状DNA（cccDNA）。cccDNA是一种独特、游离的环状染色体（episomes），可作为病毒进行复制时的模板，是造成HBV患者多年持续感染的原因之一。临床医生认为，关闭这些cccDNA“病毒工厂”是实现HBV功能性治愈的必要前提。TUNE-401不涉及切割或编辑DNA，其导致产生的活性表观沉默蛋白通过添加甲基基团与DNA结合，以抑制或失活病毒基因，同时保持人类基因的完整性。根据新闻稿，TUNE-401是首个获批进入临床，用以治疗常见传染病的表观遗传疗法。
KVA12123：公布1/2期临床试验数据
Kineta公司公布了其正在进行的1/2期临床试验的最新进展，该试验评估了其新型在研VISTA阻断免疫疗法KVA12123单药或与PD-1抑制剂pembrolizumab联用在晚期实体瘤患者中的治疗效果。KVA12123是一种单克隆抗体疗法，需每周输注两次。通过将独特的表位与优化的IgG1 Fc区相结合，KVA12123单药在临床前模型中显示出强大的肿瘤生长抑制作用，且在临床试验中没有报告细胞因子释放综合征（CRS）。KVA12123已被证明能降低VISTA靶点的风险，并提供了一种新的方法来解决肿瘤微环境中的免疫抑制问题，其作用机制与以T细胞为重点的疗法不同且互补。
截至2024年10月18日的数据，接受KVA12123单药治疗并至少进行了一次随访扫描的19例患者中，有13名实现了SD。在许多接受KVA12123单药治疗的患者中观察到持久的临床结果，其中1名此前已接受过六线治疗（包括免疫检查点抑制剂治疗）的NSCLC患者已保持SD状态60周。在接受KVA12123联合pembrolizumab治疗并至少进行了一次随访扫描的9例患者中，1例粘液表皮样癌患者获得了PR，靶病灶缩小了54%，非靶病灶获得了CR；1名免疫检查点抑制剂治疗后进展的肾细胞癌患者达到SD，靶病灶缩小了24%。安全性方面，KVA12123的耐受性良好，单药或与pembrolizumab联用在任何剂量水平上都未出现剂量限制性毒性（DLT）。
IDRX-42：公布1/1b期临床试验的新数据
IDRx公司公布了其用于治疗晚期胃肠道间质瘤（GIST）的在研口服小分子KIT酪氨酸激酶抑制剂IDRX-42的1/1b期临床试验数据。IDRX-42旨在选择性地靶向最常见的KIT突变形式，这些突变要么驱动肿瘤细胞的初始生长、增殖和生存，要么使肿瘤对现有疗法产生耐药性。
截至2024年9月30日的数据，87例中位治疗线数为四线、疗效可评估患者的ORR为29%，包括1例CR和24例PR。接受IDRX-42作为二线治疗患者的ORR为53%（8/15），包括1例CR和7例PR，这些患者的中位PFS尚未达到。接受IDRX-42作为三线治疗的患者的中位PFS估计为12.9个月。既往未使用过ripretinib、接受IDRX-42作为≥四线治疗的患者在推荐的1b期剂量下，其中位PFS估计为11.0个月。此外，IDRX-42具有良好的安全性，在推荐的1b期剂量下，8%的患者减少了剂量，没有因治疗伴发不良事件而停药的情况。
APV-527：公布1期临床试验数据
Alligator Bioscience公司和Aptevo Therapeutics公司公布了APV-527用于治疗可能表达肿瘤抗原5T4实体瘤患者的1期临床试验数据。APV-527是一种靶向4-1BB和肿瘤抗原5T4的双特异性抗体，仅在与4-1BB和5T4同时结合时才有活性。
此次公布的结果显示，16例疗效可评估的患者中有9例（56%）达到SD，其中，1例结肠癌患者已保持SD超过6个月。最长的SD持续时间发生在一名乳腺癌患者中，该患者进入研究时病情发生进展，目前病情保持稳定，且已参与研究超过11个月。安全性方面，APV-527在所有队列中均表现出积极的安全性和耐受性，尚未观察到严重的肝毒性。肝毒性是其他4-1BB靶向治疗的常见副作用，可导致患者停药。
ELI-002：公布1期临床试验的初步数据
Elicio Therapeutics公司公布了其在研治疗性癌症免疫疗法ELI-002用于治疗接受标准局部治疗后仍有疾病复发风险的KRAS突变驱动实体瘤的1期临床试验的初步结果。ELI-002由AMP修饰的KRAS突变体（mKRAS）肽段，和一种AMP修饰的免疫刺激寡核苷酸佐剂ELI-004组成，经皮下给药靶向淋巴结。它能产生RAS特异性杀伤性T细胞，以攻击术后残留肿瘤细胞，有望延长癌症患者缓解并可预防未来复发。
初步数据表明，靶向KRAS突变体的T细胞反应持久且呈剂量依赖性，并诱导了针对患者特异性新抗原的反应。观察到无病生存期（DFS）与T细胞反应强度之间存在相关性。此外，ELI-002的1期安全性及耐受性特征依然良好，未观察到DLT或CRS。
GUBamy：公布1期临床试验数据
Gubra公司公布了长效胰淀素（amylin）类似物GUBamy在单剂量递增（SAD）1期临床试验中获得的 。GUBamy耐受性良好，表现出良好的药代动力学特征，半衰期为11天，支持每周一次的给药方案。此外，单剂量的GUBamy剂量依赖性地降低体重，这一效果在试验期间（6周）内持续存在。在所有高剂量组（3.5-6.0 mg）中，受试者在6周试验期内的平均体重下降约3％，而安慰剂组的体重平均增长约1％。
▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放
参考资料（可上下滑动查看）
[1] Tune Therapeutics Moves into Clinical Spotlight with TUNE-401: A First-in-Class Epigenetic Silencer for Hepatitis B. Retrieved November 15, 2024 from https://www.businesswire.com/news/home/20241114651346/en/Tune-Therapeutics-Moves-into-Clinical-Spotlight-with-TUNE-401-A-First-in-Class-Epigenetic-Silencer-for-Hepatitis-B、
[2] Gubra announces positive GUBamy Phase 1 SAD data. Retrieved November 15, 2024, from https://storage.mfn.se/c164ef9a-479f-4e2c-8faf-b3b2c5160fe7/gubra-announces-positive-gubamy-phase-1-sad-data.pdf
[3] IDRx Announces Updated Phase 1 Data from Ongoing Phase 1/1b StrateGIST 1 Trial of IDRX-42 in Advanced Gastrointestinal Stromal Tumors (GIST) at CTOS 2024. Retrieved November 15, 2024, from https://www.businesswire.com/news/home/20241113773722/en/IDRx-Announces-Updated-Phase-1-Data-from-Ongoing-Phase-11b-StrateGIST-1-Trial-of-IDRX-42-in-Advanced-Gastrointestinal-Stromal-Tumors-GIST-at-CTOS-2024
