A Phase 1, Open-label, Single-arm Study to Investigate the Safety, Tolerability, and Preliminary Efficacy of TNFa and IL-2 Coding Oncolytic Adenovirus TILT-123 in Combination With Lymphocyte-depleting Chemotherapy and Tumor-infiltrating Lymphocytes in Melanoma Patients.

This is an open-label, phase 1 trial evaluating the safety of oncolytic adenovirus TILT-123 in combination with lymphocyte-depleting chemotherapy and TILs in metastatic melanoma patients.

开始日期2025-06-01

申办/合作机构

TILT Biotherapeutics Oy

NCT06125197

/ Recruiting临床1期

A Phase I Open-Label, Dose-escalation Trial of Tumor Necrosis Factor Alpha and Interleukin-2 Coding Oncolytic Adenovirus (TILT-123) in Combination With Pembrolizumab in Patients With Immune Checkpoint Inhibitor Refractory Non-Small Cell Lung Cancer

This is an open label, Phase 1, dose escalation trial evaluating the safety of oncolytic adenovirus TILT-123 in combination with Pembrolizumab in patients with immune checkpoint inhibitor refractory non-small cell lung cancer.

开始日期2024-07-23

申办/合作机构

TILT Biotherapeutics Oy

[+1]

NCT05222932

/ Recruiting临床1期

A Phase I Open-Label, Dose-escalation Clinical Trial of Tumor Necrosis Factor Alpha and IL-2 Coding Oncolytic Adenovirus TILT-123 and Avelumab in Solid Tumor Patients (Melanoma and SCCHN) Refractory to or Progressing After Anti-PD(L)1

This is a phase 1, dose-escalation trial evaluating the safety of oncolytic adenovirus TILT-123 in combination with avelumab in patients with advanced solid tumors refractory to or progressing after anti-PD(L)1.

开始日期2023-03-08

申办/合作机构

TILT Biotherapeutics Oy

100 项与 Igrelimogene litadenorepvec 相关的临床结果

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100 项与 Igrelimogene litadenorepvec 相关的转化医学

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100 项与 Igrelimogene litadenorepvec 相关的专利（医药）

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项与 Igrelimogene litadenorepvec 相关的文献（医药）

2025-03-01·Cell Reports Medicine

Safety and efficacy of combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus TILT-123 in metastatic melanoma

Article

作者: Vestergaard, Cecilie ; Albieri, Benedetta ; Cervera-Carrascon, Victor ; Quixabeira, Dafne C A ; Kistler, Claudia ; Lorentzen, Torben ; Santos, João M ; Clubb, James H A ; Ellebaek, Eva ; Holmstroem, Rikke B ; Dreno, Brigitte ; Borch, Troels H ; Jirovec, Elise ; Khammari, Amir ; Haybout, Lyna ; Westergaard, Marie C W ; Pakola, Santeri A ; Arias, Victor ; Met, Özcan ; Donia, Marco ; Hemminki, Akseli ; Monberg, Tine J ; Kudling, Tatiana V ; Hendel, Helle W ; Lorentzen, Cathrine ; Havunen, Riikka ; Sorsa, Suvi ; Eefsen, Rikke L ; Svane, Inge Marie

Tumor-infiltrating lymphocytes (TILs) are effective in the treatment of metastatic melanoma (MM), but toxicity limits its application. TILT-123 (igrelimogene litadenorepvec) is an oncolytic adenovirus producing interleukin-2 (IL-2) and tumor necrosis factor (TNF) upon replication. In this phase 1 trial, 17 patients with metastatic checkpoint inhibitor-resistant melanoma are treated with TILT-123 and TILs without preconditioning chemotherapy or postconditioning IL-2. The treatment is safe and feasible. According to computed tomography (CT), the objective response rate is 11.7% (2/17) and disease control is observed in 35% (6/17), including a partial response lasting >8 months and a durable complete response in a mucosal melanoma patient. According to positron emission tomography (PET), disease control is observed in 7/15 (47%) with minor or partial responses in 4/15 (27%). In the initial TILT-123 monotherapy phase of the trial, disease control is observed in 6/17 (35%) and 10/16 (63%) in CT and PET, respectively. The study demonstrates good tolerability and preliminary efficacy.

2025-01-01·Journal for ImmunoTherapy of Cancer

Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial

Article

作者: Pellinen, Teijo ; Kistler, Claudia ; Quixabeira, Dafne C A ; Pakola, Santeri A ; Cervera-Carrascon, Victor ; Hemminki, Akseli ; Clubb, James H A ; Haybout, Lyna ; Arias, Victor ; Taipale, Kristian ; Havunen, Riikka ; Santos, Joao M ; Kudling, Tatiana V ; van der Heijden, Mirte ; Jirovec, Elise ; Peltola, Katriina ; Sorsa, Suvi ; Alanko, Tuomo ; Sormunen, Jorma

Background:

Oncolytic viruses (OVs) are promising immunotherapeutics to treat immunologically cold tumors. However, research on the mechanism of action of OVs in humans and clinically relevant biomarkers is still sparse. To induce strong T-cell responses against solid tumors, TILT-123 (Ad5/3-E2F-d24-hTNFa-IRES-hIL2, igrelimogene litadenorepvec) was developed. TILT-123 encodes two transgenes: tumor necrosis alpha (TNFa) and interleukin-2 (IL-2). TUNIMO (NCT04695327) was a phase I clinical trial using TILT-123 in patients with advanced solid tumors aiming to assess the safety, efficacy, and immunological effects of TILT-123. Research presented in this study evaluated the immunological effects of TILT-123 in the TUNIMO trial by using biological samples collected from the patients during the study, with an objective to leverage the findings to develop possible biomarkers of response and gain insights into possible synergistic combination treatments.

