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

NCT05271318 / Recruiting临床1期

A Two-part, Phase I/Ib, Open-Label, Dose-escalation Trial of Tumor Necrosis Factor Alpha and Interleukin-2 Coding Oncolytic Adenovirus (TILT-123) in Combination With Pembrolizumab (Phase I Part) and Pembrolizumab and Pegylated Liposomal Doxorubicin (Phase Ib Part) in Patients With Platinum Resistant or Refractory Ovarian Cancer.

This is an open-label, phase 1, dose-escalation, multicenter and multinational trial evaluating the safety of oncolytic adenovirus TILT-123 in combination with Pembrolizumab, or Pembrolizumab and Pegylated Liposomal Doxorubicin in patients with platinum resistant or refractory ovarian cancer.

开始日期2022-05-17

申办/合作机构

TILT Biotherapeutics Oy

[+1]

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）

2024-09-03·Clinical cancer research : an official journal of the American Association for Cancer Research

Safety, Efficacy, and Biological Data of T-Cell–Enabling Oncolytic Adenovirus TILT-123 in Advanced Solid Cancers from the TUNIMO Monotherapy Phase I Trial

Article

作者: Jaakkola, Marjut ; Kistler, Claudia ; Juteau, Susanna ; Pellinen, Teijo ; Haybout, Lyna ; Santos, Joao M. ; Korpisaari, Riitta ; Kemppainen, Jukka ; Hemminki, Akseli ; Jirovec, Elise ; Quixabeira, Dafne C.A. ; Alanko, Tuomo ; Kudling, Tatiana V. ; Havunen, Riikka ; Pakola, Santeri A. ; Sormunen, Jorma ; Clubb, James H.A. ; Cervera-Carrascon, Victor ; Sorsa, Suvi ; Peltola, Katriina J. ; van der Heijden, Mirte ; Hemmes, Annabrita

Abstract:

Purpose::

TILT-123 (igrelimogene litadenorepvec) is an oncolytic adenovirus armed with TNFa and IL2, designed to induce T-cell infiltration and cytotoxicity in solid tumors.

Patients and Methods::

TUNIMO (NCT04695327) was a single-arm, multicenter phase I dose-escalation trial designed to assess the safety of TILT-123 in advanced solid cancers refractory to standard therapy. Patients received intravenous and intratumoral TILT-123. The primary endpoint was safety by adverse events (AE), laboratory values, vital signs, and electrocardiograms. Secondary endpoints included tumor response, pharmacokinetics, and predictive biomarkers.

Results::

Twenty patients were enrolled, with a median age of 58 years. Most prevalent cancer types included sarcomas (35%), melanomas (15%) and ovarian cancers (15%). No dose-limiting toxicities were observed. The most frequent treatment-related AEs included fever (16.7%), chills (13.0%), and fatigue (9.3%). Ten patients were evaluable for response on day 78 with RECIST 1.1, iRECIST or PET-based evaluation. The disease control rate by PET was 6/10 (60% of evaluable patients) and 2/10 by RECIST 1.1 and iRECIST(20%of evaluable patients). Tumor size reductions occurred in both injected and non-injected lesions. TILT-123 was detected in injected and non-injected tumors, and virus was observed in blood after intravenous and intratumoral injections. Treatment resulted in reduction of lymphocytes in blood, with concurrent lymphocyte increases in tumors, findings compatible with trafficking.

Conclusions::

TILT-123 was safe and able to produce antitumor effects in local and distant lesions in heavily pre-treated patients. Good tolerability of TILT-123 facilitates combination studies, several of which are ongoing (NCT04217473, NCT05271318, NCT05222932, and NCT06125197).See related commentary by Silva-Pilipich and Smerdou, p. 3649

2023-12-31·Oncoimmunology

Effective intravenous delivery of adenovirus armed with TNFα and IL-2 improves anti-PD-1 checkpoint blockade in non-small cell lung cancer

Article

作者: Räsänen, Jari ; Hemminki, Otto ; Aaltonen, Eero ; Quixabeira, Dafne C A ; Havunen, Riikka ; Borenius, Kristian ; Lähdeniemi, Iris A K ; Mäyränpää, Mikko I ; Sutinen, Eva ; Santos, Joao M ; Pakola, Santeri ; Arias, Victor ; Clubb, James H A ; Cervera-Carrascon, Victor ; Verschuren, Emmy W ; Hemminki, Akseli ; Kudling, Tatiana V ; Kanerva, Anna ; Sorsa, Suvi ; Ilonen, Ilkka ; Heiniö, Camilla

