Zabilugene Almadenorepvec

– Prolonged overall survival (OS) was observed in heavily pre-treated refractory Head & Neck Squamous Cell Carcinoma (HNSCC) patients administered IV VCN-01 prior to the immune checkpoint inhibitor durvalumab – – Pharmacokinetic, tissue biopsy, radiomic and transcriptomic results all support the proposed VCN-01 stroma-degrading and immune enhancing modes-of-action and resensitization of refractory tumors to durvalumab - – Increased levels of PD-L1 positive T-cells and other biomarkers were found in patients after sequential administration of VCN-01 and durvalumab, consistent with reactivation of immune responses – ROCKVILLE, Md., June 11, 2026 (GLOBE NEWSWIRE) -- Theriva™ Biologics, Inc. (NYSE American: TOVX), a diversified clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need, today announced that clinical and translational results from VCN-01’s Phase 1 clinical trial in Head & Neck Squamous Cell Carcinoma (HNSCC) were recently published on-line first in the journal Clinical Cancer Research. The article, titled “Phase I trial of intravenous VCN-01 oncolytic adenovirus and durvalumab in patients with head and neck metastatic squamous cell carcinoma refractory to immunotherapy”, can be read here . “We are very excited to see Clinical Cancer Research share the VCN-01 results in immunotherapy-refractory metastatic HNSCC patients with the broad oncology community,” said Ricard Mesia (Catalan Institute of Oncology, ICO), expert on HNSCC and coordinating investigator in this study. “The trial demonstrates the ability of VCN-01 to resensitize tumors from these heavily pretreated patients to the immune checkpoint inhibitor durvalumab. Pharmacokinetic, tissue biopsy, radiomic and transcriptomic results from the study all support the VCN-01 stroma-degrading mode-of-action, being investigated to enhance tumor penetration by VCN-01 and coadministered therapies and enable/enhance an anti-tumor immune response. There are very few treatment options available to immunotherapy-refractory metastatic HNSCC patients, and the clinically impactful findings from this report encourage further clinical development of VCN-01 with immune checkpoint inhibitors or other immune modulating anticancer therapies.” Data summary – VCN-01 Phase 1 clinical trial (NCT03799744) in metastatic, immunotherapy-refractory Head & Neck Squamous Cell Carcinoma (HNSCC) The trial enrolled 20 adult patients with refractory or metastatic HNSCC, whose disease progressed despite previous therapies, including anti-PD-(L)1 immune checkpoint inhibitors. Six patients were enrolled into the concomitant Arm I LD of the study and were administered IV low dose VCN-01 (3.3E12 virus particles; LD) four hours prior to a fixed IV dose of durvalumab (1500 mg/q4w). Eight patients were enrolled into the sequential Arm II LD of the study, receiving low dose IV