A Phase 1/2 Study to Evaluate STK-012 as a Single Agent and in Combination Therapy in Subjects With Front-line Advanced NSCLC and Other Selected Indications

This is a phase 1/2, multicenter, open-label study. The phase 1 portion is a dose escalation and expansion study of STK-012 as monotherapy and in combination therapy in patients with selected advanced solid tumors. The phase 2 portion is a randomized study of STK-012 in combination with standard of care (SoC) pembrolizumab, pemetrexed, and carboplatin versus SoC, in patients with first line, PD-L1 negative, non-squamous, non-small cell lung cancer.

开始日期2022-01-25

申办/合作机构

Synthekine, Inc.

100 项与 STK-012 相关的临床结果

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100 项与 STK-012 相关的转化医学

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100 项与 STK-012 相关的专利（医药）

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项与 STK-012 相关的新闻（医药）

2026-04-22

·BioSpace

Synthekine Presents Updated Clinical and Translational Data Demonstrating Strong Activity for STK‑012 in First‑Line Non‑Squamous NSCLC in Oral Presentation at AACR 2026

STK-012 + pembrolizumab + chemotherapy in first‑line non‑squamous NSCLC demonstrated a 50% ORR in predominantly PD‑L1-negative patients 61% ORR with the regimen in patients with at least one mutation in the STK11, KEAP1, or SMARCA4 tumor suppressor genes 50% ORR, PFS 5.5 months, and 88% 6-month OS with the regimen in patients with STK11/KEAP1 co‑mutated tumors MENLO PARK, Calif.--(BUSINESS WIRE)--Synthekine, Inc., a clinical‑stage biotechnology company developing precision cytokine therapeutics, today reported updated clinical and translational data for STK‑012 in combination with pembrolizumab, pemetrexed, and carboplatin (PCT) in first‑line PD‑L1-negative, non‑squamous (NSQ) non‑small cell lung cancer (NSCLC). The data were presented by Salman Punekar, M.D. (NYU Langone Health), in an oral presentation at the American Association for Cancer Research (AACR) Annual Meeting 2026 in San Diego, CA. STK‑012 is a first‑in‑class α/β IL‑2 receptor‑biased partial agonist designed to selectively stimulate antigen‑activated T cells, which are linked to anti‑tumor activity, while minimizing broad activation of other lymphocytes, such as natural killer cells, which are associated with IL‑2‑related toxicities. These updated results, from 36 efficacy‑evaluable patients, build on clinical data first presented at SITC 2025 and include longer follow‑up, new translational analyses, and the first detailed look at durability in the STK11/KEAP1 co‑mutated subgroup. “These data underscore the potential for STK-012 to improve outcomes for some of the hardest-to-treat patients with lung cancer,” said Naiyer A. Rizvi, M.D., Chief Medical Officer of Synthekine. “Chemoimmunotherapy remains the first‑line standard of care in non‑squamous NSCLC, but many patients derive limited benefit. These tumors are often PD‑L1-negative and/or enriched for STK11, KEAP1, and SMARCA4 loss-of-function alterations, all of which contribute to an immune-cold tumor microenvironment. The response rates and early durability signals we are seeing, together with compelling translational evidence of targeted T‑cell activation, establish a strong case that STK-012 can overcome the immune resistance that has historically limited outcomes in this population.” Efficacy and Safety in Immune Resistant Biology STK-012 plus pembrolizumab and chemotherapy (PCT) demonstrated robust activity in patient subsets typically associated with resistance to chemoimmunotherapy: Nearly all patients in the study were PD‑L1-negative (n=32/36), a population in which standard-of-care chemoimmunotherapy has historically produced objective response rates of 23% to 32%. In contrast, STK-012 plus PCT achieved a 50% objective response rate and 97% disease control rate in the overall efficacy-evaluable population. In patients with STK11, KEAP1, and/or SMARCA4 loss-of-function alterations (n=18/36)—where standard-of-care response rates have been reported in the 7% to 33% range—STK-012 