Lung cancer remains among the most difficult-to-treat malignancies and is the leading cause of cancer-related deaths worldwide. The introduction of targeted therapies and checkpoint inhibitors has improved treatment outcomes; however, most patients with advanced-stage non-small cell lung cancer (NSCLC) eventually fail these therapies. Therefore, there is a major unmet clinical need for checkpoint refractory/resistant NSCLC. Here, we tested the combination of aPD-1 and adenovirus armed with TNFα and IL-2 (Ad5-CMV-mTNFα/mIL-2) in an immunocompetent murine NSCLC model. Moreover, although local delivery has been standard for virotherapy, treatment was administered intravenously to facilitate clinical translation and putative routine use. We showed that treatment of tumor-bearing animals with aPD-1 in combination with intravenously injected armed adenovirus significantly decreased cancer growth, even in the presence of neutralizing antibodies. We observed an increased frequency of cytotoxic tumor-infiltrating lymphocytes, including tumor-specific cells. Combination treatment led to a decreased percentage of immunosuppressive tumor-associated macrophages and an improvement in dendritic cell maturation. Moreover, we observed expansion of the tumor-specific memory T cell compartment in secondary lymphoid organs in the group that received aPD-1 with the virus. However, although the non-replicative Ad5-CMV-mTNFα/mIL-2 virus allows high transgene expression in the murine model, it does not fully reflect the clinical outcome in humans. Thus, we complemented our findings using NSCLC ex vivo models fully permissive for the TNFα and IL-2- armed oncolytic adenovirus TILT-123. Overall, our data demonstrate the ability of systemically administered adenovirus armed with TNFα and IL-2 to potentiate the anti-tumor efficacy of aPD-1 and warrant further investigation in clinical trials.

2023-01-01·Frontiers in Immunology

Development of a Syrian hamster anti-PD-L1 monoclonal antibody enables oncolytic adenoviral immunotherapy modelling in an immunocompetent virus replication permissive setting.

Article

作者: Aro, Katri ; Heiniö, Camilla ; Cerullo, Vincenzo ; Schwartz, Joel ; Vattulainen, Ilpo ; Erikat, Abdullah ; Anttila, Marjukka ; Clubb, James H A ; Viitala, Tapani ; Havunen, Riikka ; Hemmes, Annabrita ; Sorsa, Suvi ; Santos, João Manuel ; Hamdan, Firas ; Arias, Victor ; Quixabeira, Dafne C A ; Basnet, Saru ; Hemminki, Akseli ; Pakola, Santeri ; Haybout, Lyna ; Grönberg-Vähä-Koskela, Susanna ; Girych, Mykhailo ; Kaptan, Shreyas ; Jirovec, Elise ; Kanerva, Anna ; Kudling, Tatiana V ; Cervera-Carrascon, Víctor

Introduction:

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, but preclinical testing of hypotheses such as combination therapies has been complicated, in part due to species incompatibility issues. For example, one of few known permissive animal models for oncolytic adenoviruses is the Syrian hamster, for which an ICI, mainly an anti-PD-L1 monoclonal antibody (mAb) was not previously available. In this study, we developed an anti-Syrian hamster PD-L1 mAb to enable the evaluation of safety and efficacy, when combining anti-PD-L1 with an oncolytic adenovirus encoding tumour necrosis factor alpha (TNFα) and interleukin-2 (IL-2) (Ad5/3-E2F-D24-hTNFα-IRES-hIL-2 or TILT-123).

Methods:

Recombinant Syrian hamster PD-L1 was expressed and mice immunized for mAb formation using hybridoma technology. Clonal selection through binding and functional studies in vitro, in silico and in vivo identified anti-PD-L1 clone 11B12-1 as the primary mAb candidate for immunotherapy modelling. The oncolytic virus (OV) and ICI combination approach was then evaluated using 11B12-1 and TILT-123 in a Syrian hamster model of pancreatic ductal adenocarcinoma (PDAC).

Results:

Supernatants from hybridoma parent subclone 11B12B4 provided the highest positive PD-L1 signal, on Syrian hamster PBMCs and three cancer cell lines (HT100, HapT1 and HCPC1). In vitro co-cultures revealed superior immune modulated profiles of cell line matched HT100 tumour infiltrating lymphocytes when using subclones of 7G2, 11B12 and 12F1. Epitope binning and epitope prediction using AlphaFold2 and ColabFold revealed two distinct functional epitopes for clone 11B12-1 and 12F1-1. Treatment of Syrian hamsters bearing HapT1 tumours, with 11B12-1 induced significantly better (p<0.05) tumour growth control than isotype control by day 12. 12F1-1 did not induce significant tumour growth control. The combination of 11B12-1 with oncolytic adenovirus TILT-123 improved tumour growth control further, when compared to monotherapy (p<0.05) by day 26.

Conclusions:

Novel Syrian hamster anti-PD-L1 clone 11B12-1 induces tumour growth control in a hamster model of PDAC. Combining 11B12-1 with oncolytic adenovirus TILT-123 improves tumour growth control further and demonstrates good safety and toxicity profiles.

项与 Igrelimogene litadenorepvec 相关的新闻（医药）

2024-12-05

·GlobeNewswire-Health Care

TILT Biotherapeutics Provides Update on International Clinical Trial Progress with Intravenous Delivery Regimen for Cancer Immunotherapies