Methods:

20 patients with advanced solid tumors were treated with TILT-123. Response to therapy was assessed with contrast-enhanced CT and fluorodeoxyglucose positron emission tomography, along with overall survival (OS) calculation. Biological samples from patients were collected in the form of blood and tumor biopsies. Collected samples were analyzed with immunohistochemistry, transcriptomics, proteomics, and flow cytometry.

Results:

TILT-123 induced cyclical decreases in blood lymphocyte count, and more substantial blood lymphocyte count correlated with better radiographical response and longer OS. Lymphocyte count findings were confirmed with external control dataset of 96 patients. More substantial lymphocyte count change was linked to stronger immune activation in plasma proteome after intravenous TILT-123 and the presence of TILT-123 mRNA in tumors. Regarding other assays. tumor biopsies profiled showed increased amounts of CD8+ T cells, CD4+ T cells and NK cells after intravenous TILT-123, but not after intratumoral TILT-123. Transcriptional differences were seen in tumors after intravenous therapy and intratumoral therapy, with patients benefitting therapy showing stronger downregulation of immune activation at all time points.

Conclusions:

TILT-123 therapy induced accumulation of effector lymphocytes in tumors. Peripheral lymphocyte count decrease is a promising biomarker for assessing oncolytic adenovirus therapy response.

2024-12-01·Immuno-oncology technology

Durable complete response after combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus (TILT-123) in a patient with metastatic mucosal melanoma

Article

作者: Quixabeira, D C A ; Westergaard, M C W ; Havunen, R ; Kudling, T ; Donia, M ; Jirovec, E ; Clubb, J ; Ellebaek, E ; Sorsa, S ; von Buchwald, C ; Santos, J M ; Monberg, T J ; Pakola, S ; Cervera-Carrascon, V ; Albieri, B ; Eefsen, R L ; Svane, I M ; Haybout, L ; Hemminki, A ; Kistler, C

Background:

Despite significant advancements in the treatment of malignant melanoma, metastatic mucosal melanoma remains a therapeutic challenge due to its complex pathogenesis, distinct pathological characteristics, and limited response to immunotherapy. Combining different immunotherapeutic approaches offers a potential strategy to address these challenges. Tumor-infiltrating lymphocyte (TIL) therapy and oncolytic virus therapy represent promising treatment modalities that may synergize with each other.

Patient and methods:

We present a case of a 48-year-old woman with metastatic sinonasal mucosal melanoma who achieved a durable complete pathological response following treatment with multiple injections of the oncolytic virus TILT-123 (igrelimogene litadenorepvec) and a single infusion of TILs, without preconditioning chemotherapy or postconditioning interleukin-2.

Results:

Immunohistochemical analysis and single-cell sequencing revealed interesting alterations in injected and noninjected tumors as well as in peripheral blood, during the treatment course, suggesting that TILT-123 facilitated TIL engraftment into the tumor, ultimately leading to a complete response.

Conclusions:

This case underscores the potential of combined immunotherapeutic approaches as a promising strategy for patients with metastatic mucosal melanoma.