plus PCT delivered a 61% objective response rate and 100% disease control rate. In the STK11/KEAP1 co‑mutated subgroup (n=8/36), STK-012 plus PCT achieved a 50% objective response rate. Median progression-free survival was 5.5 months, with two patients still on treatment, and median overall survival was not reached at a median follow-up of 6.8 months (6-month OS rate 88%). These results compare favorably to published standard-of-care benchmarks of 7%–15% ORR, ~3 months median PFS, and 5.4–7.0 months median OS in this subgroup. STK11/KEAP1 co‑mutated patients represent approximately 10% of first-line NSQ NSCLC. Across 39 safety-evaluable patients, STK-012 plus PCT was generally well tolerated, with no dose-limiting toxicities and no STK-012–related discontinuations. The most common treatment-related adverse events were rash/dermatitis (51%), nausea (51%), and fatigue (46%), which were manageable and reversible. Translational Data Show Selective and Durable Immune Activation New translational data presented at AACR provide strong biological support for the clinical findings: Sustained exposure: STK‑012 half‑life of 5.7 days supports continuous pharmacodynamic activity across the 3‑week dosing cycle Targeted cytokine induction: robust IFN‑γ and IP‑10 induction with minimal IL‑6 and TNF‑α, consistent with selective T‑cell‑driven activity rather than broad immune activation Robust expansion of activated T cells: strong proliferation of 4‑1BB+ CD8+ T cells, with limited expansion of NK cells or regulatory T cells Clonal T cell expansion: 3.5% of circulating T cells were derived from newly expanded clonotypes after a single cycle, and greater clonal expansion was associated with clinical response Immune reactivation in STK11/KEAP1 co‑mutated subgroup: STK‑012 restored proliferation of the activated T‑cell population (4‑1BB+ CD8+), reinvigorated exhausted T cells (PD‑1+ CD8+ T cells), and drove robust clonal T cell expansion—even in tumors with the most suppressive microenvironment “Although STK11/KEAP1 co-mutated tumors have a high neoantigen burden, the immunologically dysfunctional tumor microenvironment renders immune checkpoint inhibitors largely ineffective in this setting,” said Martin Oft, M.D., Chief Scientific Officer of Synthekine. “Our translational data suggest that STK-012 can work synergistically with immune checkpoint inhibitors to help re-engage antitumor immunity and enable functional T-cell responses in these tumors.” The AACR presentation is available on Synthekine’s website . About the SYNERGY-101 Randomized Phase 2 Clinical Trial Development of STK-012 is ongoing in SYNERGY-101, a global, randomized Phase 2 study evaluating STK-012 plus pembrolizumab and chemotherapy versus pembrolizumab and chemotherapy alone in first‑line, PD‑L1-negative non‑squamous NSCLC. The study is currently enrolling with the first patient dosed in November 2025. Synthekine has entered into a clinical trial collaboration and supply agreement with Merck, under which Merck provides Keytruda® (pembrolizumab) for use in the trial. Synthekine retains all commercial rights to STK-012. For additional information about the SYNERGY-101 trial, please visit and use the identifier NCT05098132 . About Synthekine Synthekine is harnessing the potential of cytokine therapeutics to develop selective immunotherapies designed to improve the treatment paradigm of cancer and inflammatory disease. Using insights on cytokine structure and function, the company engineers therapeutics designed to unlock the full efficacy potential of cytokines while avoiding their associated toxicities. Synthekine is applying principles of cytokine partial agonism and immunological specificity across multiple therapeutic areas to create a broad and deep pipeline of product candidates. These novel immunotherapies include modified cytokines and surrogate cytokine agonists. For more information, visit , and follow us on X @synthekine and LinkedIn . Contacts Totyana Simien Inizio Evoke Comms 910-467-1848 Totyana.simien@inizioevoke.com