Data Presented at ESMO-IO supports the potential of personalized treatment strategies to improve clinical trial outcomesHELSINKI, Finland, Dec. 05, 2024 (GLOBE NEWSWIRE) -- TILT Biotherapeutics (TILT), a clinical-stage biotechnology company developing intravenously delivered cancer immunotherapies, announces it will be presenting data at the European Society of Medical Oncology Immuno-Oncology Congress (ESMO-IO) 2024. The oral presentation discloses the impact of different biological features on treatment efficacy in patients treated with the oncolytic virus Igrelimogene litadenorepvec or ‘TILT-123’(1). The study used single-cell sequencing analysis to identify immunological markers in peripheral blood mononuclear cells that were related with better outcomes, including higher baseline levels of cytotoxic effector cells. Additionally, TILT-123 treatment supported the formation of immunological memory. TILT will also present data relating to the fully intravenous dosing of TILT-123 (2). These findings have the potential to support future clinical development strategy. In addition, TILT is progressing its plans for international Phase II trials of TILT-123 in ovarian cancer, to be administered intravenously, and expects Phase Ib clinical results by H2 2025. TILT Biotherapeutics’ founder and CEO, Akseli Hemminki, said: “This year we’ve made significant progress in the clinical development of TILT-123, and have now treated over 60 patients in five international trials, including our first patients in leading US cancer centres. Our data, presented at ESMO-IO this month, provides further support on the mechanism of action of our oncolytic immunotherapy. Our progress in IV administration, alongside our manufacturing process scale up work, supports our mission to make TILT-123 accessible to patients with hard-to-treat solid cancers.” TILT-123, an oncolytic adenovirus armed with tumor necrosis factor alpha (TNFα) and interleukin-2 (IL-2), is designed to enhance the efficacy of T-cell therapies, including immune checkpoint blockade or adoptive cell transfer. TILT’s approach uses oncolytic viruses to selectively replicate in and lyse cancer cells, while simultaneously stimulating immune responses towards the tumor. Reference (1) ESMO-IO Abstract 353: “Single-cell profiling of peripheral blood mononuclear cells from patients treated with oncolytic adenovirus armed with TNFα and IL-2 revealed pre-existing immunity as a predictor of therapy outcomes”. (2) ESMO-IO Abstract 458: “Effect of split intravenous dosing of oncolytic adenovirus TILT-123 on normal tissue versus tumor macrophages and virus bioavailability in patients with advanced solid tumors”. 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 T-cell therapies such as immune checkpoint inhibitors, tumor infiltrating lymphocyte (TIL) therapy, and CAR T therapies. TILT’s lead asset, TILT-123 also known as Igrelimogene litadenorepvec, is a 5/3 chimeric serotype adenovirus armed with two human cytokines: TNF alpha and IL-2. Over sixty patients have been treated in five international trials sponsored by the company with promising initial efficacy responses observed in some of the 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. It has funding from Lifeline Ventures, Finnish Industry Investment (TESI), angel investors, Business Finland, the European Innovation Council, and the U.S. Department of Defense. Media contacts TILT BiotherapeuticsCOO Aino Kalervoaino@tiltbio.com Scius CommunicationsKatja Stout+447789435990katja@sciuscommunications.com Daniel Gooch+447747875479daniel@sciuscommunications.com