项与 Igrelimogene litadenorepvec 相关的新闻（医药）

2025-05-13

·GlobeNewswire-Health Care

TILT Biotherapeutics Announces Closing of USD 25 Million Series B Financing

Initiates Phase 2 platinum-resistant ovarian cancer trialHELSINKI, May 13, 2025 (GLOBE NEWSWIRE) -- TILT Biotherapeutics (Tiltbio), a clinical-stage biotechnology company developing intravenously delivered cancer immunotherapies, announces it has raised USD 25.6 million (EUR 22.6 million) in a Series B financing. The financing was supported by existing investors; the European Innovation Council (EIC) Fund, Lifeline Ventures, Finnish Industry Investment (TESI), and Stephen Industries Inc Oy. It will support a Phase 2 clinical trial of Tiltbio’s lead product, TILT-123, in patients with platinum-resistant epithelial ovarian cancer, a Phase 1b trial in melanoma in combination with TILs and other Phase 1b trials. The Company recently published data from its Phase 1a clinical trial (PROTA) in platinum-resistant ovarian cancer in Nature Communications (1), which was also presented at AACR (2). The data showed that treatment was well tolerated with an excellent safety profile and promising efficacy observed in some patients. Disease control was achieved in 64% of evaluable patients (9/14) while the overall response rate was 20% at the highest dose level. Median progression-free survival and overall survival were 98 and 190 days respectively. Interim results from ongoing Phase 1b trials are expected to read out in H2 2026. Tiltbio’s founder and CEO, Akseli Hemminki, said: “We are delighted to have secured our Series B financing and thank our investors for their continued support. We’ve been making good progress in ovarian cancer and this financing will support the roll out of our Phase 2 clinical trials. We’re excited to have already opened the first site in the USA and are looking forward to dosing our first patients soon and opening at least five more sites this year.” He continued, “Ovarian cancer continues to be an unmet medical need despite recent therapies being approved. There are no oncolytic viruses or checkpoint inhibitors currently approved for use in this indication. We are committed to our mission to transform the treatment options for patients with ovarian cancer with TILT-123.” TILT-123 (Igrelimogene litadenorepvec), an oncolytic adenovirus armed with tumor necrosis factor (TNF) and interleukin-2 (IL-2), is designed to enhance the efficacy of T-cell therapies and immune checkpoint blockade. Tiltbio has a collaboration with MSD (Merck & Co., Inc., Rahway, NJ, USA) investigating TILT-123 in combination with KEYTRUDA® (pembrolizumab) in ovarian cancer (NCT05271318). Reference (1) Nature Communications paper: “The oncolytic adenovirus TILT-123 with pembrolizumab in platinum resistant or refractory ovarian cancer: the phase 1a PROTA trial.”(2) American Association for Cancer Research (AACR) Annual Meeting 2025 poster link: ‘Clinical immunology correlates in platinum resistant or refractory ovarian cancer patients treated with chimeric oncolytic adenovirus encoding TNF and IL-2 (TILT-123) in combination with pembrolizumab’ Notes to Editors About TILT Biotherapeutics TILT Biotherapeutics is a clinical-stage biotechnology company developing cancer therapeutics based on its proprietary oncolytic adenoviruses armed with molecules including cytokines that can activate T cells and destroy cancer cells. The company’s patented TILT® technology can be delivered intravenously, locoregionally, or intratumorally. It modifies the tumor microenvironment and has a broader systemic effect. By making cold tumors hot, it eliminates cancer’s ability to evade immune responses, thereby enhancing immune checkpoint inhibitors or T-cell therapies such as tumor infiltrating lymphocyte (TIL) and CAR T therapies. Over eighty patients have been treated in five international trials sponsored by the company with excellent safety profiles and promising initial efficacy responses observed in some patients. The company’s pioneering approach has been recognized by industry leaders. It has two collaborations with MSD (Merck & Co., Inc., Rahway, NJ, USA) investigating TILT-123 in combination with KEYTRUDA® (pembrolizumab) in ovarian cancer (NCT05271318) and in refractory non-small cell lung cancer (NCT06125197). The company is also collaborating with Merck KGaA (Darmstadt, Germany) and investigating TILT-123 in combination with Bavencio® (avelumab). Based in Helsinki, Finland, and with an office in Boston, the company was established over a decade ago as a spin-out from the University of Helsinki. To date Tiltbio has secured over EUR 72 million in financing from investors including the European Innovation Council (EIC) Fund, Lifeline Ventures, Finnish Industry Investment (TESI), Stephen Industries, angel investors, Business Finland, the EIC Accelerator programme, and the U.S. Department of Defense. Media contacts TILT Biotherapeutics COO Aino Kalervoaino@tiltbio.com Scius CommunicationsKatja Stout+447789435990katja@sciuscommunications.com Daniel Gooch+447747875479daniel@sciuscommunications.com

临床2期临床1期临床结果免疫疗法AACR会议

2025-05-13

·Firstwordpharma

Tiltbio nabs $25M to launch mid-stage study of oncolytic virus

Tilt Biotherapeutics raised €22.6 million ($25.6 million) in a series B on Tuesday to advance its experimental oncolytic adenovirus therapy into a Phase II trial for platinum-resistant ovarian cancer (PROC). Armed with TNFα and IL-2, the adenovirus — dubbed TILT-123 — is designed to be given in combination with T cell–based therapies such as tumour-infiltrating lymphocytes (TILs) or checkpoint inhibitors to boost their efficacy. The round, which brings the Finnish biotech's total funding to over €72 million, was backed by the European Innovation Council Fund, Finnish Industry Investment, Stephen Industries Inc Oy and Lifeline Ventures; the latter led Tiltbio's €22-million financing in 2023.Combo dataThe fresh capital comes on the heels of Tiltbio's presentation at the American Association for Cancer Research (AACR) meeting last month.In the PROTA Phase I study, patients with PROC were given TILT-123 in combination with Merck & Co.'s PD-1 inhibitor Keytruda (pembrolizumab). Of 14 evaluable patients, nine achieved disease control (64%); median progression-free survival was 98 days, with a median overall survival of 190 days. In the five-patient high-dose cohort, the drug duo led to an overall response rate of 20%. "Ovarian cancer continues to be an unmet medical need despite recent therapies being approved," CEO Akseli Hemminki said. "We’ve been making good progress in ovarian cancer and this financing will support the roll out of our Phase II clinical trials. We’re excited to have already opened the first site in the US and are looking forward to dosing our first patients soon and opening at least five more sites this year.”Tiltbio is exploring other cancers outside of ovarian. Tuesday's funding will help launch a Phase Ib study dosing TILT-123 in combination with TILs in patients with melanomaThe biotech is also evaluating Keytruda plus TILT-123 in patients with refractory non–small-cell lung cancer. In addition, Tiltbio previously inked a partnership with Merck KGaA to study TILT-123 with PD-L1 inhibitor Bavencio (avelumab).