[4] Kineta Updates KVA12123 Clinical Results from Ongoing Phase 1/2 VISTA101 Study at Society for Immunotherapy of Cancer (2024). Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/08/2977670/0/en/Kineta-Updates-KVA12123-Clinical-Results-from-Ongoing-Phase-1-2-VISTA101-Study-at-Society-for-Immunotherapy-of-Cancer-2024.html
[5] Cue Biopharma Presents Positive Updated Data from its Phase 1 Trials of CUE-101 and CUE-102 in Head and Neck Cancer and WT1 Positive Cancers at the SITC 39th Annual Meeting. Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/08/2977826/0/en/Cue-Biopharma-Presents-Positive-Updated-Data-from-its-Phase-1-Trials-of-CUE-101-and-CUE-102-in-Head-and-Neck-Cancer-and-WT1-Positive-Cancers-at-the-SITC-39th-Annual-Meeting.html
[6] Elicio Therapeutics Presents Updated Translational Data from ELI-002 Phase 1 AMPLIFY-7P Study at the Society for Immunotherapy of Cancer (“SITC”) 2024 Annual Meeting. Retrieved November 15, 2024, from https://elicio.com/press_releases/elicio-therapeutics-presents-updated-translational-data-from-eli-002-phase-1-amplify-7p-study-at-the-society-for-immunotherapy-of-cancer-sitc-2024-annual-meeting/
[7] NuCana Announces Encouraging Initial Data from Phase 1b/2 Modular Study of NUC-3373 in Combination with Pembrolizumab or Docetaxel. Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/11/2978192/0/en/NuCana-Announces-Encouraging-Initial-Data-from-Phase-1b-2-Modular-Study-of-NUC-3373-in-Combination-with-Pembrolizumab-or-Docetaxel.html
[8] First-in-Class Bispecific Antibody, ALG.APV-527, Meets Important Trial Endpoints in Phase 1 Solid Tumor Trial. Retrieved November 15, 2024, from https://alligatorbioscience.se/en/mfn_news/first-in-class-bispecific-antibody-alg-apv-527-meets-important-trial-endpoints-in-phase-1-solid-tumor-trial/
[9] Immunic Announces Publication of Data From Phase 1/1b Clinical Trial of IMU-856 in the Peer Reviewed Journal, The Lancet Gastroenterology & Hepatology. Retrieved November 15, 2024, from https://www.prnewswire.com/news-releases/immunic-announces-publication-of-data-from-phase-11b-clinical-trial-of-imu-856-in-the-peer-reviewed-journal-the-lancet-gastroenterology--hepatology-302303813.html
[10] Synthekine Announces Presentation of New Translational Data from Phase 1a/1b Clinical Trial of α/β Biased IL-2, STK-012, at the Society for Immunotherapy of Cancer (SITC) 39th Annual Meeting. Retrieved November 15, 2024, from https://www.synthekine.com/news/synthekine-announces-presentation-of-new-translational-data-from-phase-1a-1b-clinical-trial-of-%ce%b1-%ce%b2-biased-il-2-stk-012-at-the-society-for-immunotherapy-of-cancer-sitc-39th-annual-meeting/
[11] Infinitopes to Showcase Breakthroughs on Cancer Vaccine Development at SITC 2024: Insight into a double-blind, Phase I/IIa clinical trial. Retrieved November 15, 2024, from https://www.prnewswire.com/news-releases/infinitopes-to-showcase-breakthroughs-on-cancer-vaccine-development-at-sitc-2024-insight-into-a-double-blind-phase-iiia-clinical-trial-302299015.html
[12] Mural Oncology Presents Clinical and Preclinical Data Across its Pipeline at the 39th Annual Meeting of the Society for Immunotherapy of Cancer (SITC). Retrieved November 15, 2024, from https://ir.muraloncology.com/news-releases/news-release-details/mural-oncology-presents-clinical-and-preclinical-data-across-its