免疫疗法临床研究

2024-09-15

·药明康德

94%患者肿瘤缩小的靶向疗法；将化疗效果提高40%的抗癌疗法…… | 一周盘点

▎药明康德内容团队编辑本期看点 1. 口服人类表皮生长因子受体2（HER2）酪氨酸激酶抑制剂（TKI）zongertinib治疗非小细胞肺癌（NSCLC）患者在一项早期临床试验中获积极结果，94%患者的肿瘤有缩小。 2. HER2靶向疗法BAY 2927088在一项1/2期临床试验中治疗携带HER2 YVMA插入突变的晚期NSCLC患者，客观缓解率（ORR）达90%。 3. 口服靶向抗癌化合物ibrilatazar联用化疗（紫杉醇/卡铂）在一项1/2期临床试验中使子宫内膜癌患者的无进展生存期（PFS）相比历史对照组延长了40%。药明康德内容团队整理 Zongertinib：公布1b期临床试验的初步数据勃林格殷格翰（Boehringer Ingelheim）公布了旗下口服HER2靶向疗法zongertinib（BI 1810631）在NSCLC患者中的最新积极临床结果。Zongertinib不与野生型表皮生长因子受体（EGFR）结合，进而相关毒性较低。Zongertinib于2023年获得美国FDA授予快速通道资格，并随后于2024年获得美国FDA和中国国家药监局药品审评中心（CDE）授予的突破性疗法认定，用于治疗曾接受过全身性疗法、携带HER2激活突变的晚期NSCLC成人患者。此次公布的结果显示，截至2024年5月，共132例患者每天接受一次120 mg/240 mg zongertinib治疗（n=75/n=57）。经盲法独立中央审评（BICR）评估，试验达到主要终点，患者的确认ORR为66.7%（97.5% CI：53.8–77.5，p<0.0001）。在所有剂量的患者中，94%的患者观察到任何程度的肿瘤缩小。此外，数据还显示，zongertinib具有初步的脑活性。根据BICR评估的RANO-BM（神经肿瘤脑转移瘤的疗效评估），33%（120 mg，n=27）和40%（240 mg，n=25）的无症状脑转移患者达成确认的客观缓解，疾病控制率（DCR）分别为74%和92%。Zongertinib在120 mg和240 mg剂量下的耐受性通常良好，没有因治疗导致的死亡，且导致剂量减少（11%）和停药（3%）的不良事件发生率低。 BAY 2927088：公布1/2期临床试验数据拜耳（Bayer）公布了1/2期SOHO-01研究扩展部分的积极结果。该研究评估了其口服、可逆的HER2靶向疗法BAY 2927088在携带HER2变异的晚期NSCLC患者中的安全性和初步疗效。入组患者在接受≥1种晚期疾病全身治疗后病情出现进展，但未曾接受过HER2靶向治疗。BAY 2927088能够强效抑制突变的HER2，包括HER2外显子20插入突变和HER2点突变，同时也能抑制EGFR，对突变型EGFR具有高选择性，且不和野生型EGFR相结合。美国FDA和中国药品审评中心于2024年授予BAY 2927088突破性疗法认定，用于治疗携带HER2激活突变且曾接受过全身治疗的不可切除或转移性NSCLC成年患者。此次公布的结果显示，43名可评估疗效患者的确认ORR为72.1%，1名（2.3%）患者实现完全缓解（CR）。中位缓解持续时间（DOR）和PFS分别为8.7个月和7.5个月。在携带HER2 YVMA插入突变（最常见的变异）的患者中，ORR为90.0%，DOR为9.7个月，PFS为9.9个月。此外，BAY 2927088的安全性是可控的，并且与之前的报告一致。 Ibrilatazar（ABTL0812）：公布1/2期临床试验数据 AbilityPharma公司公布了ibrilatazar联用化疗（紫杉醇/卡铂）治疗晚期或复发性子宫内膜癌患者的1/2期临床试验ENDOLUNG的最终数据。Ibrilatazar是一种潜在“first-in-class”、差异化的口服靶向抗癌化合物，通过诱导内质网应激和抑制PI3K/Akt/mTOR通路来引发自噬。在临床试验中，ibrilatazar对子宫内膜癌和肺癌患者显示出临床益处。此外，它在包括肺癌、子宫内膜癌、胰腺癌、神经母细胞瘤和胶质母细胞瘤等癌症类型的动物模型中展示了强有力的临床前概念验证。此次公布的结果显示，ibrilatazar联用化疗的总缓解率为65.8%，其中13.2%的患者达到CR，52.6%的患者达到部分缓解（PR），中位DOR为7.4个月。中位PFS为9.8个月，相比历史对照组延长了40%。中位总生存期（OS）为23.6个月。这些结果表明，接受ibrilatazar联用化疗治疗的患者的ORR、PFS和OS相较于历史对照组（分别为51%、7.1个月和20.4个月）均有所提高。安全性方面，ibrilatazar联用化疗治疗显示出良好的安全性，未引入与化疗相关的重大不良事件，其安全性与历史对照组一致。药代动力学参数与临床前试验中观察到的靶点作用相符，血液药效学生物标志物表明治疗开始后至少28天内靶点调节持续存在。 RLY-2608：公布首个人体试验数据 Relay Therapeutics公司公布了其在研疗法RLY-2608的首个人体试验的积极中期数据。RLY-2608是Relay Therapeutics开发针对PI3Kα突变体的选择性抑制剂。该激酶是所有癌症中最常出现突变的激酶之一，约在14%的实体瘤患者检测出PI3Kα的致癌突变。传统上，PI3Kα抑制剂的开发聚焦于蛋白的活性位点。然而，这些抑制剂缺乏对突变型PI3Kα的选择性，导致治疗效果欠佳。为了增强PI3Kα抑制剂的选择性，Relay Therapeutics解析了PI3Kα的全长蛋白冷冻电镜结构，以阐明野生型和突变型PI3Kα的构象差异，并利用这些见解支持RLY-2608的设计。此次公布的数据显示，此前接受过大量治疗，携带PI3Kα突变的HR阳性、HER2阴性局部晚期或转移性乳腺癌患者在接受RLY-2608（600 mg）联合fulvestrant治疗后，表现出具有临床意义的PFS。中位随访时间为7.5个月时，所有携带PI3Kα突变患者的中位PFS为9.2个月。在30名具有可测量疾病的患者中，1/3的患者达到PR，ORR为33%。新闻稿指出，RLY-2608是首个针对PI3Kα，具有突变体和异构体（isoform）选择性的别构抑制剂。 ▲RLY-2608让73%患者的肿瘤缩小（图片来源：Relay Therapeutics公司官网） Mosliciguat：公布1b期临床试验数据 Roivant公司公布了其肺动脉高压（PH）疗法mosliciguat的1b期概念验证试验的结果。Mosliciguat是一种每日给药一次、潜在"first-in-class"和“best-in-class”的吸入性可溶性鸟苷酸环化酶（sGC）激动剂，可靶向递送至肺部。sGC是一种一氧化氮（NO）/环磷酸鸟苷（cGMP）信号通路中的关键酶，可催化cGMP生成，从而增加血管扩张、减少炎症和细胞凋亡、逆转血管重塑和抗纤维化作用。与需要减少血红素和NO才能对sGC产生作用的sGC激动剂不同，mosliciguat是一种独立于血红素和NO的sGC激活剂。这使mosliciguat可能在典型PH患者体内高氧化环境中保持有效性。该疗法目前正在开发用于治疗与间质性肺病（PH-ILD）相关的肺动脉高压。此次公布的结果显示，1.0、2.0和4.0毫克mosliciguat分别使患者的肺血管阻力（PVR）相对于基线的平均最大峰值降低达25.9%、38.1%和36.3%，超过预定主要结果≥20%降幅的阈值。此外，该疗法的耐受性良好，治疗引起的不良事件发生率低。根据新闻稿，这是迄今为止PH相关试验中观察到PVR的最大降低幅度之一。Mosliciguat的全球2期PHocus研究即将启动。 CT-996：公布1期临床试验数据罗氏（Roche）公布了其每日一次的口服胰高血糖素样肽-1（GLP-1）受体小分子激动剂CT-996的1期临床试验结果。罗氏在去年12月与Carmot Therapeutics达成合并协议，斥资约31亿美元收购了Carmot公司，囊获包括CT-996在内的多款处于临床开发阶段的皮下和口服肠促胰岛素疗法。此次公布的结果显示，CT-996在未患有2型糖尿病的肥胖人群中，在4周内将受试者体重减轻7.3%（约7公斤），安慰剂同期将体重降低1.2%。与安慰剂相比，CT-996提供了具有临床意义的体重减轻。安全性方面，所有的治疗伴发不良事件（TEAE）均为轻度或中度，没有发现3级以上TEAE。没有出现与在研药物相关的停止用药。