临床2期临床结果临床1期AACR会议

2025-04-16

·靶点圈

靶点解析：IL-2/IL-2R的作用机制与临床数据的大盘点

Vol.01-IL-2/IL-2R靶点概述-IL-2的生物学特性①结构特征：IL-2是由153-169个氨基酸组成的单链多肽，属于γ链细胞因子家族（γc家族），含有四个α-螺旋区域和两个折叠域，分子量为15-16kDa，其基因位于人类染色体4q26-q27，由2个内含子和5个外显子组成。②产生来源：IL-2主要由激活的CD4+T细胞分泌，可通过自分泌和旁分泌发挥作用。此外，激活的CD8+T细胞、NK细胞、自然杀伤T细胞和树突状细胞等也能少量分泌。其产生受T细胞受体（TCR）信号和共刺激信号调控，具有重要的免疫调节功能，对免疫系统的平衡至关重要。在免疫激活时迅速且短暂表达，可促进活化T细胞的克隆扩增，增强CD8+T细胞和NK细胞的细胞毒性。图1 IL-2和IL-2R基因在染色体上的定位以及蛋白质形成和组装过程IL-2R的生物学特性①结构特征：IL-2R是膜结合受体，由IL-2Rα（CD25）、IL-2Rβ（CD122）和IL-2Rγ（CD132）亚基通过非共价键组合而成，各亚基基因也有特定染色体定位，不同亚基组合形成不同亲和力的受体，三条链共同组装形成的高亲和力受体对IL-2的结合力更强，在免疫细胞的激活和功能调节中发挥关键作用。②表达调控：IL-2R的表达和功能受NFAT、AP-1等转录因子及SOCS1、FoxP3等调节剂的调控。此外，可溶性IL-2R（sIL-2R）和IL-2Rα可作为癌症诊断、预后和监测治疗效果的生物标志物，且具有潜在的治疗价值。图2 IL-2R的不同亚基以及它们的位置和意义IL-2/IL-2R系统IL-2通过与IL-2R结合激活淋巴细胞，发挥调节免疫的作用。与受体结合后，激活JAK-STAT、MAPK和PI3K-AKT等信号通路，影响Tregs、CD4⁺T细胞、CD8⁺T细胞和NK细胞等多种免疫细胞的功能。IL-2/IL-2R系统不仅存在于免疫细胞，还广泛分布于中枢神经系统的多种神经细胞中。它们在中枢神经系统中参与神经细胞的生长、存活、神经递质释放以及神经电活动的调节。图3 IL-2相关信号通路表1 参与调节IL-2/IL-2R的转录因子和调节因子IL-2/IL-2R的氨基酸序列IL-2：MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLTIL-2α：MDSYLLMWGLLTFIMVPGCQAELCDDDPPEIPHATFKAMAYKEGTMLNCECKRGFRRIKSGSLYMLCTGNSSHSSWDNQCQCTSSATRNTTKQVTPQPEEQKERKTTEMQSPMQPVDQASLPGHCREPPPWENEATERIYHFVVGQMVYYQCVQGYRALHRGPAESVCKMTHGKTRWTQPQLICTGEMETSQFPGEEKPQASPEGRPESETSCLVTTTDFQIQTEMAATMETSIFTTEYQVAVAGCVFLLISVLLLSGLTWQRRQRKSRRTIExtracellularHelicalCytoplasmic22-240241-259260-272IL-2β：MLRLYVLVMGVSAFTLQPAAHTGAARSCRFRGRHYKREFRLEGEPVALRCPQVPYWLWASVSPRINLTWHKNDSARTVPGEEETRMWAQDGALWLLPALQEDSGTYVCTTRNASYCDKMSIELRVFENTDAFLPFISYPQILTLSTSGVLVCPDLSEFTRDKTDVKIQWYKDSLLLDKDNEKFLSVRGTTHLLVHDVALEDAGYYRCVLTFAHEGQQYNITRSIELRIKKKKEETIPVIISPLKTISASLGSRLTIPCKVFLGTGTPLTTMLWWTANDTHIESAYPGGRVTEGPRQEYSENNENYIEVPLIFDPVTREDLHMDFKCVVHNTLSFQTLRTTVKEASSTFSWGIVLAPLSLAFLVLGGIWMHRRCKHRTGKADGLTVLWPHHQDFQSYPKExtracellularHelicalCytoplasmic14-343344-369370-398IL-2γ：MLKPSLPFTSLLFLQLPLLGVGLNTTILTPNGNEDTTADFFLTTMPTDSLSVSTLPLPEVQCFVFNVEYMNCTWNSSSEPQPTNLTLHYWYKNSDNDKVQKCSHYLFSEEITSGCQLQKKEIHLYQTFVVQLQDPREPRRQATQMLKLQNLVIPWAPENLTLHKLSESQLELNWNNRFLNHCLEHLVQYRTDWDHSWTEQSVDYRHKFSLPSVDGQKRYTFRVRSRFNPLCGSAQHWSEWSHPIHWGSNTSKENPFLFALEAVVISVGSMGLIISLLCVYFWLERTMPRIPTLKNLEDLVTEYHGNFSAWSGVSKGLAESLQPDYSERLCLVSEIPPKGGALGEGPGASPCNQHSPYWAPPCYTLKPETExtracellularHelicalCytoplasmic23-262263-283284-369Vol.02-IL-2/IL-2R的生理功能及作用-IL-2/IL-2R在免疫细胞中的作用IL-2对调节性T细胞（Tregs）的胸腺发育、外周诱导、谱系稳定和稳态维持至关重要。