PO.CT01.02 · 临床试验
从临床前模型到STC-1010免疫疗法治疗不可切除晚期结直肠癌的首次人体评价
From preclinical models to first-in-human evaluation of STC-1010 immunotherapy in unresectable advanced colorectal cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：结直肠癌（CRC）是全球第三大常见癌症，也是癌症死亡的第二大原因。它包括两种生物学亚型：微卫星稳定型（MSS，85-95%）和微卫星不稳定型（MSI-H）肿瘤。MSI-H肿瘤对免疫疗法有响应，而MSS肿瘤仍为“冷”肿瘤并依赖化疗。STC-1010是一种首创的、源自刺激鬼影细胞（SGC）平台的同种异体抗原诱导免疫疗法。SGC通过对CRC细胞系施加受控的物理或化学应激产生，随后进行半抗原化以增强免疫识别；随后细胞被灭活。BreAK CRC 001是一项首次人体试验，评估STC-1010联合标准化疗治疗不可切除晚期CRC。本研究旨在通过评估STC-1010联合化疗的免疫原性和抗肿瘤活性，将临床前发现转化至临床。
方法：进行了多组学分析以识别STC-1010抗原与CRC异质性的相关性。在同基因CRC模型中评估了鼠源替代物的抗肿瘤活性。开展了离体机制研究以评估STC-1010致敏的CD8⁺ T细胞对CRC细胞系的杀伤效力。BreAK CRC 001是一项首次人体、开放标签的I/IIa期研究，评估STC-1010联合低剂量环磷酰胺、GM-CSF（STC-1010方案）并联合标准化疗治疗不可切除的局部晚期或转移性CRC。I期评估安全性、剂量限制性毒性和推荐2期剂量（RP2D）；IIa期将评估安全性、临床活性和免疫应答。
结果：STC-1010提供了广泛的免疫原性抗原库，涵盖CRC异质性。在鼠模型中，mSTC-1010减少了肿瘤负荷、改善了生存，且当与FOLFOX化疗联合时，与对照相比显著减小了肿瘤体积。这些效应与CD8⁺ T细胞浸润增加相关。离体研究中，经STC-1010处理的树突状细胞致敏的CD8⁺ T细胞在多种CRC细胞系（HCT116、HT29、SW620）中诱导了强烈的凋亡。截至2026年1月，6例不可切除转移性CRC患者在I期剂量递增部分接受了STC-1010方案联合标准治疗（SOC）化疗。治疗耐受良好，主要为1级输注相关反应，在前两个剂量水平未出现剂量限制性毒性。尽管治疗持续时间不一，但观察到初步临床活性，包括按RECIST v1.1评估的部分缓解和疾病稳定。
结论：STC-1010方案在CRC模型中恢复了抗肿瘤免疫并增强了免疫细胞活化，支持其继续临床开发。联合化疗时，其显示出可控的安全性和早期临床活性迹象，与临床前模型中观察到的抗肿瘤效应一致。
查看英文原文 English abstract
Background: Colorectal cancer (CRC) is the third most common cancer worldwide and the second leading cause of cancer death. It comprises two biological subtypes: microsatellite-stable (MSS, 85-95%) and microsatellite-instable (MSI-H) tumors. While MSI-H tumors respond to immunotherapy, MSS tumors remain “cold” and rely on chemotherapy. STC-1010 is a first-in-class, allogeneic antigen-induced immunotherapy derived from the Stimulated Ghost Cells (SGC) platform. SGC are produced by applying controlled physical or chemical stress to CRC cell lines, followed by haptenation to boost immune recognition; the cells are then inactivated. BreAK CRC 001 is a first-in-human trial evaluating STC-1010 with standard chemotherapy in unresectable advanced CRC. This study aims to translate preclinical findings into the clinical setting by evaluating the immunogenicity and antitumor activity of STC-1010 in combination with chemotherapy.
Methods: Multi-omics analyses were performed to identify STC-1010 antigens relevance to CRC heterogeneity. The anti-tumor activity of a murine surrogate was evaluated in syngeneic CRC models. Mechanistic studies were conducted ex vivo to evaluate STC-1010-primed CD8⁺ T cells killing potency against CRC cell lines. BreAK CRC 001 is a first-in-human, open-label phase I/IIa study of STC-1010 combined with low-dose of cyclophosphamide, GM-CSF (STC-1010 regimen), and associated to standard chemotherapy for unresectable locally advanced or metastatic CRC. Phase I evaluated safety, dose-limiting toxicities, and recommended phase II dose (RP2D); phase IIa will assess safety, clinical activity and immune responses.