免疫疗法临床结果临床2期AACR会议

2026-03-22

·CartGo

科研动态周报｜2026年3月15日—22日

一、临床疾病的免疫治疗（CAR-T、TCR-T、过继细胞治疗）1. 体内位点特异性基因编辑实现T细胞原位重编程为CAR-T细胞 In vivo site-specific engineering to reprogram T cells期刊：Nature（开放获取）发表日期：2026年3月18日DOI：https://www.nature.com/articles/s41586-026-10235-x（PubMed: 41851456）机构：加州大学旧金山分校（UCSF）/ Azalea Therapeutics 摘要：UCSF团队开发了结合CRISPR-Cas9核糖核蛋白（通过包膜递送载体EDV靶向T细胞递送）和腺相关病毒AAV-hT7（经工程改造对人T细胞具有高趋向性的新型变体）的双载体系统，在活体人源化小鼠中首次实现了CAR基因精准整合至T细胞TRAC位点。在B细胞急性淋巴细胞白血病（B-ALL）模型中实现80%小鼠完全缓解，并对多发性骨髓瘤（BCMA-CAR）和实体瘤（B7-H3 CAR）同样有效。体内生成的CAR-T细胞表达率最高达脾脏T细胞的19.7%，保留TCF1+记忆前体表型，增殖能力强于传统体外制备CAR-T。重要性：全球首次在体内通过位点特异性方式成功整合大片段基因（CAR）至人T细胞，彻底绕开耗时2–4周、成本极高的体外制备流程，代表细胞治疗领域的范式性突破。2. 瘤内注射工程化CD40激动剂抗体引发全身肿瘤消退 Fc-engineered CD40 agonist antibody induces tertiary lymphoid structures and systemic antitumor immunity in metastatic cancer期刊：Cancer Cell报道日期：2026年3月16日DOI：https://doi.org/10.1016/j.ccell.2025.07.013机构：洛克菲勒大学（Jeffrey V. Ravetch团队）摘要：将Fc工程化CD40激动剂抗体2141-V11（效力较原版提升约10倍）由传统静脉注射改为直接瘤内注射，在12名转移性癌症患者（黑色素瘤、肾细胞癌、乳腺癌等）的I期临床试验中：6名患者（50%）出现全身性肿瘤缩小，2名患者（约17%）达到完全缓解（包括远端未注射部位的转移灶）。活检显示肿瘤内形成三级淋巴结构（TLS），证明局部注射激发全身性免疫应答，且无严重毒副反应。重要性：首次临床证明通过瘤内注射工程化CD40抗体可安全激发"远隔效应"，已启动针对近200名患者的I/II期扩大试验，覆盖膀胱癌、胶质母细胞瘤等难治癌种。3. 前药脂质纳米颗粒协同mRNA癌症免疫治疗 Prodrug-tethered lipid nanoparticles for synergistic messenger RNA cancer immunotherapy期刊：Nature Nanotechnology发表日期：2026年3月18日DOI：https://www.nature.com/articles/s41565-025-02102-z机构：宾夕法尼亚大学（Michael J. Mitchell团队）摘要：设计新型前药可离子化脂质（prodrug ionizable lipids, pILs），通过谷胱甘肽响应性二硫键将IDO抑制剂（Indoximod）共价连接到脂质上，与IL-12 mRNA共同组装成前药脂质纳米颗粒（pLNPs）。瘤内注射后肿瘤内高水平谷胱甘肽触发IDO抑制剂释放，同时IL-12 mRNA翻译激活T细胞，在MC38结肠癌小鼠模型中实现100%原发瘤完全消退，诱导强力免疫记忆和远端效应，全身毒性极低。重要性：将mRNA递送与小分子免疫检查点抑制剂"同步、局部、按需"释放相结合，将"冷"肿瘤转化为"热"肿瘤，是mRNA癌症免疫治疗领域的重大技术突破。4. 澳大利亚TGA批准首个靶向KMA新靶点的CAR-T人体临床试验 TGA Grants First-Ever Australian Clinical Trial Authorisation for KMCAR™ T-cell Therapy in Multiple Myeloma（KOALA Study）来源：HaemaLogiX Ltd / Peter MacCallum Cancer Centre 官方新闻稿发布日期：2026年3月17日链接：https://haemalogix.com/news-details/tga-grants-first-ever-australian-clinical-trial-authorisation-for-a-first-in-human-car-t-cell-therapy 摘要：澳大利亚TGA正式批准靶向全新靶点Kappa骨髓瘤抗原（KMA）的KMCAR™ T细胞疗法I期试验（KOALA研究），用于复发/难治性多发性骨髓瘤。KMA仅表达于骨髓瘤细胞，不在正常免疫细胞（包括B细胞）上表达，有望避免靶向BCMA疗法中常见的严重感染并发症。预计2026年Q2在Peter MacCallum Cancer Centre招募首例患者。重要性：全球首个靶向KMA新型肿瘤特异性抗原的CAR-T疗法进入人体试验，可能克服现有骨髓瘤CAR-T疗法中B细胞缺失/严重免疫抑制的安全性瓶颈。5. 中国细胞与基因治疗新规出台：加速全球最大规模CAR-T临床试验体系 New rules spur cell and gene therapy trials in China期刊：Nature Biotechnology（卷44，第335页）发表日期：2026年3月17日DOI：https://doi.org/10.1038/s41587-026-03065-9 摘要：全球CAR-T临床试验格局分析（1,908项试验）显示，中国（1,006项）和美国（549项）主导了超过80%的全球CAR-T临床试验。