VCN-01 14 days prior to IV durvalumab administration. An additional six patients were entered into Arm II HD, receiving high dose IV VCN-01 (1.0E13 virus particles; HD) 14 days prior to IV durvalumab administration. Median progression-free survival (PFS) was 1.6 months in Arm I LD, 3.7 months in Arm II LD, and 2.1 months in Arm II HD. Median overall survival (OS) was 10.3 months in Arm I LD, 15.5 months in Arm II LD, and 17.3 months in Arm II HD. Circulating levels of the stroma-degrading hyaluronidase enzyme PH20 (expressed during selective VCN-01 intratumoral replication) increased significantly after VCN-01 administration in all tested patients, peaking on day 3-8 for most patients and detectable until day 28 in 11 of 12 patients. Similarly, VCN-01 viral genome levels detected in patient blood exhibited an initial peak immediately following administration and a secondary peak on day 3-8, consistent with continued viral replication in tumors followed by a return of virus to circulation. Upregulation of CD8 and IDO was observed in tumor biopsy samples, consistent with increased tumor infiltration by activated cytotoxic T cells – historically associated with increased HNSCC patient survival. Diminished levels of FoxP3, CD25, and CTLA4 were also observed, consistent with a reduction in tumor Tregs and inhibition of tumor immunosuppression. Tumor biopsies revealed upregulation of PD-1 and PD-L1 in most patients following VCN-01 administration that correlated with patient survival, suggesting that immune system activity and heightened PD-L1 expression in tumors contributed to the improved outcomes from VCN-01 and durvalumab combination. About Theriva™ Biologics, Inc. Theriva™ Biologics (NYSE American: TOVX), is a diversified clinical-stage company developing therapeutics designed to treat cancer and related diseases in areas of high unmet need. The Company’s subsidiary Theriva Biologics, S.L., has been developing a new oncolytic adenovirus platform designed for intravenous (IV), intravitreal and antitumoral delivery to trigger tumor cell death, improve access of co-administered cancer therapies to the tumor, and promote a robust and sustained anti-tumor response by the patient’s immune system. The Company’s lead clinical-stage candidate is VCN-01 (zabilugene almadenorepvec), an oncolytic adenovirus designed to replicate selectively and aggressively within tumor cells, and to degrade the tumor stroma barrier that serves as a significant physical and immunosuppressive barrier to cancer treatment. An exploratory clinical trial with SYN-004 (ribaxamase) in allogeneic hematopoietic cell transplant (HCT) recipients has completed 2 of 3 cohorts, with initiation of the third cohort dependent on additional funding. SYN-004 (ribaxamase) is designed to degrade certain commonly used IV beta-lactam antibiotics within the gastrointestinal (GI) tract