A5052034162- Virus-based gene therapy research
- Cancer Research and Treatments
- Viral Infectious Diseases and Gene Expression in Insects
- CAR-T cell therapy research
- Immunotherapy and Immune Responses
- Renal and related cancers
- Monoclonal and Polyclonal Antibodies Research
- Neuroblastoma Research and Treatments
- Viral gastroenteritis research and epidemiology
- Pancreatic and Hepatic Oncology Research
University of Helsinki
2023-2025
Biocenter Finland
2023-2025
Abstract Immune checkpoint inhibitors have demonstrated modest efficacy as a monotherapy in ovarian cancer. Originally developed to improve of T-cell therapies such immune and adoptive cell transfer, TILT-123 (Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is serotype chimeric oncolytic adenovirus encoding tumor necrosis factor alpha interleukin-2. Here we report results from phase 1a PROTA, single-arm, multicentre dose escalation trial with pembrolizumab female patients platinum resistant or refractory...
Abstract Purpose: TILT-123 (igrelimogene litadenorepvec) is an oncolytic adenovirus armed with TNFa and IL2, designed to induce T-cell infiltration cytotoxicity in solid tumors. Patients Methods: TUNIMO (NCT04695327) was a single-arm, multicenter phase I dose-escalation trial assess the safety of advanced cancers refractory standard therapy. received intravenous intratumoral TILT-123. The primary endpoint by adverse events (AE), laboratory values, vital signs, electrocardiograms. Secondary...
Background Oncolytic viruses (OVs) are promising immunotherapeutics to treat immunologically cold tumors. However, research on the mechanism of action 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. encodes two transgenes: tumor necrosis alpha (TNFa) interleukin-2 (IL-2). TUNIMO ( NCT04695327 ) a phase I clinical trial using patients...
T cell-focused cancer immunotherapy including checkpoint inhibitors and cell therapies has been rapidly evolving over the past decade. Nevertheless, there remains a major unmet medical need in oncology generally immuno-oncology specifically. We have constructed an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), which is armed with human aMUC1aCD3 engager IL-2. TILT-322 treatment stimulated cytotoxicity through increased presence of granzyme B, perforin, interferon-gamma....
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer, but preclinical testing hypotheses such as combination therapies has been complicated, in part due to species incompatibility issues. For example, one few known permissive animal models for oncolytic adenoviruses is Syrian hamster, which an ICI, mainly anti-PD-L1 monoclonal antibody (mAb) was not previously available. In this study, we developed anti-Syrian hamster PD-L1 mAb enable evaluation safety and...
Abstract Background A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) a chimeric adenovirus suitable intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It armed with tumor necrosis alpha interleukin-2 promoting T-cell activation lymphocyte trafficking tumors, thereby enhancing the antitumor immune response. Here, we present findings...
Pancreatic ductal adenocarcinoma (PDAC) is a highly treatment-resistant cancer. Currently, the only curative treatment for PDAC surgery, but most patients are diagnosed with metastatic disease and thus outside scope of surgery. The majority receive chemotherapy, responses limited. New therapeutics urgently needed PDAC. One major limitation in treating has been immunosuppressive tumor microenvironment (TME) which inhibits anti-cancer immune responses. We have constructed an oncolytic...
Abstract Background TILT-123 (Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a serotype chimeric dual safety device oncolytic adenovirus armed with tumor necrosis factor alpha and interleukin-2. It was designed to improve efficacy of T-cell therapies such as immune checkpoint blockade or adoptive cell transfer. We present biological immunological endpoints from an open-label phase 1 dose escalation study in combination anti-PD-1 pembrolizumab platinum resistant refractory ovarian cancer patients....
5562 Background: Platinum-resistant or refractory ovarian cancer remains a hard-to-treat disease given the poor prognosis and survival rates. Immune checkpoint inhibitors (ICI; such as pembrolizumab) have not been approved in this indication. Igrelimogene litadenorepvec (Ad5/3-E2F-d24-hTNF-IRES-hIL2; TILT-123), is an oncolytic adenovirus encoding for IL-2 TNFa, designed to selectively lyse tumor cells while recruiting activating T-cells, turning immunologically cold tumors hot. The...