中国于2026年3月发布新规（将于5月生效）：将医院主导的细胞与基因治疗临床试验纳入正式监管框架，要求仅限大型教学研究医院开展，需经科学与伦理审查，同时允许经验证的疗法向患者收费提供。重要性：揭示了中国正在主导全球CAR-T临床试验规模的重要事实，新规将进一步加速中国领域的临床转化速度，对全球免疫治疗格局具有深远影响。二、AI在科研领域的应用1. AI辅助乳腺癌筛查达到人类水平，减少63.6%放射科医生工作量 AI-based Triage and Decision Support in Mammography and Digital Tomosynthesis for Breast Cancer Screening: A Paired, Noninferiority Trial期刊：Nature Medicine发表日期：2026年3月19日DOI：https://www.nature.com/articles/s41591-026-04277-x（试验注册：NCT04849776）摘要：这项在31,301名女性中开展的前瞻性配对非劣效性试验评估了AI分诊系统（Transpara v1.7）在乳腺X线摄影（DM）和数字断层合成（DBT）筛查中的效能。AI策略将放射科医生读片工作量降低了63.6%，同时癌症检出率（CDR）从6.3‰提升至7.3‰（相对增加15.2%，P<0.001）。在DM亚组中，CDR相对增加达33.7%，且更多检出为早期T1期、淋巴结阴性的Luminal A型肿瘤。重要性：迄今规模最大的AI乳腺癌筛查随机对照试验之一，首次在临床对照条件下同时证明AI可以显著减少医生工作量并提高癌症检出率，为AI辅助筛查大规模推广提供了高级别循证证据。2. OpenAI全力冲刺"全自动AI研究员"，计划2026年9月推出研究实习生版本 OpenAI is Throwing Everything into Building a Fully Automated Researcher来源：MIT Technology Review发布日期：2026年3月20日链接：https://www.technologyreview.com/2026/03/20/1134438/ 摘要：OpenAI首席科学家Jakub Pachocki宣布将全面转向"AI研究员"战略目标：计划于2026年9月推出可独立处理科研任务的"AI研究实习生"，并在2028年实现能攻克数学证明、生物化学难题等复杂科学问题的全自动多智能体研究系统。GPT-5（Codex底层模型）已协助研究人员解决多个生物、化学和物理领域的未解问题。重要性：OpenAI将资源全面押注于自动化科研智能体，标志着AI在科学发现中的角色正从辅助工具向主动参与者转变，将对整个生物医学研究范式产生深远影响。3. Nature Machine Intelligence发布LLM驱动机器人实验室操作系统框架 A Robot Operating System Framework for Using Large Language Models in Embodied AI期刊：Nature Machine Intelligence发表日期：2026年3月16日DOI：https://www.nature.com/articles/s42256-026-01186-z开源代码：github.com/huawei-noah/HEBO/tree/master/ROSLLM 摘要：华为诺亚方舟实验室联合伦敦大学、苏黎世联邦理工学院等机构发布了将大语言模型（LLM）与机器人操作系统（ROS）深度集成的通用框架（ROSLLM）。该系统可将自然语言指令自动转化为机器人可执行的原子动作序列，通过模仿学习获取新技能，并已在12步咖啡制备、化学实验模拟等复杂任务中完成验证，框架完全基于开源LLM。重要性：大幅降低实验室自动化编程门槛，是向"机器人实验室"迈进的关键基础设施，对生命科学领域的高通量实验自动化具有直接应用价值。4. MIT生成式AI模型在密码子优化任务上全面超越商业工具 AI Breakthroughs in 2026: March Update（MIT Codon Optimization AI Model）来源：Kersai Research Team（2026年3月12日）链接：https://kersai.com/ai-breakthroughs-in-2026-march-update/ 摘要：MIT研究人员发布了专用于密码子优化和蛋白质产量预测的生成式AI模型，在人生长激素、曲妥珠单抗、IL-2、促红细胞生成素等6种治疗性蛋白的测试中，5种超过了4款主流商业工具。密码子优化是生物制剂开发中耗时数月的瓶颈步骤，该模型基于大规模实验室实验数据集训练，可将流程缩短至数小时。分析师估计AI驱动的早期生物制剂开发每年可为全球制药业节省150–400亿美元。重要性：类AlphaFold式范式转变在药物制造链前端的最新体现，AI正在系统性地替代昂贵的实验室试错，直接加速新型蛋白质药物（含抗体、细胞因子、疫苗抗原）的研发周期。5. AI系统DeepRare在罕见病诊断中首次超越经验丰富医生 AI System Outperforms Physicians in Rare Disease Diagnosis（DeepRare）机构：上海交通大学报道来源：The Next Web（2026年3月7日）；humai.blog 3月19日汇总链接：https://www.humai.blog/ai-news-trends-march-2026-complete-monthly-digest/ 摘要：上海交通大学开发的AI诊断系统DeepRare整合了40种专业分析工具，在罕见病诊断测试中首次诊断建议准确率达64.4%，显著优于经验丰富医生的54.6%；当给出3个诊断建议时，AI准确率提升至79%（医生为66%）。