最常见的TEAE为胃肠道相关不良事件，与其它肠促胰岛素疗法类似。接受更高剂量治疗的参与者TEAE更多，不过更缓慢的剂量滴定可能改善耐受性。基于这些积极结果，该公司计划在2025年启动2期临床试验。 ▲CT-996的减重效果（图片来源：参考资料[5]） Radiprodil：公布1b期临床试验数据 GRIN Therapeutics公司公布了其正在进行的全球1b期开放标签临床试验的初步结果。该试验的两个部分正在评估radiprodil的安全性、耐受性、药代动力学以及疗效。Radiprodil是一种在研选择性强效N-甲基-D-天冬氨酸受体亚基2B（GluN2B）的负变构调节剂，用于治疗GRIN相关神经发育障碍。GRIN相关神经发育障碍是一组由GRIN基因突变引起的罕见儿科神经发育障碍，目前尚无批准的疗法。此次公布的结果显示，radiprodil在具有GRIN基因功能增加突变的患者中，无论基线时是否存在可数的运动性癫痫发作（CMS），均表现出良好的耐受性。具有CMS患者的中位癫痫发作频率与基线相比降低了86%，超过了背景抗癫痫药物，其中71%的患者癫痫发作频率降低了50%以上。这些结果预计将支持GRIN Therapeutics与监管机构的讨论，以推动radiprodil进入3期关键性试验。 Elraglusib：公布1/2期临床试验的新数据 Actuate Therapeutics公司更新了elraglusib用于治疗复发/难治性尤文氏肉瘤（r/r EWS）的1/2期临床试验进展。该研究旨在评估elraglusib在复发/难治性恶性肿瘤儿科患者中的安全性和疗效，涵盖EWS及EWS相关的小圆细胞肉瘤。所有患者均接受了elraglusib与环磷酰胺/拓扑替康的联合治疗。此次公布的结果显示，在首批8名复发/难治性EWS及相关肉瘤患者中，两名患者正在经历持续的CR，两名患者实现疾病稳定（SD），1名患者取得了PR，肿瘤缩小了52%。Elraglusib展现了抗肿瘤活性，DCR为62.5%。该研究招募正在进行，预计2025年上半年有望公布顶线数据。 ▲Elraglusib联用环磷酰胺/拓扑替康的1/2期临床试验结果（图片来源：参考资料[6]） ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看） [1] Relay Therapeutics Announces Positive Interim Data for RLY-2608 Demonstrating Clinically Meaningful Progression Free Survival. Retrieved September 9, 2024, from https://ir.relaytx.com/news-releases/news-release-details/relay-therapeutics-announces-positive-interim-data-rly-2608 [2] Boehringer’s zongertinib shows encouraging efficacy and tolerability profile in previously treated HER2 mutated lung cancer patients. Retrieved September 10, 2024 from https://www.boehringer-ingelheim.com/human-health/cancer/lung-cancer/zongertinib-positive-results-non-small-cell-lung-cancer [3] New results from the Investigational agent BAY 2927088 in HER2-mutant non-small cell lung cancer (NSCLC) presented at WCLC. Retrieved September 10, 2024 from https://www.businesswire.com/news/home/20240909979023/en/New-results-from-the-Investigational-agent-BAY-2927088-in-HER2-mutant-non-small-cell-lung-cancer-NSCLC-presented-at-WCLC [4] Roivant Unveils New Pipeline Program Mosliciguat, A Potential First-In-Class and Best-In-Category Inhaled Once-Daily Soluble Guanylate Cyclase (sGC) Activator. Retrieved September 10, 2024 from https://www.globenewswire.com/news-release/2024/09/10/2943472/0/en/Roivant-Unveils-New-Pipeline-Program-Mosliciguat-A-Potential-First-In-Class-and-Best-In-Category-Inhaled-Once-Daily-Soluble-Guanylate-Cyclase-sGC-Activator.html [5] Safety, Pharmacokinetics, and Pharmacodynamics of CT-996, an Oral Small-Molecule, Signal-Biased GLP-1 Receptor Agonist Over 4 Weeks in Adults With Obesity. Retrieved September 11, 2024, from https://medically.roche.com/global/en/metabolism/easd-2024/medical-material/EASD-2024-presentation-chakravarthy-ct-996-an-oral-small-molecule-signal-biased-pdf.html [6] Actuate Therapeutics Obtains Complete Responses and Provides Update on Clinical Trial of Elraglusib for the Treatment of Relapsed/Refractory Ewing Sarcoma. Retrieved September 14, 2024, from https://actuatetherapeutics.com/press_releases/actuate-therapeutics-obtains-complete-responses-and-provides-update-on-clinical-trial-of-elraglusib-for-the-treatment-of-relapsed-refractory-ewing-sarcoma/ [7] IBRILATAZAR (ABTL0812) from AbilityPharma increases chemotherapy effectiveness by 40% in patients with endometrial cancer. Retrieved September 14, 2024, from https://abilitypharma.com/en/main-menu/media-center-2/press-release/ibrilatazar-(abtl0812)-from-abilitypharma-increases-chemotherapy-effectiveness-by-40-in-patients-with-endometrial-cancer [8] GRIN Therapeutics Announces Positive Topline Data from Honeycomb Trial of Radiprodil in GRIN-Related Neurodevelopmental Disorder. Retrieved September 14, 2024, from