<h3>Background</h3> Ad5/3-E2F-D24-hTNFa-IRES-hIL-2 (TILT-123) is a chimeric serotype oncolytic adenovirus armed with tumor necrosis factor alpha and interleukin-2. The cytokine pairing showed superior immunomodulation T-cell trafficking in preclinical studies.<sup>1 2</sup> TILT-123 now being tested an open-label phase 1 dose escalation study (PROTA) combination pembrolizumab, platinum-resistant or -refractory ovarian cancer patients. In search of predictive factors for treatment benefit, we...
<p><b>A</b>, Response evaluation in all injected lesions, evaluated by CT. <b>B</b>, PET. <b>C</b>, allimaged non-injected <b>D</b>, imaged Best response shown for <b>A–D</b> if patient continued to extension. <b>E</b>, Intravenous dose given versus sum SUVmax change of measured lesions on day 78. <b>F</b>, Intratumoral <b>G</b>, Overall survival the trial. <b>H</b>,...
<p>Supplementary Table S1-S5, Supplementary Figure S1-S6</p>
<p>Patient demographics.</p>
<p>Supplementary Table S1-S5, Supplementary Figure S1-S6</p>
<p><b>A</b>, Trial outline. <b>B</b>, Lymphocyte changes after TILT-123, all cohorts pooled. <b>C</b>, Leukocyte <b>D</b>, Neutrophil <b>E</b>, Virus detection in blood by qPCR, before treatment, 1 hour post-treatment and 16 hours post-treatment, dose available pooled (<i>N =</i> 10 patients). <b>F</b>, qPCR intravenous dose, stratified given. <b>G</b>, intratumoral For graphs, mean ± SEM...
<p>Adverse events related to TILT-123 therapy as judged and reported by the investigator, stratified grade, cohort, unique patients with adverse event.<a href="#t2n1" target="_blank"><sup>a</sup></a></p>
<p>Patient demographics.</p>
<p>Adverse events related to TILT-123 therapy as judged and reported by the investigator, stratified grade, cohort, unique patients with adverse event.<a href="#t2n1" target="_blank"><sup>a</sup></a></p>
<div>AbstractPurpose:<p>TILT-123 (igrelimogene litadenorepvec) is an oncolytic adenovirus armed with TNFa and IL2, designed to induce T-cell infiltration cytotoxicity in solid tumors.</p>Patients Methods:<p>TUNIMO (NCT04695327) was a single-arm, multicenter phase I dose-escalation trial assess the safety of TILT-123 advanced cancers refractory standard therapy. Patients received intravenous intratumoral TILT-123. The primary endpoint by adverse events (AE), laboratory...
<p><b>A</b>, Volume and PET signal changes in patient 20103 with metastatic anaplastic thyroid carcinoma, showing disappearance of for injected abdominal lesion, mesenteric pulmonal lesions by CT. <b>B</b>, Changes 20202 NSCLC, decrease (62% SUVmax decrease) non-injected lesion (54% decrease). <b>C</b>, Visual tumor 20108 adenocystic adenocarcinoma the head neck, marked necrosis post-treatment.</p>
<p><b>A</b>, Virus staining (violet) in tumor biopsies from patient 20202 at different time points across the trial, showing productive virus replication injected and noninjected lesions; scale bar, 50 mm. <b>B</b>, Tumor IHC for DAPI, CD8, CD56 increased numbers of effector lymphocytes non-injected lesions post-treatment; 100 μm. <b>C</b>, Neutralizing antibodies (NAbs) against TILT-123 baseline all patients. <b>D</b>, antibody presence...
<p><b>A</b>, Volume and PET signal changes in patient 20103 with metastatic anaplastic thyroid carcinoma, showing disappearance of for injected abdominal lesion, mesenteric pulmonal lesions by CT. <b>B</b>, Changes 20202 NSCLC, decrease (62% SUVmax decrease) non-injected lesion (54% decrease). <b>C</b>, Visual tumor 20108 adenocystic adenocarcinoma the head neck, marked necrosis post-treatment.</p>