IL-2或其受体亚基缺陷会导致Treg功能缺失，引发自身免疫疾病。此外，IL-2对CD8+T细胞和CD4+T细胞的分化和功能也有重要影响，对维持免疫平衡具有重要意义。图4 IL-2和IL-2R的生物学功能IL-2/IL-2R在肿瘤微环境中的作用在肿瘤微环境（TME）中，IL-2/IL-2R信号通路作用复杂，既可促进Tregs扩增抑制抗肿瘤免疫，也能促进细胞毒性T淋巴细胞（CTL）和自然杀伤（NK）细胞浸润增强抗肿瘤免疫。可通过调节效应T细胞和Tregs的平衡影响肿瘤生长，还与肿瘤的预后相关，失调时可能预示不良预后。此外，IL-2/IL-2R对NK细胞、巨噬细胞、中性粒细胞、B细胞、DCs和MDSCs等免疫细胞在TME中的功能均有调节作用，影响肿瘤的发生、发展和免疫逃逸。图5 IL-2/IL-2R在肿瘤微环境中的作用IL-2/IL-2R在免疫调节中的双重作用①免疫激活：IL-2作为T细胞的关键生长因子，在免疫反应启动时，促进效应T细胞的增殖和激活，增强机体对病原体的免疫防御。②免疫耐受：Tregs组成性表达高水平的IL-2Rα，能有效竞争摄取IL-2，限制效应T细胞的激活，维持免疫稳态，防止自身免疫疾病的发生。图6 由不同IL-2R组成介导的IL-2信号传导的双重作用高剂量与低剂量IL-2疗法①高剂量IL-2（HDIL-2）用于治疗转移性癌症，虽有一定疗效，但会引发严重副作用，如毛细血管渗漏综合征、低血压等，还会导致Tregs扩增和维持、血小板减少等系统异常。②低剂量IL-2（LDIL-2）疗法利用Treg对IL-2的高敏感性，选择性扩增Treg，在动物研究和临床试验中显示出良好的耐受性和一定的治疗效果，但也存在一些剂量相关的轻度至中度不良反应。图7 高剂量与低剂量IL-2疗法的对比IL-2/IL-2R在疾病中的作用①癌症免疫治疗：高剂量IL-2疗法在20世纪90年代被FDA批准用于治疗转移性黑色素瘤和转移性肾细胞癌，能够促进多种免疫细胞的生长、分化和功能发挥，增强机体的抗肿瘤免疫反应，部分患者可实现持久缓解甚至完全缓解。但高剂量IL-2疗法会引发严重副作用，限制了其广泛应用。尽管降低剂量可减少毒性，但疗效也会降低。②自身免疫性疾病治疗：低剂量IL-2疗法旨在通过选择性靶向Treg细胞上的高亲和力IL-2R，调节免疫系统，治疗自身免疫性疾病。可增加Treg细胞数量，调节免疫平衡，用于治疗如1型糖尿病、类风湿关节炎、系统性红斑狼疮和多发性硬化症等自身免疫性疾病。但其长期安全性和有效性仍需进一步研究，存在局限性，如部分患者临床症状改善不彻底、停药后疗效不佳等。③移植领域应用：在器官移植中，IL-2可促进Tregs存活，限制效应T细胞激活，诱导免疫耐受，减少移植排斥反应。低剂量IL-2疗法在动物实验和临床研究中显示出促进移植物长期存活的潜力，但仍面临选择性激活Tregs而避免激活效应T细胞的挑战。Vol.03-IL-2/IL-2R的临床应用-IL-2/IL-2R的临床药物清单表2 IL-2的临床药物表3 IL-2R的临床药物第二代IL-2疗法①分子修饰：通过PEGylation、突变、融合蛋白和糖基化等方法对recIL-2进行修饰，旨在增强其疗效、降低毒性、提高选择性。②递送系统改进：采用纳米颗粒和溶瘤腺病毒等方式改进recIL-2的递送，可实现靶向给药和控制药物释放。图8 基于IL-2的免疫疗法的新方法聚乙二醇化IL-2：通过聚乙二醇（PEG）修饰IL-2，改善其溶解度和药代动力学。如NKTR-214，是最早的PEGylated IL-2R激动剂之一，为IL-2Rβ偏向性激动剂，可优先扩增CD8+Teff和NK细胞，减少与高亲和力受体结合，降低Tregs扩增，延长半衰期，减少给药频率和毒性。此外，还有THOR-707、NL-201、STK-012和TransConIL-2β/γ等也在研发中，各有其作用特点和临床研究进展。IL-2融合蛋白：与蛋白融合可延长IL-2的半衰期（如MDNA11），可选择性激活NK和幼稚CD8⁺T细胞，在临床前模型中展现出强大的抗肿瘤功效；以及IL-2/IL-2Rα融合蛋白（如ALKS4230），能选择性刺激IL-2Rβγc，在多种癌症治疗的临床试验中进行评估。双特异性免疫分子：如GI-101、eciskafusp-alfa、simlukafusp-alfa和IBI363等，具有两个结合域，能同时靶向不同表位或抗原，分别通过不同机制发挥作用，增强药物向肿瘤的递送并产生协同效应。IL-2/mAb复合物：如ANV419、SLC-3010、AU-007、Darleukin和Daromun等，将IL-2与单克隆抗体结合，通过阻断IL-2与IL-2Rα的结合，优先激活CD8⁺T和NK细胞，部分药物已进入临床试验阶段。脂质纳米颗粒（LNP）封装的编码IL-2的mRNA：如BNT151和BNT153，利用LNP包裹编码IL-2的mRNA，进入细胞后产生IL-2，增强抗肿瘤免疫力，相关临床试验正在进行或已完成但结果未报道。