罕见病通常需要平均4–7年才能确诊，该系统有望大幅缩短确诊时间。重要性：首个在严格对比测试中超越有经验临床医生的罕见病AI诊断系统，具有重要的临床转化价值，尤其对中国数量庞大的罕见病患者群体意义重大。三、抗体改造最新进展1. 双特异性T细胞衔接器首次成功治疗难治性自身免疫性结缔组织病 Bispecific T Cell Engagers for Treatment-Refractory Autoimmune Connective Tissue Diseases期刊：Nature Medicine发表日期：2026年2月19日（3月进入广泛临床讨论期）DOI：https://www.nature.com/articles/s41591-026-04238-4 摘要：病例系列研究（n=10）探索了已批准的双特异性T细胞衔接器——blinatumomab（CD19×CD3）用于难治性抗合成酶综合征（ASyS，n=5），teclistamab（BCMA×CD3）用于难治性系统性硬化症（SSc，n=5）。所有患者对包含利妥昔单抗在内的≥3种免疫调节方案无效。治疗后ASyS患者肌酸激酶迅速恢复正常、肌力改善；SSc患者皮肤纤维化评分改善、间质性肺病稳定。自身抗体滴度显著下降，B细胞/浆细胞被深度清除，主要安全事件为细胞因子释放综合征（多为1–2级）。重要性：双特异性抗体治疗适应症从血液肿瘤跨越到难治性自身免疫疾病的重要里程碑，证明了CAR-T之外还存在更便捷的"现成型"细胞靶向清除策略。2. AACR 2026重磅预告：全球首个三有效载荷ADC亮相，多载荷ADC浪潮持续涌现 AACR 2026 – Conjugates Remain Centre Stage来源：ApexOnco / Oncology Pipeline发布日期：2026年3月19日链接：https://www.oncologypipeline.com/apexonco/aacr-2026-conjugates-remain-centre-stage 摘要：AACR 2026摘要（会议将于4月17–22日举行）披露重磅ADC进展：①Araris（大冢子公司）的ARC-401，靶向Nectin-4的全球首个三有效载荷ADC，大冢为此支付4亿美元首付款；②DualityBio的DB-1326（靶向TA-MUC1双载荷）；③Astellas的ASP2998（首次揭示为TROP2双载荷ADC）；④Sutro Biopharma的HER2双载荷ADC；⑤GSK/Hansoh的Risvutatug rezetecan（B7-H3靶向）进入关键临床阶段。重要性：三有效载荷ADC的首次亮相标志着ADC设计达到新的工程复杂度，有望进一步拓宽治疗窗口并克服耐药性。3. HER2靶向ADC新药SHR-A1811全球1期最终数据：乳腺癌ORR达78.7%，ILD发生率仅2.5% SHR-A1811, a novel HER2-targeting ADC, in advanced solid tumors（HORIZON-X）: a global phase 1 trial final results期刊：Signal Transduction and Targeted Therapy（Nature出版集团）发表日期：2026年3月19日DOI：https://www.nature.com/articles/s41392-026-02612-9 摘要：HORIZON-X是SHR-A1811（恒瑞医药开发的HER2靶向ADC）的全球多中心1期最终分析，纳入396名经大量前线治疗的晚期实体瘤患者。HER2阳性乳腺癌的客观缓解率（ORR）高达78.7%，中位无进展生存期（mPFS）达25个月；所有肿瘤类型综合ORR为58.6%。特别值得关注的是，即使在HER2超低表达/IHC 0乳腺癌患者（n=54）中，ORR仍达59.3%，显示显著旁观者效应。间质性肺病（ILD）发生率仅2.5%，远低于同类药物。重要性：SHR-A1811较低的ILD毒性是相对于T-DXd（DS-8201）的差异化优势，HER2超低表达适应症的探索更是将ADC可及患者群体大幅扩展。4. ESMO 2026靶向疗法大会：四特异性抗体MDX2001/MDX2003展示同时靶向双抗原+共刺激的临床前数据 From Bi- to Multispecific Antibodies: A Highly Promising Field — ESMO Targeted Anticancer Therapies Congress 2026来源：ESMO Daily Reporter，ESMO TAT Congress 2026发布日期：2026年3月18日链接：https://dailyreporter.esmo.org/esmo-targeted-anticancer-therapies-congress-2026/opinions/from-bispecific-to-multispecific-antibodies-a-highly-promising-field 摘要：Zymeworks的Nina Weisser综述了多特异性抗体最新进展。关键亮点：①四特异性抗体MDX2001（靶向CD3×CD28×cMET×Trop2）和MDX2003（CD3×CD28×CD19×CD20）临床前数据显示，结合双肿瘤抗原靶向+共刺激功能的设计可克服肿瘤异质性，显著增强T细胞活化、增殖和存活；②BCMAxGPRC5DxCD3三特异性抗体在复发/难治多发性骨髓瘤中展现良好前景；③tarlatamab（DLL3×CD3双抗）联合PD-L1抑制剂用于小细胞肺癌一线治疗的III期试验正在推进。