Gregory Richard C, Lineberry Neil, Parent Alex, Rajasekaran Karthik, Ow Thomas J, Nathan Cherie-Ann, Hatton Beryl A, Jenkins Wendy, Grenley Marc, Burns Connor, Merrell Angela, Frazier Jason P, Derry Jonathan M J, Beirne Emily, Klinghoffer Richard A
Takeda Development Center Americas, Inc. (TDCA), Cambridge, Massachusetts.
University of Pennsylvania, Philadelphia, Pennsylvania.
Cancer Res Commun. 2025 Jul 1;5(7):1243-1255. doi: 10.1158/2767-9764.CRC-25-0314.
The tumor microenvironment (TME) is difficult to model in an in vivo cancer research setting. This study leveraged intratumor microdosing using comparative in vivo oncology (CIVO) with spatial profiling to evaluate the effects of the stimulator of interferon genes agonist dazostinag, alone or with chemotherapy, on cellular responses within the native TME of intact human tumors.
This phase 0 study enrolled adult patients with head and neck squamous cell carcinoma (HNSCC) planned for surgical intervention. Intratumoral microdose injections of dazostinag (maximum dose: 1.68 μg in a 0.05 mg/mL solution), alone or combined with various chemotherapies, were delivered via CIVO to tumors 24, 48, 72, or 96 hours prior to resection. Each tumor sample was prepared for analysis using IHC and ISH. Analysis of the microdosed tumors using the GeoMx Digital Spatial Profiler and CosMx Spatial Molecular Imager was performed in one patient.
Type 1 IFN signaling was induced with dazostinag alone and in combination with chemotherapy from multiple cell types within the TME, including immune cells. Dazostinag also shifted the polarization of macrophages from an immune-suppressive phenotype to a proinflammatory phenotype at 24 hours after injection. Enrichment of cytotoxic T cells was observed in regions of localized dazostinag exposure, coinciding with increased chemokine (CXCL9) expression. Based on cleaved caspase-3, an apoptosis marker, dazostinag plus chemotherapy increased cellular apoptosis relative to either drug alone.
Utilizing CIVO and spatial profiling technology, dazostinag alone and combined with chemotherapy promoted an early proinflammatory response and enhanced chemotherapy-mediated cell death in the native TME of intact human HNSCC tumors.
The CIVO approach demonstrates that dazostinag alone and combined with chemotherapy promotes both proapoptotic and early proinflammatory responses in the native TME of intact human HNSCC tumors, providing clinical evidence for an on-target mechanism of action and rationale for further clinical investigation.
肿瘤微环境（TME）在体内癌症研究环境中难以建模。本研究利用肿瘤内微剂量给药，结合比较体内肿瘤学（CIVO）和空间分析，评估干扰素基因激动剂达佐司他单独或与化疗联合使用时，对完整人类肿瘤天然TME内细胞反应的影响。
本0期研究纳入计划接受手术干预的成年头颈部鳞状细胞癌（HNSCC）患者。通过CIVO在切除前24、48、72或96小时向肿瘤内微剂量注射达佐司他（最大剂量：0.05 mg/mL溶液中1.68 μg），单独或与各种化疗联合使用。每个肿瘤样本均采用免疫组化（IHC）和原位杂交（ISH）进行分析准备。对一名患者使用GeoMx数字空间分析仪和CosMx空间分子成像仪对微剂量给药的肿瘤进行分析。
单独使用达佐司他以及与化疗联合使用时，可诱导TME内多种细胞类型（包括免疫细胞）产生1型干扰素信号。达佐司他还在注射后24小时将巨噬细胞的极化状态从免疫抑制表型转变为促炎表型。在达佐司他局部暴露区域观察到细胞毒性T细胞富集，同时趋化因子（CXCL9）表达增加。基于凋亡标志物裂解的半胱天冬酶-3，与单独使用任一药物相比，达佐司他加化疗可增加细胞凋亡。
利用CIVO和空间分析技术，单独使用达佐司他以及与化疗联合使用时，可在完整人类HNSCC肿瘤的天然TME中促进早期促炎反应并增强化疗介导的细胞死亡。
CIVO方法表明，单独使用达佐司他以及与化疗联合使用时，可在完整人类HNSCC肿瘤的天然TME中促进促凋亡和早期促炎反应，为靶向作用机制提供临床证据，并为进一步临床研究提供理论依据。