溶瘤病毒：如TILT-123，是一种编码IL-2和TNF-α的溶瘤腺病毒，可破坏癌细胞，增强T细胞浸润和细胞毒性，初步显示出良好的耐受性和一定的临床反应。联合治疗方法：与免疫检查点抑制剂联合、与放疗联合、与过继细胞疗法联合以及使用正交IL-2/IL-2Rb突变对，这些联合疗法在临床前和临床试验中显示出增强抗肿瘤效果的潜力。Vol.04-IL-2/IL-2R在不同疾病的应用-慢性感染在慢性感染中，IL-2可激活耗竭的CD8+T细胞，增强其增殖能力、细胞毒性和细胞因子分泌能力，使其重新发挥抗病毒作用。IL-2还能促进记忆性CD8+T细胞的产生和维持，有助于长期控制感染。目前针对慢性感染的IL-2免疫疗法大多还处于临床前研究或早期临床试验阶段，尚未广泛应用于临床治疗。中枢神经系统疾病多发性硬化症（MS）：IL-2/IL-2R基因多态性影响MS易感性，患者血清中IL-2和sIL-2R水平升高与疾病进展相关，脑脊液IL-2水平与残疾程度、疾病活动度及风险标志物相关。在实验性自身免疫性脑脊髓炎（EAE）模型中，也有类似发现。IL-2/IL-2R的相关治疗可通过调节NK细胞和Tregs功能来减轻炎症。阿尔茨海默病（AD）：IL-2在AD患者中的表达模式复杂，血浆IL-2水平在疾病不同阶段有变化，与认知功能和病理改变有关。在APP/PS1小鼠等模型及临床研究中，发现IL-2在脑内的表达变化及对疾病的潜在影响。低剂量IL-2治疗可调节Tregs数量，改善认知功能。缺血性中风（IS）：IS发病后，患者血清和脑内IL-2及IL-2R表达发生变化，且与预后相关，血清IL-2水平在急性期降低，之后升高，而sIL-2Rα水平与病情严重程度相关，但不同年龄段的表达变化存在差异。可通过调节IL-2/IL-2R，作用于Tregs和CD8+T细胞，可改善预后，减少脑损伤。脑炎：在不同类型脑炎中，IL-2表达不同。如抗NMDAR脑炎患者血清IL-2水平升高，HSV-1诱导的脑炎小鼠脑内IL-2等细胞因子表达上调，SSPE患者血清IL-2水平也显著升高，但IL-2与脑炎预后的关系尚不清楚。部分自身免疫性脑炎患者接受低剂量IL-2治疗有效，在感染性脑炎中，IL-2可增强免疫反应，降低死亡率。图9 IL-2在中枢神经系统疾病中的作用自身免疫性和风湿性疾病血管炎：低剂量IL-2可治疗丙型肝炎病毒（HCV）诱导的血管炎患者，能改善患者症状，扩大Treg细胞数量，减轻炎症和氧化应激。1型糖尿病（T1D）：多项临床试验表明，低剂量IL-2疗法在T1D患者中耐受性良好，能有效扩增Treg群体，部分研究还观察到对胰岛β细胞功能的改善，且未发现对糖尿病控制、胰岛素需求或β细胞功能的负面影响。联合治疗虽显示出潜力，但存在脱靶效应。系统性红斑狼疮（SLE）：低剂量IL-2疗法可减少SLE患者的TFH和TH17细胞的频率，增加TFR细胞的频率，促进Treg细胞的扩增，改善疾病严重程度，降低感染风险，部分患者疾病活动度降低，且安全性良好，不同研究在剂量、治疗方案和持续时间上有所差异。干燥综合征：低剂量IL-2可逆转原发性干燥综合征患者外周血中TH17细胞和Treg细胞的失衡状态，但还需体内实验进一步验证。类风湿关节炎：低剂量IL-2治疗可能恢复循环中的Treg细胞，减轻疾病活动度。皮肌炎和特发性炎症性肌病：低剂量IL-2治疗可增加Treg细胞数量，改善患者临床症状和缓解情况。自身免疫性肝炎：在自身免疫性肝炎小鼠模型中，低剂量IL-2治疗可增加循环和肝脏内的Treg细胞，改善肝脏特异性ALT水平。在临床病例中，该疗法安全有效，能限制肝脏损伤，其益处可能主要源于Treg细胞的增加。其他疾病：在缺血性心脏病、溃疡性结肠炎等炎症性疾病的临床试验中显示出一定潜力，还在蛛网膜下腔出血损伤、严重斑秃和骨髓增生异常综合征等疾病的治疗中进行探索。但在肌萎缩侧索硬化症（ALS）的试验中未显示出临床疗效，可能与治疗持续时间较短有关。表4 IL-2治疗自身免疫性疾病和风湿性疾病的临床试验移植慢性移植物抗宿主病（GVHD）：低剂量IL-2治疗可有效诱导Treg介导的免疫耐受，促进其存活、增殖和胸腺输出，对常规T细胞影响较小，使部分患者临床症状改善，恢复Treg细胞的稳态。造血干细胞移植（HSCT）：在HSCT患者中，低剂量IL-2治疗可诱导Treg和NK细胞增加，在预防GVHD和促进移植物抗白血病效应方面有一定效果，部分患者症状改善且能减少糖皮质激素用量。然而，该疗法也存在感染并发症、影响抗体反应等问题，其长期效果和风险仍需进一步研究。实体器官移植（SOT）：动物实验表明，低剂量IL-2在不同SOT模型中效果各异。在一些模型中，它可增加Treg数量、延长移植物存活时间；但在非人类灵长类动物的肾脏移植模型中，却会引发排斥反应，提示在SOT中使用低剂量IL-2需谨慎。目前关于低剂量IL-2在SOT中的临床研究较少，已有的一项肝移植临床试验因安全问题提前终止。总结与展望RenyuBioIL-2治疗面临的主要挑战是在免疫刺激和免疫抑制之间难以平衡。高剂量用于癌症治疗时毒性大，低剂量用于自身免疫性疾病治疗时效果有限且可能存在安全隐患。未来需要关注降低毒性、激活肿瘤特异性记忆T细胞反应，并根据患者的免疫状态和肿瘤特征进行个性化治疗，进一步优化IL-2的使用策略，如精准的剂量调控、开发更有效的IL-2变体，以及探索联合治疗方案，以充分发挥其治疗潜力，满足不同疾病的治疗需求。