to prevent microbiome damage, thereby limiting overgrowth of pathogenic organisms such as VRE (vancomycin resistant Enterococci) and reducing the incidence and severity of acute graft-versus-host-disease (aGVHD). For more information, please visit Theriva™ Biologics’ website at . Forward-Looking Statement This release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. In some cases forward-looking statements can be identified by terminology such as “may,” “should,” “potential,” “continue,” “expects,” “anticipates,” “intends,” “plans,” “believes,” “estimates,” and similar expressions, and include statements regarding the development of therapeutics designed to treat cancer and related diseases in areas of high unmet need; the ability of VCN-01 to resensitize tumors from these heavily pretreated patients to the immune checkpoint inhibitor durvalumab; pharmacokinetic, tissue biopsy, radiomic and transcriptomic results from the study supporting the VCN-01 stroma-degrading mode-of-action, being researched to enhance tumor penetration by VCN-01 and coadministered therapies and enable/enhance an anti-tumor immune response; the clinically impactful findings from the study report encouraging further clinical development of VCN-01 with immune checkpoint inhibitors or other immune modulating anticancer therapies; Theriva Biologics, S.L.’s development of a new oncolytic adenovirus platform designed for intravenous (IV), intravitreal and antitumoral delivery to trigger tumor cell death, improve access of co-administered cancer therapies to the tumor, and promote a robust and sustained anti-tumor response by the patient’s immune system; and the initiation of the third cohort of the exploratory clinical trial with SYN-004 (ribaxamase) in allogeneic hematopoietic cell transplant (HCT) recipients, which remains subject to additional funding; the ability of SYN-004 (ribaxamase) to degrade certain commonly used IV beta-lactam antibiotics within the gastrointestinal (GI) tract to prevent microbiome damage, thereby limiting overgrowth of pathogenic organisms such as VRE and reducing the incidence and severity of aGVHD.. Important factors that could cause actual results to differ materially from current expectations include, among others, the Company’s ability to finalize protocols for future clinical trials evaluating VCN-01 with immune checkpoint inhibitors or other immune modulating agents; result of future trials supporting further clinical development of CVN-01; the Company’s ability to obtain development funding and/or partnerships; the Company’s commencement of planned clinical trials, which remains subject to sufficient financing; the Company’s ability to raise capital and/or enter into one or more strategic alternatives, that may include a business combination, merger or reverse merger; the Company’s ability to reach clinical milestones