[13] Tectonic Therapeutic Announces Positive Phase 1a Results in AHA 2024 Presentation for TX45, a Long-acting, Fc-Relaxin Fusion Protein. Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/11/2978120/0/en/Tectonic-Therapeutic-Announces-Positive-Phase-1a-Results-in-AHA-2024-Presentation-for-TX45-a-Long-acting-Fc-Relaxin-Fusion-Protein.html
[14] CG Oncology Announces Nature Medicine Publication of Phase 1b Study Results Evaluating Cretostimogene Grenadenorepvec in Combination with Nivolumab in Muscle-Invasive Bladder Cancer. Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/11/2978266/0/en/CG-Oncology-Announces-Nature-Medicine-Publication-of-Phase-1b-Study-Results-Evaluating-Cretostimogene-Grenadenorepvec-in-Combination-with-Nivolumab-in-Muscle-Invasive-Bladder-Cance.html
[15] Next Generation Gene Therapeutics (NGGT) Announces Positive New Data on NGGT002 for the Treatment of Phenylketonuria (PKU). Retrieved November 15, 2024, from https://www.prnewswire.com/news-releases/next-generation-gene-therapeutics-nggt-announces-positive-new-data-on-nggt002-for-the-treatment-of-phenylketonuria-pku-302300911.html
[16] Fate Therapeutics Highlights Cancer-selective, HER2-Targeting Profile of FT825 / ONO-8250 CAR T-cell Product Candidate for Treatment of Advanced Solid Tumors at 2024 SITC Annual Meeting. Retrieved November 15, 2024, from https://ir.fatetherapeutics.com/news-releases/news-release-details/fate-therapeutics-highlights-cancer-selective-her2-targeting
[17] Neurogene Reports Positive Interim Efficacy Data from First Four Low-Dose Pediatric Participants in NGN-401 Gene Therapy Clinical Trial for Rett Syndrome. Retrieved November 15, 2024, from https://ir.neurogene.com/news-releases/news-release-details/neurogene-reports-positive-interim-efficacy-data-first-four-low
[18] IND for ATA-200, a Gene Therapy for the Treatment of Limb-Girdle Muscular Dystrophy Type 2C/R5 (LGMD2C/R5), cleared to proceed by FDA. Retrieved November 15, 2024, from https://www.businesswire.com/news/home/20241112690214/en/IND-for-ATA-200-a-Gene-Therapy-for-the-Treatment-of-Limb-Girdle-Muscular-Dystrophy-Type-2CR5-LGMD2CR5-cleared-to-proceed-by-FDA
[19] Nammi Therapeutics, Inc. Announces First Patient Dosed with QXL138AM in a Phase 1 Study Evaluating Advanced Solid Tumors and Multiple Myeloma. Retrieved November 15, 2024, from https://www.prnewswire.com/news-releases/nammi-therapeutics-inc-announces-first-patient-dosed-with-qxl138am-in-a-phase-1-study-evaluating-advanced-solid-tumors-and-multiple-myeloma-302299498.html
[20] Palleon Pharmaceuticals Presents Results from the Phase 1/2 GLIMMER-01 Trial of E-602 in Combination with Cemiplimab in Patients with Solid Tumors at the Society for Immunotherapy of Cancer (SITC) Annual Meeting. Retrieved November 15, 2024, from https://www.businesswire.com/news/home/20241108273263/en/Palleon-Pharmaceuticals-Presents-Results-from-the-Phase-12-GLIMMER-01-Trial-of-E-602-in-Combination-with-Cemiplimab-in-Patients-with-Solid-Tumors-at-the-Society-for-Immunotherapy-of-Cancer-SITC-Annual-Meeting/