抗体发现服务 & 产品01羊驼免疫&骆驼免疫—自建现代化养殖农场02万亿级天然抗体库产品—轻松DIY科研抗体03配套产品—助您轻松搭建基因工程抗体平台关于仁域生物成都仁域生物成立于2019年1月，是一家专注基因工程抗体技术和天然抗体库开发的公司，拥有优化的噬菌体展示抗体库技术和现代化的骆驼/羊驼养殖免疫基地。可为客户提供14天、100%成功率的先导抗体分子发现服务，彻底解决传统抗体定制的周期长、失败率高、成本高三大难题。目前已经成功完成300+靶点抗体筛选项目！protocol 获取 / 产品咨询邮箱｜find@renyubio.com电话｜19136178673地址｜成都市经开区科技产业孵化园关注我们，持续更新中参考文献Tanigawa K, Redmond WL. Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy. Oncoimmunology. 2025 Dec;14(1):2452654.Paul P, Choong C, Heinemann J, Al-Hallaf R, Agha Z, Ganatra S, Abdulrahman L, Sinha A, Kumar H, Nourbakhsh B, Hamad ARA. The Lasting Impact of IL-2: Approaching 50 Years of Advancing Immune Tolerance, Cancer Immunotherapies, and Autoimmune Diseases. Immunol Invest. 2025 Mar 17:1-15.Zhang Y, Kong Q, Fan J, Zhao H. Interleukin-2 and its receptors: Implications and therapeutic prospects in immune-mediated disorders of central nervous system. Pharmacol Res. 2025 Mar;213:107658.Roser LA, Sommer C, Ortega Iannazzo S, Sakellariou C, Waibler Z, Gogesch P. Revival of recombinant IL-2 therapy - approaches from the past until today. J Immunotoxicol. 2024 Oct;21(sup1):S38-S47. Im SJ, Lee K, Ha SJ. Harnessing IL-2 for immunotherapy against cancer and chronic infection: a historical perspective and emerging trends. Exp Mol Med. 2024 Sep;56(9):1900-1908.Shouse AN, LaPorte KM, Malek TR. Interleukin-2 signaling in the regulation of T cell biology in autoimmunity and cancer. Immunity. 2024 Mar 12;57(3):414-428. Rokade S, Damani AM, Oft M, Emmerich J. IL-2 based cancer immunotherapies: an evolving paradigm. Front Immunol. 2024 Jul 24;15:1433989. Sprent J, Boyman O. Optimising IL-2 for Cancer Immunotherapy. Immune Netw. 2024 Jan 26;24(1):e5.Zhang R, Zhao Y, Chen X, Zhuang Z, Li X, Shen E. Low-dose IL-2 therapy in autoimmune diseases: An update review. Int Rev Immunol. 2024 May;43(3):113-137. Lykhopiy V, Malviya V, Humblet-Baron S, Schlenner SM. "IL-2 immunotherapy for targeting regulatory T cells in autoimmunity". Genes Immun. 2023 Oct;24(5):248-262.Muhammad S, Fan T, Hai Y, Gao Y, He J. Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies. Mol Cancer. 2023 Jul 29;22(1):121. Hernandez R, Põder J, LaPorte KM, Malek TR. 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细胞疗法临床结果临床研究免疫疗法