Results: STC-1010 provides a broad repertoire of immunogenic antigens capturing CRC heterogeneity. In murine models, mSTC-1010 reduced tumor burden, improved survival, and, when combined with FOLFOX chemotherapy, significantly decreased tumor volumes compared with control. These effects were associated with increased CD8⁺ T cell infiltration. Ex vivo, CD8⁺ T cells primed by STC-1010-treated dendritic cells induced robust apoptosis in multiple CRC cell lines (HCT116, HT29, SW620). As of January 2026, 6 patients with unresectable metastatic CRC received STC-1010 regimen with SOC chemotherapy in the phase I dose-escalation part. Treatment was well tolerated, with predominantly grade 1 infusion-related reactions and no dose-limiting toxicities at the first two dose levels. Despite variable treatment duration, preliminary clinical activity was observed, including partial responses and stable disease per RECIST v1.1.
Conclusion: STC-1010 regimen restores anti-tumor immunity and enhances immune cell activation in CRC models, supporting its continued clinical development. Combined with chemotherapy, it showed a manageable safety profile and early signs of clinical activity, consistent with the antitumor effects observed in preclinical models.
利益披露 Disclosure
D. Tosi,
Brenus Independent Contractor, Institutional funding.
Mabqi Independent Contractor.
Tes Pharma Independent Contractor.
AAA Travel, Meeting attendance.
Pfizer Travel, Meeting attendance.
MSD Travel, Meeting attendance.
Ipsen Travel, Meeting attendance.
Novartis Other, Meeting inscription fee.
A. Italiano,
Bayer ).
Merck ).
MSD ).
BMS ).
AstraZeneca ).
Roche ).
Amgen ).
A. Hollebecque,
Amgen Travel.
Roche Travel.
Incyte Independent Contractor.
Taiho Independent Contractor.
Abbvie Other.
B. You,
Roche/Genentech Independent Contractor.
AstraZeneca Independent Contractor.
Novartis Independent Contractor.
GSK-Tesaro Independent Contractor.
Bayer Independent Contractor.
Amgen Independent Contractor.
Clovis Oncology Independent Contractor.
MSD Independent Contractor.
Merck KGaA Independent Contractor.
Pharma& Independent Contractor.
ECS Progastrin Independent Contractor.
Gilead Independent Contractor.
Myriad Genetics Independent Contractor.
Seagen Independent Contractor.
BMS Independent Contractor.
Menarini Independent Contractor.
Eisai Independent Contractor.
Abbvie Independent Contractor.
See2Cure company Stock.
P. Cassier,
AstraZeneca; Boehringer Ingelheim; Brenus Pharma; Bristol Myers Squibb; GreyWolf therapeutics; MabQuest; Merck Sharp Dohme; Ose Immunotherapeutics; Pierre Fabre; Servier; Scenic Independent Contractor.
Novartis; Pierre Fabre Travel.
Debio Pharm; GSK; Merck Sharp Dohme; Novartis Other, Non-financial support.
Abbvie; Adlai Nortye; Amgen; Arcus; Astellas; Boehringer Ingelheim; Blueprint; C4 Therapeutics; Debio Pharm; Daiichi Sankyo; Dragonfly; Ellipse; Exelixis; Incyte; Iteos; Ipsen; Janssen; Kinnate ).
Lilly/Loxo; Mabquest; Molecular Partners; Novartis; Ose Immunotherapeutics; Pierre Fabre; Regeneron; Relay; Roche/Genentech; Sotio; Taiho; Tango; Toray; Transgene ).
F. Sclafani,
AMAL Therapeutics Independent Contractor.
Amgen Independent Contractor, ), Travel.
Bayer Independent Contractor, ), Travel.
BMS Independent Contractor, ).
Dragonfly Therapeutics Independent Contractor.
GSK Independent Contractor.
Medimix Independent Contractor.
Merck Independent Contractor, ), Travel.
Nordic Pharma Independent Contractor.
Roche Independent Contractor, ), Travel.
Servier Independent Contractor, ), Travel.
AstraZeneca ), Travel.
Astellas ).
Sanofi ).
MSD ).
Pierre-Fabre ).
Sanofi ).
Eli Lilly Travel.
D. Tougeron,
Pierre Fabre ), Travel.
Gilead ).
Roche ), Travel.
MSD ), Travel.
Takeda ).
Servier ), Travel.
Amgen ), Travel.
Astrazeneca Travel.
E. Christenson,
Boston Scientific; Parabilis; Roche; Seres Therapeutics; SirTex; Tatum Biosciences; Urogen Independent Contractor.
Affimed GMBH; Parabilis; Haystack; Incyte; NextCure; Pfizer; Regeneron ).
NextCure Travel.
Brenus Pharma Uncompensated Relationship.
C. Gongora, None.
I. Richert,
Brenus Pharma Employment.
G. Alzeeb,
Brenus Pharma Employment.
P. Marteau, None.
M. Brun,
Brenus Pharma Employment.
L. Feki,
Brenus Pharma Employment.
L. Chalus,
Brenus Pharma Employment.
B. Pinteur,
Brenus Pharma Employment.
P. Bravetti,
Brenus Pharma Employment.
S. Kerbouche,
Brenus Pharma Employment.
C. Tortorelli,
Brenus Pharma Employment.
F. Ghiringhelli,
AstraZeneca ).
Roche ).
Servier Travel.
Amgen Travel.
MSD Travel.