when anticipated, including the ability to continue to enroll patients as planned; generating clinical data that establishes VCN-01 may improve patient outcomes in cancer patients; the ability to obtain regulatory approval for commercialization of product candidates or to comply with ongoing regulatory requirements, including approval of VCN-01 to treat cancer patients; regulatory limitations relating to the Company’s ability to promote or commercialize its product candidates for the specific indications; acceptance of the Company’s product candidates in the marketplace; the successful development, marketing or sale of the Company’s products; developments by competitors that render such products obsolete or non-competitive; the Company’s ability to maintain license agreements; the continued maintenance and growth of the Company’s patent estate; the ability to continue to remain well financed; and other factors described in the Company’s Annual Report on Form 10-K for the year ended December 31, 2025 and its other filings with the SEC, including subsequent periodic reports on Forms 10-Q and current reports on Form 8-K. The information in this release is provided only as of the date of this release, and Theriva Biologics undertakes no obligation to update any forward-looking statements contained in this release on account of new information, future events, or otherwise, except as required by law. For further information, please contact: Investor Relations Kevin Gardner LifeSci Advisors, LLC kgardner@lifesciadvisors.com

实体瘤依赖高度免疫抑制的肿瘤微环境（TME）抵抗免疫治疗。工程化溶瘤病毒（Oncolytic Viruses, OVs）及基于细胞因子的基因疗法（Cytokine-based Gene Therapies, GTs）能够重编程TME，将“冷肿瘤”转化为免疫响应状态，并放大抗肿瘤免疫。目前已有数种药物获得监管批准，临床研究证实即使有限次给药也可诱导持续的免疫浸润及细胞因子信号改变。然而，持久且稳定的临床应答仍然难以实现。本文综合近期试验的转化见解，强调克服障碍、增强这类TME重塑生物制剂治疗影响力的新兴策略。 肿瘤微环境：免疫治疗的“堡垒” 免疫检查点抑制剂（ICIs）虽革新了癌症治疗，但多数患者仍面临原发或获得性耐药。关键障碍在于TME的深度 immunosuppressive 状态：免疫细胞匮乏或功能耗竭，调节性T细胞（Treg）、髓源性抑制细胞（MDSCs）及肿瘤相关巨噬细胞（TAMs）大量存在，分泌IL-10、TGFβ、VEGF等抑制性因子，并上调PD-1/PD-L1、CTLA-4、LAG3等检查点分子。此外，肿瘤相关成纤维细胞（CAFs）及异常内皮细胞进一步阻碍免疫浸润。溶瘤病毒和细胞因子GTs的独特价值在于靶向TME全局，而非单一靶点。 OVs与细胞因子GTs：TME重编程的双引擎 OVs通过选择性感染、复制并裂解肿瘤细胞，释放损伤相关分子模式（DAMPs）及肿瘤相关抗原（TAAs），触发免疫原性细胞死亡（ICD），进而激活树突状细胞、交叉呈递，诱导肿瘤特异性CD4+/CD8+T细胞应答，并产生“表位扩散”（epitope spreading）现象，建立长期免疫记忆。另一方面，细胞因子GTs（如编码IFNα2b、GM-CSF、IL-12等）通过局部高浓度免疫刺激分子，直接募集并活化NK细胞、巨噬细胞及T细胞，同样重塑免疫状态。临床活检已证实：单次瘤内注射后数月，CD3+/CD8+T细胞浸润仍持续增强，甚至非注射病灶出现退缩，提示系统性免疫激活。 📌 图1 | OVs与细胞因子GTs引发抗肿瘤免疫应答 OV感染肿瘤细胞→直接细胞毒作用+ICD→释放DAMPs/TAAs→激活先天免疫→募集并活化DC、巨噬细胞、NK细胞→启动适应性免疫（T细胞）。同时，细胞因子GTs通过局部表达促炎因子（如IL-12、GM-CSF）放大此过程；后续免疫介导的杀伤释放更多抗原，驱动表位扩散及效应T细胞扩增，最终形成持久抗肿瘤免疫。 主要溶瘤病毒及病毒基因治疗平台特性 表1 基于原文数据整理。涵盖HSV-1、腺病毒、牛痘、呼肠孤病毒等主要平台及基因修饰。 已获监管批准的OV/GT药物及其临床现状 全球范围共5种获得批准（图2）：中国2005年批准H101（头颈癌联合化疗）；拉脱维亚Rigvir因疗效和质控问题2019年暂停；日本批准G47Δ（DELYTACT®）用于高级别胶质瘤，中位总生存20.2个月（自手术28.8个月）；美国FDA批准T-VEC（瘤内注射，用于不可切除黑色素瘤，Ⅲ期OPTIM试验DRR 16.3%）和Nadofaragene firadenovec（膀胱内基因疗法，用于卡介苗无反应非肌层浸润性膀胱癌）。