https://www.prnewswire.com/news-releases/grin-therapeutics-announces-positive-topline-data-from-honeycomb-trial-of-radiprodil-in-grin-related-neurodevelopmental-disorder-302240847.html [9] Seres Therapeutics Reports SER-155 Phase 1b Placebo-Controlled Cohort 2 Study Safety and Clinical Results in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT). Retrieved September 13, 2024, from https://www.globenewswire.com/news-release/2024/09/12/2945049/0/en/Seres-Therapeutics-Reports-SER-155-Phase-1b-Placebo-Controlled-Cohort-2-Study-Safety-and-Clinical-Results-in-Patients-Undergoing-Allogeneic-Hematopoietic-Stem-Cell-Transplant-allo-.html [10] Vironexis Biotherapeutics Launches with FDA Clearance of IND Application for First-Ever Clinical Trial of an AAV-delivered Cancer Immunotherapy. Retrieved September 13, 2024, from https://www.globenewswire.com/news-release/2024/09/12/2945063/0/en/Vironexis-Biotherapeutics-Launches-with-FDA-Clearance-of-IND-Application-for-First-Ever-Clinical-Trial-of-an-AAV-delivered-Cancer-Immunotherapy.html [11] Cytonics Announces Completion Of Enrollment For Phase 1 Clinical Study Evaluating CYT-108, A Novel Recombinant Protease Inhibitor, In Patients Suffering From Osteoarthritis Of The Knee. Retrieved September 13, 2024, from https://www.prnewswire.com/news-releases/cytonics-announces-completion-of-enrollment-for-phase-1-clinical-study-evaluating-cyt-108-a-novel-recombinant-protease-inhibitor-in-patients-suffering-from-osteoarthritis-of-the-knee-302239925.html [12] Phanes Therapeutics Announces First Patient Dosed in Clinical Study of PT886 in Combination with Chemotherapy. Retrieved September 13, 2024, from https://www.prnewswire.com/news-releases/phanes-therapeutics-announces-first-patient-dosed-in-clinical-study-of-pt886-in-combination-with-chemotherapy-302242421.html [13] Upstream Bio Announces Oral Presentation of New Data from a Phase 1b Multiple Ascending Dose Trial of Verekitug (UPB-101) in Adults with Asthma at the European Respiratory Society Congress. Retrieved September 13, 2024, from https://www.globenewswire.com/news-release/2024/09/09/2942765/0/en/Upstream-Bio-Announces-Oral-Presentation-of-New-Data-from-a-Phase-1b-Multiple-Ascending-Dose-Trial-of-Verekitug-UPB-101-in-Adults-with-Asthma-at-the-European-Respiratory-Society-Co.html [14] CytomX Therapeutics Announces First Patient Dosed with CX-801, a Dually-Masked Interferon-Alpha 2b PROBODY®, in a Phase 1 Study in Patients with Solid Tumors. Retrieved September 13, 2024, from https://www.globenewswire.com/news-release/2024/09/09/2942754/37704/en/CytomX-Therapeutics-Announces-First-Patient-Dosed-with-CX-801-a-Dually-Masked-Interferon-Alpha-2b-PROBODY-in-a-Phase-1-Study-in-Patients-with-Solid-Tumors.html#:~:text=SOUTH%20SAN%20FRANCISCO%2C%20Calif.%2C%20Sept.%2009%2C%202024%20%28GLOBE,1%20study%20%28NCT06462794%29%20in%20patients%20with%20solid%20tumors. [15] ORYZON announces first patient dosed in an Investigator-initiated Phase Ib study of iadademstat in first-line acute myeloid leukemia. Retrieved September 13, 2024, from https://www.oryzon.com/en/news-events/news/oryzon-announces-first-patient-dosed-investigator-initiated-phase-ib-study [16] PolTREG Treg cell therapy for patients with type-1 diabetes shows long-term clinical remission and insulin independence. Retrieved September 13, 2024, from https://poltreg.com/poltreg-treg-cell-therapy-for-patients-with-type-1-diabetes-shows-long-term-clinical-remission-and-insulin-independence/ [17] Centessa Announces Positive Interim Phase 1 Clinical Data with its Novel Orexin Receptor 2 (OX2R) Agonist, ORX750, in Acutely Sleep-Deprived