[21] Cerevance’s CVN293 Demonstrated Positive Phase 1 Results in Healthy Volunteers. Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/11/2978299/0/en/Cerevance-s-CVN293-Demonstrated-Positive-Phase-1-Results-in-Healthy-Volunteers.html
[22] Cytokinetics Announces Initiation of Phase 1 Clinical Study of CK-4015089. Retrieved November 15, 2024, from https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-initiation-phase-1-clinical-study-ck-2#:~:text=SOUTH%20SAN%20FRANCISCO%2C%20Calif.%2C%20Nov.%2011%2C%202024%20%28GLOBE,study%20of%20CK-4015089%20%28CK-089%29%20in%20healthy%20human%20participants.
[23] EnteroBiotix Announces Positive Ph1b Clinical Results of EBX-102 in Liver Cirrhosis. Retrieved November 15, 2024, from https://www.enterobiotix.com/news/enterobiotix-positive-clinical-results-ebx-102-liver-cirrhosis
[24] GenVivo to Present Phase 1 Trial Results for GEN2, A Personalizing Gene Vector Therapy, at the 2024 Society for Immunotherapy of Cancer (SITC) Annual Meeting. Retrieved November 15, 2024, from https://genvivoinc.com/2024/11/08/genvivo-to-present-phase-1-trial-results-for-gen2-a-personalizing-gene-vector-therapy-at-the-2024-society-for-immunotherapy-of-cancer-sitc-annual-meeting/
[25] Sparian Biosciences Announces Results from the Phase 1 Clinical Trial of First in Class Novel Arylepoxamide Receptor (AEAr) Agonist Analgesic SBS-1000. Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/12/2979419/0/en/Sparian-Biosciences-Announces-Results-from-the-Phase-1-Clinical-Trial-of-First-in-Class-Novel-Arylepoxamide-Receptor-AEAr-Agonist-Analgesic-SBS-1000.html
[26] Spyre Therapeutics Announces Positive Interim Results from Phase 1 Healthy Volunteer Trial for SPY001, Its Novel Half-Life Extended anti-α4β7 Antibody for the Treatment of Inflammatory Bowel Disease, with a Half-Life of >90 Days Supporting the Potential for Both Q3M & Q6M Maintenance Dosing. Retrieved November 15, 2024, from https://www.prnewswire.com/news-releases/spyre-therapeutics-announces-positive-interim-results-from-phase-1-healthy-volunteer-trial-for-spy001-its-novel-half-life-extended-anti-47-antibody-for-the-treatment-of-inflammatory-bowel-disease-with-a-half-life-of-90-days-s-302302014.html
[27] Nuvectis Pharma Reports Encouraging NXP800 Interim Data Supporting Ongoing Enrollment in Phase 1b Study in Patients with Platinum-Resistant ARID1a-Mutated Ovarian Cancer. Retrieved November 15, 2024, from https://www.globenewswire.com/news-release/2024/11/14/2981017/0/en/Nuvectis-Pharma-Reports-Encouraging-NXP800-Interim-Data-Supporting-Ongoing-Enrollment-in-Phase-1b-Study-in-Patients-with-Platinum-Resistant-ARID1a-Mutated-Ovarian-Cancer.html
[28] Enlivex Announces the Dosing of the First Patient in a Phase I Clinical Trial Evaluating Allocetra in Patients with Psoriatic Arthritis. Retrieved November 15, 2024, from https://enlivex.com/investors/news-releases/enlivex-announces-the-dosing-of-the-first-patient-in-a-phase-i-clinical-trial-evaluating-allocetra-in-patients-with-psoriatic-arthritis/#:~:text=Nes-Ziona%2C%20Israel%2C%20Nov.%2014%2C%202024%20%E2%80%94%20Enlivex%20Therapeutics,an%20affected%20joint%20in%20patients%20with%20psoriatic%20arthritis.
免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。