重要性：从双特异性到四特异性的抗体工程化改造已从概念验证迈向实体验证，整合共刺激信号是克服实体瘤T细胞衔接器局限性的前沿策略。5. 无细胞蛋白合成+生物层干涉技术构建纳米抗体突变体超高速筛选平台 A Rapid Cell-Free Expression Platform for Screening of Nanobody Mutants期刊：Biotechnology and Bioprocess Engineering（Springer Nature）发表日期：2026年3月16日DOI：https://link.springer.com/article/10.1007/s12257-026-00273-7 摘要：开发了将无细胞蛋白质合成（CFPS）与生物层干涉技术（BLI）深度集成的纳米抗体高通量筛选平台：仅需线性DNA模板（无需分子克隆），在4小时内合成纳米抗体；通过GFP荧光融合标签即时定量蛋白浓度；无需纯化直接用于BLI亲和力分析。对黄曲霉毒素B1（AFB1）纳米抗体突变体的测试显示，平台与传统方法的Pearson相关系数高达0.968，将筛选周期从数周缩短至数小时，效率提升>95%。重要性：纳米抗体工程化改造流程的重大加速器，特别适合需要大规模并行突变筛选的场景，将有力推动新一代高亲和力纳米抗体药物的发现。四、其他免疫分子的工程改造1. 双特异性DC-T细胞衔接器（BiDT）重激活肿瘤浸润耗竭T细胞 Reactivating exhausted tumor-infiltrating T cells by a bispecific DC-T cell engager in mice期刊：Nature Communications（开放获取）发表日期：2026年3月17日DOI：https://doi.org/10.1038/s41467-026-70876-4通讯作者：Yang-Xin Fu（傅阳心），Wenyan Wang 摘要：设计双特异性分子BiDT（抗TIM3-IFNα融合蛋白），通过抗TIM3抗体靶向肿瘤浸润耗竭T细胞，通过IFNα激活肿瘤内树突状细胞（DC）的I型干扰素受体，在肿瘤微环境内重建DC-T细胞协同对话。BiDT上调抗凋亡蛋白Bcl-2保护耗竭T细胞，并借助DC分泌的IL-2等信号重激活其效应功能。为解决全身IFNα毒性，进一步开发了前体药物形式Pro-BiDT（IFNα仅在肿瘤内被MMP酶激活），在临床前模型中显示与BiDT相当的抗肿瘤疗效，全身毒性显著降低。重要性：融合蛋白与免疫检查点分子工程改造的有机结合，创新地利用"桥接衔接器"策略同时靶向检查点分子TIM3和激活先天免疫（DC-IFNα轴），为克服T细胞耗竭提供了全新分子设计思路。2. IL-7/IL-15/IL-21三联细胞因子融合支架（HCW9206）生成高功能性记忆干性CAR-T细胞 IL-7/IL-15/IL-21 cytokine-fusion scaffold generates highly functional CAR T cells substantially enriched for T memory stem cells期刊：Science Advances发表日期：2026年3月13日PubMed：PMID 41824575；DOI：https://www.science.org/doi/10.1126/sciadv.aec2632 摘要：开发了名为HCW9206的三联细胞因子融合蛋白支架，将IL-7、IL-15/IL-15Rα复合物及IL-21整合于单一分子中，用于CAR-T细胞的制备。无需TCR刺激（αCD3/CD28）即可高效扩增和转导T细胞，所产生CAR-T细胞中T记忆干细胞（TSCM）比例超过50%，具有更强自我更新能力。在HIV感染人源化小鼠模型和CD19+ B细胞白血病（NALM-6）模型中均展现出优于传统方法的持久性和抗肿瘤/抗病毒活性。重要性：三联细胞因子融合支架策略从源头重塑CAR-T细胞的干性和持久性，代表了细胞因子工程与细胞疗法制造的重要整合突破。3. Synthekine公布STK-012（α/β偏向性IL-2精准激动剂）联合帕博利珠单抗治疗免疫抵抗型肺癌的1期临床更新数据 STK-012: An α/β IL-2 receptor-biased partial agonist in 1L PD-L1-negative nonsquamous NSCLC with features of immunotherapy resistance（AACR 2026 口头报告）来源：Synthekine Inc. 新闻稿发布日期：2026年3月17日链接：https://www.synthekine.com/news/synthekine-announces-aacr-2026-oral-presentation... 摘要：STK-012是工程化的α/β受体偏向性IL-2部分激动剂，选择性激活抗原激活的T细胞（而非静息Treg细胞），规避传统IL-2的系统毒性。Phase 1a/1b临床试验针对PD-L1阴性、STK11突变等具有免疫抵抗特征的一线非鳞状NSCLC患者，联合帕博利珠单抗+化疗标准方案，现已完成患者入组。随机Phase 2试验（SYNERGY-101）已在全球招募，约**40%**新诊断非鳞状NSCLC患者具有上述免疫抵抗特征。重要性：精准工程化IL-2变体克服免疫治疗抵抗的前沿临床策略，是IL-2分子工程化进入关键人群验证阶段的标志性进展。