然而除膀胱内疗法外，多数疗法因给药途径、狭窄适应症及与ICI联合未达优效等原因，临床采纳仍有限。 📊 图2 | 全球获批的OV/GT疗法（示意图） ✔️ H101（中国） ✔️ Teserpaurev/G47Δ（日本） ✔️ T-VEC（美国） ✔️ Nadofaragene firadenovec（美国） ❌ Rigvir（已暂停） 注：T-VEC因编码GM-CSF兼具基因治疗属性；多数限于局部/瘤内给药途径。 TME重编程的暗面：持久应答为何困难？ 虽然OV/GT可驱动初始免疫激活，但肿瘤迅速上调补偿性抑制机制。例如：胰导管癌患者静脉注射pelareorep后Treg及CTLA-4+T细胞扩增；高级别胶质瘤中IL-12基因治疗后M2型巨噬细胞占优；CAN-3110治疗后IGF2上调介导耐药。IFNγ慢性暴露导致非编码RNA调控的检查点上调与免疫抑制（图3）。同时肿瘤可塑造VEGF高表达的缺氧生态位排斥CD8+T细胞。这提示抗血管生成药物与OV/GT的序贯联合可能克服逃逸。 ⚠️ 图3 | 慢性免疫激活导致反作用性免疫抑制 OV/GT治疗后初始TME炎性激活，但IFNγ等持续信号可通过非编码RNA、检查点分子（PD-1/PD-L1、CTLA-4）上调以及Treg、MDSC积聚，再次建立抑制性微环境。抗VEGF、免疫检查点联合等策略可阻断该过程。 给药途径与抗病毒免疫的双面性 过去认为预存抗病毒抗体会削弱疗效，但当前观点更复杂：瘤内给药时细胞间传播可逃逸中和抗体，甚至预存HSV-1血清阳性患者在CAN-3110治疗中总生存期更长。NK细胞及病毒特异性T细胞能杀灭感染病毒的肿瘤细胞，增强抗癌效果。相反，如果病毒过早被清除则降低溶瘤活性。对于脑肿瘤，瘤内注射仍是主流；系统给药面临补体清除、肝脏滞留及血脑屏障挑战，但部分病毒如H-1PV可跨过血脑屏障。 安全性方面常见注射部位反应、发热、乏力，细胞因子风暴罕见，颅内给药可致瘤周水肿，可用低剂量地塞米松或贝伐珠单抗管理。 推动领域前进：生物标志物、联合策略与下一代工程 生物标志物引导患者选择 不同患者TME异质性显著。如干扰素信号通路组成性激活预测麻疹病毒耐药；DNX-2401联合pembrolizumab在中等PDCD1表达、低其他免疫抑制因子的TME中应答更佳。未来需整合基因突变谱、免疫细胞组成和全身细胞因子动态来匹配获益人群。 联合疗法——成败参半 化疗：荟萃分析显示OV联合化疗可改善客观缓解率但无生存优势，不确定获益。放疗：协同增效明确，放射可增强OV复制及抗原释放。免疫检查点抑制剂：OV/GT诱导检查点上调（PD-1/PD-L1/CTLA-4），为联合提供强逻辑。然而关键III期MASTERKEY-265（T-VEC+pembrolizumab）未改善PFS/OS；小样本研究中T-VEC+ipilimumab显示ORR达50%，但大样本未达预期。部分“冷肿瘤”经IL-12质粒治疗后对后续抗PD-1敏感。总体提示需要更精准的联合时序与多靶点阻断。 剂量优化非传统 牛痘病毒低剂量反而与更佳肿瘤应答相关，符合毒物兴奋效应；儿童胶质瘤中较低剂量G207也出现长期生存；而JX-594高剂量延长肝癌患者OS（14.1 vs 6.7个月）。重复给药策略逐渐被接受（日本G47Δ最多6次瘤内注射，CAN-3110试验预设6次）。 下一代工程学策略 🧬 图4 | 新一代OV工程策略 改造病毒进入：靶向肿瘤富集受体（如RGD-整合素、CD46） 转录靶向：肿瘤选择性启动子（nestin, E2F-1等） miRNA响应元件：抑制正常组织中的复制 武装有效载荷：细胞因子（IL-12, IL-15, GM-CSF, FLT3L）、基质修饰酶（透明质酸酶）或前药转化酶（FCU1） 例如TILT-123可静脉给药，7天后肿瘤活检可见免疫浸润；Ad-RTS-hIL12通过口服激活剂调控IL-12表达，降低系统毒性；VG161携带三功能融合蛋白同时激活IL-12/IL-15轴及阻断PD-1，在晚期肝癌中重绘TME并恢复治疗敏感性。  超越传统终点：免疫相关疗效标准 OV/GT常导致假性进展（免疫浸润致影像增大），需采用免疫相关缓解标准（irRC）。CAN-3110试验中，连续多组学分析显示尽管MRI提示进展，但组织学证实T细胞浸润和新T细胞克隆扩增，生存延长，强调基于组织/体液的纵向采样价值。 结论与展望 OVs与细胞因子基因疗法代表一类多模态免疫疗法，主要通过重编程TME发挥作用，可以将免疫学上的“冷”肿瘤转化为“热”状态。尽管持久应答、递送障碍及经济因素仍限制临床普及，但基于生物标志物的患者分层、巧妙组合治疗（尤其联合ICI或抗血管生成）、剂量优化以及新一代多重武装病毒载体，正逐步提升其临床价值。未来需强化分子与免疫学分析，将OV/GT真正整合到精准免疫肿瘤学中。 🔑 核心要点（临床与转化启示） ✅ 溶瘤病毒与细胞因子GT不仅直接溶瘤，主要作用为免疫微环境重编程，驱动表位扩散。 ✅ 单次注射可诱导数月的T细胞浸润，但继发性免疫抑制（检查点上调、M2极化、IGF2等）常限制持久应答。 ✅ 瘤内或区域给药仍是主流，但系统给药的工程化病毒（TILT-123、VCN-01）已显示潜力。 ✅ OV/GT联合ICIs的Ⅲ期结果褒贬不一，需更精细生物标志物和联合时序。 ✅ 新一代OV携带多效细胞因子（IL-12/IL-15/GM-CSF）或基质降解酶，提高抗肿瘤免疫深度。 关键临床数据摘要（基于原文） G47Δ（日本）：高级别胶质瘤治疗后中位OS 20.2个月（自首次手术28.8个月），部分患者接受最多6次瘤内注射。 T-VEC（OPTIM Ⅲ期）：DRR 16.3%，早期黑色素瘤获益更显著；新辅助可降低复发率。 Nadofaragene firadenovec：BCG无应答NMIBC患者完全缓解率良好，获FDA批准。 Ad-TD-nsIL12（儿童弥漫内生型桥脑胶质瘤）：疾病稳定/部分缓解，总生存优于历史对照。 VG161（肝癌 Ⅰ期）：在难治性患者中观察到TME重塑，部分患者再次获得治疗敏感，转录特征与生存相关。 CAN-3110（复发胶质母细胞瘤）：T细胞克隆多样性增加，单次注射后数月仍见免疫活化，HSV-1血清阳性者生存更长。 参考文献与来源 本文基于原文：Bernstock JD, Spanehl L, Chiocca EA.Oncolytic viruses and cytokine-based gene therapies reprogram the tumor microenvironment. Nat Cancer. 2026 Apr 24. doi: 10.1038/s43018-026-01153-y. 内容忠实翻译整理，保留全部核心数据、表格及图式描述。适合专业人员阅读 · 肿瘤免疫治疗前沿 · 溶瘤病毒及基因疗法深度解析.