Healthy Volunteers. Retrieved September 13, 2024, from https://investors.centessa.com/news-releases/news-release-details/centessa-announces-positive-interim-phase-1-clinical-data-its [18] Cytokinetics Announces Data From Phase 1 Study of CK-4021586. Retrieved September 13, 2024, from https://www.globenewswire.com/news-release/2024/09/09/2942724/35409/en/Cytokinetics-Announces-Data-From-Phase-1-Study-of-CK-4021586.html [19] Antennova to Present Latest Data of ATN-037 in a Mini Oral Presentation at ESMO Congress. Retrieved September 13, 2024, from https://www.prnewswire.com/news-releases/antennova-to-present-latest-data-of-atn-037-in-a-mini-oral-presentation-at-esmo-congress-2024-302240448.html [20] TILT Biotherapeutics Presents Clinical Data on TILT-123 After Fully Intravenous Delivery Regimen at ESMO 2024. Retrieved September 13, 2024, from https://www.globenewswire.com/news-release/2024/09/09/2942525/0/en/TILT-Biotherapeutics-Presents-Clinical-Data-on-TILT-123-After-Fully-Intravenous-Delivery-Regimen-at-ESMO-2024.html [21] Terns Pharmaceuticals Announces Positive Phase 1 Clinical Trial Results with TERN-601 Once-Daily Oral GLP-1R Agonist for the Treatment of Obesity. Retrieved September 9, 2024 from https://ir.ternspharma.com/news-releases/news-release-details/terns-pharmaceuticals-announces-positive-phase-1-clinical-trial [22] Zealand Pharma announces positive topline results from 13-week Phase 1b multiple ascending dose clinical trial with GLP-1/GLP-2 receptor dual agonist dapiglutide. Retrieved September 9, 2024 from https://www.globenewswire.com/news-release/2024/09/09/2943004/0/en/Zealand-Pharma-announces-positive-topline-results-from-13-week-Phase-1b-multiple-ascending-dose-clinical-trial-with-GLP-1-GLP-2-receptor-dual-agonist-dapiglutide.html [23] BridgeBio Receives FDA’s Regenerative Medicine Advanced Therapy (RMAT) Designation for BBP-812 Canavan Disease Gene Therapy Program. Retrieved September 11, 2024 from https://www.globenewswire.com/news-release/2024/09/10/2944157/0/en/BridgeBio-Receives-FDA-s-Regenerative-Medicine-Advanced-Therapy-RMAT-Designation-for-BBP-812-Canavan-Disease-Gene-Therapy-Program.html [24] NKGen Biotech’s Positive Phase 1 Clinical Data in Moderate Alzheimer’s Disease Advances Troculeucel into Phase 2 with First Patient Dosed in Phase 1/2a Trial. Retrieved September 12, 2024, from https://www.globenewswire.com/news-release/2024/09/12/2945163/0/en/NKGen-Biotech-s-Positive-Phase-1-Clinical-Data-in-Moderate-Alzheimer-s-Disease-Advances-Troculeucel-into-Phase-2-with-First-Patient-Dosed-in-Phase-1-2a-Trial.html [25] HotSpot Therapeutics Presents First-in-Human Phase 1 Clinical Data on its Novel CBL-B Inhibitor, HST-1011, at ESMO Congress 2024. Retrieved September 13, 2024, from https://www.prnewswire.com/news-releases/hotspot-therapeutics-presents-first-in-human-phase-1-clinical-data-on-its-novel-cbl-b-inhibitor-hst-1011-at-esmo-congress-2024-302246957.html [26] Sernova Announces New Positive Data from Phase I/II Trial Regarding Islet Survival and Function. Retrieved September 13, 2024, from https://www.globenewswire.com/news-release/2024/09/12/2945121/0/en/Sernova-Announces-New-Positive-Data-from-Phase-I-II-Trial-Regarding-Islet-Survival-and-Function.html [27] VYNE Therapeutics Announces Positive Phase 1a SAD Data for VYN202, a Novel BD2-Selective BET Inhibitor. Retrieved September 13, 2024, from https://www.globenewswire.com/news-release/2024/09/12/2945109/0/en/VYNE-Therapeutics-Announces-Positive-Phase-1a-SAD-Data-for-VYN202-a-Novel-BD2-Selective-BET-Inhibitor.html 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