4. Forlong Biotechnology发布FL116（PD-1/IL-18双特异性融合抗体）临床前数据：AI平台驱动的可调控IL-18变体逃逸诱骗受体并重塑肿瘤免疫微环境 FL116, a PD-1/IL-18 bispecific antibody, enables cis-activation of PD-1+ T cells and reshapes the suppressive tumor microenvironment（AACR 2026摘要）来源：Forlong Biotechnology 新闻稿发布日期：2026年3月17日链接：https://www.pharmiweb.com/press-release/2026-03-17/forlong-biotechology-to-present-preclinical-data-from-fl115-a-novel-interleukin-15-il-15-superago 摘要：复融生物利用AI驱动的智能生物分子发现平台，工程化设计了能完全逃逸IL-18结合蛋白（IL-18BP诱骗受体）中和、同时具有可调IL-18R1亲和力的IL-18变体（IL-18v）。将该IL-18v与抗PD-1抗体融合构建的双特异性融合抗体FL116，可实现对PD-1+肿瘤浸润T细胞的"顺式激活（cis-activation）"——在阻断PD-1抑制信号的同时，通过融合的IL-18v原位激活IL-18信号通路。临床前多瘤种模型中FL116显示强大抗肿瘤活性及免疫记忆形成，将肿瘤微环境改造为高炎性、效应T细胞主导的状态。重要性：AI辅助的蛋白质工程与双特异性抗体融合策略的有机结合，通过克服IL-18的天然屏障并整合PD-1检查点阻断，展现了下一代免疫检查点/细胞因子联合分子平台的强大潜力。5. 《Nature Reviews Immunology》综述：细胞因子武装的CAR-T细胞——用可调控系统平衡疗效与安全性 Progress in the development of cytokine armoured CAR T cells期刊：Nature Reviews Immunology发表日期：2026年3月DOI：https://www.nature.com/articles/s41577-026-01280-8 摘要：综述了第四代"武装型"CAR-T细胞的研发进展，聚焦于IL-12、IL-18、IL-15、IL-7/CCL19、IL-10、IL-2、IL-23等多种细胞因子武装CAR-T细胞的临床前及临床结果。重点介绍了两类新兴条件性表达系统：①基于NFAT、PD-1等内源性启动子的可诱导表达；②基于synNotch等合成受体的逻辑门控表达，用于将细胞因子表达精确限制在肿瘤微环境内，同时最大化疗效、降低全身毒性。重要性：为免疫分子工程改造的最新方向提供了全面的参考框架，特别是条件性细胞因子分泌策略代表了克服武装CAR-T毒性瓶颈的关键思路。本周重点文献详细介绍⭐ 本周最值得关注：体内位点特异性T细胞重编程——CAR-T细胞治疗的范式性突破论文标题：In vivo site-specific engineering to reprogram T cells 期刊与发表日期：Nature，2026年3月18日在线发表（开放获取） DOI/链接：https://www.nature.com/articles/s41586-026-10235-x 研究背景 CAR-T细胞治疗在血液肿瘤领域取得了令人瞩目的成就，已有6款产品在全球获批上市。然而，这一疗法长期面临一个根本性障碍：每位患者需要经历"采血→体外扩增→基因工程改造→回输"的完整流程，耗时2–4周，费用高达数十万至上百万美元，且约10%–30%的患者因病情进展等原因无法等到回输时机。如何将CAR-T细胞治疗从"体外制造"转为"体内生成"，是过去十年该领域最重要的前沿方向之一。研究问题与方法 UCSF团队提出了一套精巧的双载体系统，解决了体内CAR-T生成面临的两大核心难题：如何靶向递送、如何实现位点特异性整合（而非传统慢病毒的随机整合）。具体方案：①包膜递送载体（EDV）——表面展示抗CD3单链抗体，特异性靶向T细胞，携带CRISPR-Cas9核糖核蛋白，在T细胞TRAC位点（内源性TCR基因座）产生精准切割；②新型腺相关病毒AAV-hT7——通过对AAV衣壳进行工程化进化，产生对人T细胞亲和力极高且能抵抗血清中和抗体的新型变体，携带靶向TRAC位点的同源修复模板（包含CAR编码序列）。两种载体协同作用：EDV切开位点，AAV递送CAR"插件"，利用T细胞自身的同源定向修复机制，将CAR基因精准"嵌入"TRAC位点，由内源性TRAC启动子驱动生理性表达。主要发现在人源化小鼠（NSG MHC-I/II双敲除，植入人PBMC）模型中，单次静脉注射双载体后：①脾脏T细胞中CAR+细胞比例最高达19.7%；②体内生成的CAR-T细胞保留TCF1+记忆前体细胞表型，自我更新能力更强；③在B-ALL（CD19-CAR）模型中，80%小鼠实现完全缓解，且能抵抗肿瘤再次攻击；④在多发性骨髓瘤（BCMA-CAR）和肉瘤（B7-H3 CAR）模型中也展示了显著抗肿瘤活性；⑤体内CAR-T细胞的扩增速度和质量均优于传统体外制备的CAR-T细胞。科学意义这项工作在技术层面实现了三个"第一"：第一次在活体内完成大片段DNA（CAR基因全长）的位点特异性整合；第一次在人源化小鼠体内实现体内生成的CAR-T细胞对多种血液肿瘤和实体瘤的有效治疗；第一次验证了EDV+进化型AAV双载体系统在T细胞靶向基因编辑中的可行性。从临床转化角度，该平台如成功进入临床，将使CAR-T疗法彻底摆脱个性化体外制造流程，降低生产成本和时间，显著提升患者可及性。承接该项目的初创公司Azalea Therapeutics已于文章发表当日发布公告，将推进临床转化。写在最后从"体外制造"到"体内生成"，从"打一针一处"到"全身效应"，从"医生读片"到"AI辅助"……这一周的科研进展告诉我们：免疫治疗的未来，正在快速变得更便宜、更快捷、更精准。虽然大多数研究目前还在动物模型或早期临床阶段，距离真正用于每位患者还需要更多时间和验证——但方向已经越来越清晰。科学家们正在合力打造一套新武器，让更多癌症患者能够获得希望。