100 项与 Igrelimogene litadenorepvec 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
铂耐药性输卵管癌	临床2期	美国	TILT Biotherapeutics Oy	2022-05-17
铂耐药性输卵管癌	临床2期	芬兰	TILT Biotherapeutics Oy	2022-05-17
铂耐药性卵巢癌	临床2期	美国	TILT Biotherapeutics Oy	2022-05-17
铂耐药性卵巢癌	临床2期	芬兰	TILT Biotherapeutics Oy	2022-05-17
铂类耐药性原发性腹膜癌	临床2期	美国	TILT Biotherapeutics Oy	2022-05-17
铂类耐药性原发性腹膜癌	临床2期	芬兰	TILT Biotherapeutics Oy	2022-05-17
铂敏感性输卵管癌	临床2期	美国	TILT Biotherapeutics Oy	2022-05-17
铂敏感性输卵管癌	临床2期	芬兰	TILT Biotherapeutics Oy	2022-05-17
铂敏感性卵巢癌	临床2期	美国	TILT Biotherapeutics Oy	2022-05-17
铂敏感性卵巢癌	临床2期	芬兰	TILT Biotherapeutics Oy	2022-05-17

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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


NCT04695327 \| NCT05271318 \| NCT04217473 (TUNINTIL \| TUNIMO \| PROTA, Pubmed \| J Exp Clin Cancer Res)	临床1期	晚期恶性实体瘤	52	TILT-123 3 × 10^9 VP	顧鬱鏇鹽範鏇窪膚築鹹(選鏇膚構艱艱築廠糧衊) = 壓膚廠衊網願鹽積齋遞鹹蓋淵築糧鏇餘衊顧選 (艱網鬱製鹹糧鹽齋艱鑰 )	积极	2024-11-06
	临床1期	晚期恶性实体瘤	52	TILT-123 4 × 10^12 VP	顧鬱鏇鹽範鏇窪膚築鹹(選鏇膚構艱艱築廠糧衊) = 繭艱窪顧觸鏇網選壓遞鹹蓋淵築糧鏇餘衊顧選 (艱網鬱製鹹糧鹽齋艱鑰 )	积极	2024-11-06
NCT05271318 (PROTA, ASCO2024) 人工标引	临床1期	难治性卵巢癌 \| 铂耐药性卵巢癌	14	PembrolizumabIgrelimogene litadenorepvec	網鏇憲願顧積鏇糧繭夢(鏇鬱糧願衊構觸範鬱願) = Frequent grade 1-4 treatment-related AEs (>30% of patients) were anemia, nausea, lymphocyte count decreased, fever and diarrhea 網夢鑰顧願製簾鑰醖範 (憲範繭鹹選網襯積積廠 )	积极	2024-05-24
NCT05271318 (PROTA, ASCO2024) 人工标引	临床1期	难治性卵巢癌 \| 铂耐药性卵巢癌	14	PembrolizumabosomIgrelimogene litadenorepvec		积极	2024-05-24
NCT04695327 \| NCT05271318 \| NCT04217473 (TILT-123, ASCO2024)	临床1期	肿瘤	52	TILT-123	製糧鑰壓繭糧願遞鑰餘(蓋鏇艱淵範蓋鹽齋廠鑰) = increased in the patients´ serum 鑰窪壓夢醖廠鏇壓範鹽 (糧積衊觸觸壓衊憲鹽餘 )	积极	2024-05-24
NCT05271318 (AACR2024) 人工标引	临床1期	卵巢癌	15	TILT-123+pembrolizumab	簾窪鹽憲壓衊選淵遞窪(觸遞淵選遞鏇糧鏇積繭) = not observed 構簾願鏇構襯艱壓齋製 (網遞繭齋製蓋衊艱艱艱 ) 更多	积极	2024-04-05
NCT04695327 (TUNIMO, Pubmed)	临床1期	晚期恶性实体瘤	20	TILT-123	鏇積鑰鏇選齋襯範繭壓(膚鑰獵繭選觸鹹鬱鹹鑰) = 醖衊壓範鹹憲選鹽遞襯繭廠簾獵衊壓鑰窪繭鬱 (齋餘鏇願餘齋淵鏇壓願 )	积极	2024-03-28
NCT04217473 (ESMO_IO 12023 \| ESMO_IO 22023) 人工标引	临床1期	黑色素瘤	16	TILT-123	顧構艱選積艱膚築齋膚(醖窪遞糧遞觸積淵鹽齋) = The most frequently reported adverse events (AEs) related to TILT-123 were fever (63%) and pain at the injection site (44%) while most frequent AEs related to TIL therapy were fever (50%) and chills (24%). 顧獵構鏇窪窪鑰鹽構觸 (網願鬱壓艱憲齋願範壓 )	积极	2023-12-06
NCT04695327 (TUNIMO , SITC 12023 \| SITC 22023) 人工标引	临床1期	实体瘤	20	TILT-123	鹹範築觸鏇襯遞鏇選艱(淵窪鑰築糧簾範選淵積) = not observed 憲衊範簾網壓選醖簾築 (選製憲簾窪艱繭願憲夢 ) 更多	积极	2023-10-31
NCT04695327 \| NCT05222932 \| NCT05271318 \| NCT04217473 (SITC 12022 \| SITC 22022) 人工标引	临床1期	实体瘤	18	TILT-123	膚艱膚窪積遞簾觸襯網(鹹網鹽積齋齋壓窪窪觸) = 選願積夢遞積選膚窪繭製願繭簾獵鹽築範淵夢 (憲淵獵窪窪壓衊壓範齋 )	积极	2022-11-01