突破性疗法临床结果快速通道临床2期

2024-09-09

·PipelineReview

TILT Biotherapeutics Presents Clinical Data on TILT-123 After Fully Intravenous Delivery Regimen at ESMO 2024

Results reinforce potential to develop TILT-123 as a systemic therapy in Phase II setting HELSINKI, Finland I September 09, 2024 I TILT Biotherapeutics (TILT), a clinical-stage biotechnology company developing cancer immunotherapies, announces that it will present data at the European Society of Medical Oncology (ESMO) Congress 2024. The results further demonstrate the potential for TILT-123 as an intravenous therapy. The data presented covers the results of a Phase I clinical cohort of TILT-123 monotherapy for the treatment of advanced solid cancers (NCT04695327), demonstrating the regimen is safe, resulting in tumor transduction and immunological effects in metastases. A fully intravenous delivery regimen of TILT-123 was studied in a total of 6 patients, whose cancer types included three rectal carcinomas, gastric intestinal type carcinoma, pancreatic ductal adenocarcinoma, and liposarcoma. TILT-123 was administered twice daily, first twice a week and subsequently at 3-week intervals. Of patients evaluable by imaging by data cutoff, disease control was seen in 33% of patients with RECIST1.1 and 66% of patients with PET-based criteria. Updated data will be presented at the meeting (1). TILT Biotherapeutics’ founder and CEO, Akseli Hemminki, a cancer clinician who has personally treated hundreds of cancer patients with oncolytic viruses, said “This data presented at ESMO 2024 provides additional validation on the potential of TILT-123 as fully intravenous therapy in very difficult to treat patient population. I am also proud of our progress with two other studies investigating the fully intravenous regimen of TILT-123. We are moving according to our plan towards Phase II and making good clinical progress.” TILT-123, an oncolytic adenovirus armed with tumor necrosis factor alpha (TNFα) and interleukin-2 (IL-2), is designed to enhance the efficacy of T-cell therapies, including immune checkpoint blockade or adoptive cell transfer. TILT’s approach uses oncolytic viruses to selectively replicate in and lyse cancer cells, while simultaneously stimulating immune responses towards the tumor. References: (1) Abstract: Poster #1025P presented 14 Sep at 09:00-17:00: 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 T-cell therapies such as immune checkpoint inhibitors, tumor infiltrating lymphocyte (TIL) therapy, and CAR T therapies. TILT’s lead asset, TILT-123 also known as Igrelimogene litadenorepvec , is a 5/3 chimeric serotype adenovirus armed with two human cytokines: TNF alpha and IL-2. Over sixty patients have been treated in five international trials sponsored by the company with promising initial efficacy responses observed in some of the 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. It has funding from Lifeline Ventures, Finnish Industry Investment (TESI), angel investors, Business Finland, the European Innovation Council, and the U.S. Department of Defense. SOURCE: TILT Biotherapeutics

临床1期免疫疗法临床结果临床2期

100 项与 Igrelimogene litadenorepvec 相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
黑色素瘤	临床1期	美国	TILT Biotherapeutics Oy	2023-03-08
黑色素瘤	临床1期	芬兰	TILT Biotherapeutics Oy	2023-03-08
头颈部鳞状细胞癌	临床1期	美国	TILT Biotherapeutics Oy	2023-03-08
头颈部鳞状细胞癌	临床1期	芬兰	TILT Biotherapeutics Oy	2023-03-08
非小细胞肺癌	临床1期	美国	TILT Biotherapeutics Oy	2022-09-26
铂耐药性输卵管癌	临床1期	美国	TILT Biotherapeutics Oy	2022-05-17
铂耐药性输卵管癌	临床1期	芬兰	TILT Biotherapeutics Oy	2022-05-17
铂耐药性卵巢癌	临床1期	美国	TILT Biotherapeutics Oy	2022-05-17
铂耐药性卵巢癌	临床1期	芬兰	TILT Biotherapeutics Oy	2022-05-17
铂类耐药性原发性腹膜癌	临床1期	美国	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	願鏇齋壓廠艱齋構憲淵(憲壓繭窪範夢鑰醖窪積) = 襯壓憲遞製網憲襯鬱積齋淵糧網窪襯廠餘獵範 (鏇醖鹽夢窪衊簾餘醖憲 )	积极	2024-11-06
	临床1期	晚期恶性实体瘤	52	TILT-123 4 × 10^12 VP	願鏇齋壓廠艱齋構憲淵(憲壓繭窪範夢鑰醖窪積) = 鹹願艱壓艱衊鹹糧網壓齋淵糧網窪襯廠餘獵範 (鏇醖鹽夢窪衊簾餘醖憲 )	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	衊構鬱築鹹鏇餘衊鑰遞(鹹鏇襯齋簾窪繭選獵鑰) = Frequent grade 1-4 treatment-related AEs (>30% of patients) were anemia, nausea, lymphocyte count decreased, fever and diarrhea 夢醖餘窪衊製艱網糧壓 (積鬱網齋鑰鬱顧淵範襯 )	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	壓選廠鏇選夢膚構淵築(艱襯廠繭廠膚觸願獵廠) = increased in the patients´ serum 衊壓鑰繭齋壓艱繭鬱積 (積選簾憲鏇襯窪壓鏇窪 )	积极	2024-05-24
NCT05271318 (AACR2024) 人工标引	临床1期	卵巢癌	15	TILT-123+pembrolizumab	獵觸網鹹繭艱糧願膚鑰(簾製繭鹹鹹憲製鏇壓餘) = not observed 窪網願願壓糧齋窪糧構 (願衊範鏇憲積顧鹽範鬱 ) 更多	积极	2024-04-05
NCT04695327 (TUNIMO, Pubmed)	临床1期	晚期恶性实体瘤	20	TILT-123	網積蓋鹽糧糧選築遞構(衊艱窪願鑰夢鹹艱範築) = 鹽顧選網鹽艱齋鹹獵製齋憲製糧積獵鑰繭糧範 (壓齋糧鹽窪鬱襯鑰壓窪 )	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	糧糧醖築鹹製憲鏇繭範(淵齋繭鏇壓簾繭築夢鹹) = 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%). 醖鹽壓獵獵遞夢襯築範 (鏇願遞顧餘齋鹽簾壓廠 )	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	夢積襯網簾簾蓋醖鹽窪(艱蓋鏇鏇網蓋鑰獵壓艱) = not observed 範願憲構簾繭糧餘艱構 (構願願壓蓋製衊壓遞鬱 ) 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	糧廠淵齋網觸艱淵餘餘(窪廠選願糧簾鬱網鹽遞) = 淵簾壓淵鹽膚選網壓襯鹽鹽製鹽鹽網鏇鑰淵鹹 (簾顧觸顧願選構壓鹹積 )	积极	2022-11-01