细胞疗法免疫疗法临床1期临床申请信使RNA

2026-03-18

·BioSpace

Synthekine Announces AACR 2026 Oral Presentation of Updated Phase 1a/1b Clinical and Translational Data for STK‑012 in First‑Line Nonsquamous NSCLC with Features of Immunotherapy Resistance

STK-012 is an α/β biased IL-2 precision immunotherapy designed to specifically stimulate antigen activated T cells Updated clinical and translational results for STK‑012 plus pembrolizumab and chemotherapy will be presented, demonstrating potential to benefit first‑line nonsquamous NSCLC patients whose tumors have features of immune resistance Immune resistance features include PD-L1 negative tumor histology, STK11 mutations, and STK11/KEAP1 co-mutations MENLO PARK, Calif.--(BUSINESS WIRE)-- Synthekine Inc ., an engineered cytokine therapeutics company, today announced that updated clinical and translational data from a Phase 1a/1b clinical trial of its α/β biased IL-2 partial agonist, STK-012, will be presented in an oral presentation at the upcoming American Association for Cancer Research (AACR) Annual Meeting 2026 taking place in San Diego, CA from April 17 - 22, 2026. In this now fully enrolled study, STK-012 is being evaluated in combination with standard-of-care pembrolizumab + chemotherapy in first-line nonsquamous (NSQ) non-small cell lung cancer (NSCLC) patients with features of immune resistance such as PD-L1 negative histology and STK11/KEAP1 mutations. “We are encouraged to share updated clinical and translational data from first‑line NSQ NSCLC patients treated with STK‑012, building on our prior oral presentation at SITC 2025 and further supporting our novel and differentiated, α/β‑biased IL‑2 approach to precision immunotherapy,” said Debanjan Ray, chief executive officer of Synthekine. “40% or more of newly diagnosed NSQ NSCLC patients have features of immune resistance, including PD‑L1‑negative histology or STK11/KEAP1 mutations, and typically derive limited benefit from standard‑of‑care chemoimmunotherapy. We believe STK‑012, in combination with pembrolizumab and chemotherapy, has the potential to meaningfully improve outcomes in this underserved patient population, and we look forward to presenting these updated data at AACR. Development of STK-012 is ongoing in our SYNERGY-101 study, a global, randomized Phase 2 trial which is currently enrolling patients.” Details are as follows and are available in the AACR Online Program Planner : Title: Selective immune activation of antigen activated T cells with STK-012, an a/b IL-2 receptor biased partial agonist, with pembrolizumab and chemotherapy in 1L PD-L1 negative non-squamous NSCLC Session Title: Immunotherapy: Mechanisms and Responses Session Date & Time: Tuesday, April 21, 2026, 2:30 – 4:30 PM PT Location: Listed in the AACR Online Program Planner Abstract Number: 6740 A copy of the presentation will be available on Synthekine’s website following presentation at the meeting. About Synthekine Synthekine is harnessing the potential of cytokine therapeutics to develop selective immunotherapies designed to improve the treatment paradigm of cancer and inflammatory disease. Using insights on cytokine structure and function, the company engineers therapeutics designed to unlock the full efficacy potential of cytokines while avoiding their associated toxicities. Synthekine is applying principles of cytokine partial agonism and immunological specificity across multiple therapeutic areas to create a broad and deep pipeline of product candidates. These novel immunotherapies include modified cytokines and surrogate cytokine agonists. For more information, visit , and follow us on X @synthekine and LinkedIn . Contacts Totyana Simien Inizio Evoke Comms 910-467-1848 Totyana.simien@inizioevoke.com

AACR会议免疫疗法临床2期

100 项与 STK-012 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
晚期恶性实体瘤	临床2期	美国	Synthekine, Inc.	2022-01-25
非小细胞肺癌	临床2期	美国	Synthekine, Inc.	2022-01-25

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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


NCT05098132 (SYNERGY-101, AACR2026)	临床1期	PD-L1阳性非鳞状非小细胞肺癌一线 PD-L1 negative \| LoF TSG mutations \| mucinous histology	22	STK-012 + pembrolizumab + chemotherapy	獵醖廠鑰憲淵膚淵醖簾(鹽築衊憲獵窪餘顧積醖) = induced key cytokines IFNγ and IL-18 characterizing an activated CD8+ T cell response and increased IP-10 which is associated with enhanced T cell trafficking into tumor tissues (13x,14x and 23x mean increase from baseline, respectively). Sustained elevation of cytokines across treatment cycles (IFNγ median peak of 71, 95, 96 pg/mL in C1, C2 and C6) was observed, supportive of the emerging durability of the combination. 獵鏇襯鹽選憲觸壓獵襯 (醖醖糧齋製壓積築憲憲 ) 更多	积极	2026-04-21
NCT05098132 (SYNERGY-101, AACR2026)	临床1期		22	STK-012 + pembrolizumab + chemotherapy (PD-L1<1%)		积极	2026-04-21
NCT05098132 (STK-012-101, ESMO2025)	临床1期	非小细胞肺癌一线	50	STK-012 + pembrolizumab + carboplatin + pemetrexed	鹹願鹹淵壓網鬱淵選鹹(壓遞夢餘蓋廠艱廠製膚) = 鑰鏇範築蓋憲遞淵憲餘襯窪願壓鬱簾廠衊鏇鏇 (觸構艱夢鑰壓鑰廠鹽鹽 ) 更多	积极	2025-10-17
NCT05098132 (STK-012-101, SITC2024) 人工标引	临床1期	晚期恶性实体瘤	-	STK-012 2.25mg Q3W	餘獵襯觸憲製廠膚鹽襯(繭築構蓋願壓窪鹽糧壓) = 艱鑰顧獵築願獵鏇餘壓襯餘廠積醖鬱衊鏇壓遞 (鏇觸積鏇衊獵衊顧遞鬱 ) 更多	积极	2024-11-05
NCT05098132 (Biospace) 人工标引	临床1期	实体瘤	47	STK-012	積齋壓製網餘鬱觸築鑰(構膚網選憲襯遞鏇壓齋) = Treatment-related adverse events (TRAEs) were reversible with standard management and mostly Grade 1 or 2 in severity. Most common TRAEs (≥10% of subjects) were maculopapular rash, fatigue, injection site reaction, nausea, diarrhea, pruritis, vomiting, and arthralgia. 選鬱顧鬱醖繭築餘蓋鏇 (築餘襯淵襯鑰鏇齋鑰構 ) 更多	积极	2024-04-09