A5072358689- Virus-based gene therapy research
- CAR-T cell therapy research
- Cancer Research and Treatments
- Viral Infectious Diseases and Gene Expression in Insects
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
- Immune Cell Function and Interaction
- Viral gastroenteritis research and epidemiology
- T-cell and B-cell Immunology
- Monoclonal and Polyclonal Antibodies Research
- Renal and related cancers
- RNA Interference and Gene Delivery
- Pancreatic and Hepatic Oncology Research
- Neuroblastoma Research and Treatments
- Autoimmune Bullous Skin Diseases
- CRISPR and Genetic Engineering
- Acute Lymphoblastic Leukemia research
- Atmospheric and Environmental Gas Dynamics
- Eosinophilic Disorders and Syndromes
- Pluripotent Stem Cells Research
- Mast cells and histamine
Biocenter Finland
2017-2025
University of Helsinki
2017-2025
Alethia Biotherapeutics (Canada)
2024
Gene Therapy Laboratory
2020
Utrecht University
2017-2018
University Medical Center Utrecht
2018
Adoptive cell therapy holds much promise in the treatment of cancer but results solid tumors have been modest. The notable exception is tumor-infiltrating lymphocyte (TIL) melanoma, this approach only works with high-dose preconditioning chemotherapy and systemic interleukin (IL)-2 postconditioning, both which are associated toxicities. To improve broaden applicability adoptive transfer, we constructed oncolytic adenoviruses coding for human IL-2 (hIL2), tumor necrosis factor alpha (TNF-α),...
Releasing the patient's immune system against their own malignancy by use of checkpoint inhibitors is delivering promising results. However, only a subset patients currently benefit from them. One major limitation these therapies relates to inability T cells detect or penetrate into tumor resulting in unresponsiveness inhibition. Virotherapy an attractive tool for enabling as viruses are naturally recognized innate defense elements which draws attention system. Besides intrinsic stimulating...
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...
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...
γ9δ2T cells play a critical role in daily cancer immune surveillance by sensing mediated metabolic changes. However, major limitation of the therapeutic application is their diversity and regulation through innate co-receptors. In order to overcome natural obstacles cells, we have developed concept T engineered express defined γδT cell receptor (TEGs). This next generation chimeric antigen (CAR-T) not only allows for targeting hematological, but also solid tumors, therefore overcomes...
Ovarian cancers often contain significant numbers of tumor-infiltrating lymphocytes (TILs) that can be readily harnessed for adoptive T-cell therapy (ACT). However, the immunosuppressive ovarian tumor microenvironment and lack reactivity in TILs limit effectiveness therapy. We hypothesized by using an oncolytic adenovirus (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) to deliver necrosis factor alpha (TNFa) interleukin-2 (IL-2), we could counteract immunosuppression, enhance antitumor TIL...
Immune checkpoint inhibitors (ICI) have provided significant improvement in clinical outcomes for some patients with solid tumors. However, head and neck cancer, the response rate to ICI monotherapy remains low, leading exploration of combinatorial treatment strategies. In this preclinical study, we use an oncolytic adenovirus (Ad5/3) encoding hTNFα hIL-2 non-replicate adenoviruses (Ad5) mTNFα mIL-2 achieve superior tumor growth control improved survival outcomes. The vitro effect...
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...
Cancer treatment with local administration of armed oncolytic viruses could potentially induce systemic antitumor effects, or the abscopal effect, as they self-amplify in tumors, danger signaling, and promote tumor-associated antigen presentation. In this study, adenovirus coding for human tumor necrosis factor alpha (TNF-α) interleukin-2 (IL-2) Ad5/3-E2F-d24-hTNF-α-IRES-hIL-2 (also known [a.k.a.] TILT-123) provoked efficacy tumors that were injected those left non-injected same animal....
Lymphodepleting preconditioning with high-dose chemotherapy is commonly used to increase the clinical efficacy of adoptive T cell therapy (ACT) strategies, however, severe toxicity for patients. Conversely, oncolytic adenoviruses are safe and, when engineered express interleukin-2 (IL-2) and tumor necrosis factor alpha (TNF-α), they can achieve antitumor immunomodulatory effects similar lymphodepletion. Therefore, we compare safety such a cyclophosphamide- fludarabine-containing...
Despite some promising results, the majority of patients do not benefit from T cell therapies, as tumors prevent cells entering tumor, shut down their activity, or downregulate key antigens. Due to nature and mechanism action, oncolytic viruses have features that can help overcome many barriers currently facing therapies solid tumors. This study aims understand how four different (adenovirus, vaccinia virus, herpes simplex reovirus) perform in task. For purpose, an immunocompetent vivo tumor...
Oncolytic viruses provide a biologically multi-faceted treatment option for patients who cannot be cured with currently available options. We constructed an oncolytic adenovirus, TILT-123, to support T-cell therapies and immune checkpoint inhibitors in solid tumors. Adenoviruses are immunogenic by nature, easy produce large quantities, can carry relatively transgenes. They the most commonly used gene therapy vectors well tolerated patients. TILT-123 expresses two potent cytokines, tumor...
Cytokines have proven to be effective for cancer therapy, however whilst low-dose monotherapy with cytokines provides limited therapeutic benefit, high-dose treatment can lead a number of adverse events. Interleukin 7 has shown promising results in clinical trials, but anti-cancer effect was limited, part due low concentration the cytokine within tumor. We hypothesized that arming an oncolytic adenovirus 7, enabling high expression localized tumor microenvironment, would overcome systemic...
Lung cancer remains among the most difficult-to-treat malignancies and is leading cause of cancer-related deaths worldwide. The introduction targeted therapies checkpoint inhibitors has improved treatment outcomes; however, patients with advanced-stage non-small cell lung (NSCLC) eventually fail these therapies. Therefore, there a major unmet clinical need for refractory/resistant NSCLC. Here, we tested combination aPD-1 adenovirus armed TNFα IL-2 (Ad5-CMV-mTNFα/mIL-2) in an immunocompetent...
In order to break tumor resistance towards traditional treatments, we investigate the response of and immune cells a novel, cytokine-armed oncolytic adenovirus: Ad5/3-d24-E2F-hTNFa-IRES-hIL2 (also known as TILT-123 OAd.TNFa-IL2). There are several pattern recognition receptors (PRR) that might mediate adenovirus-infection recognition. However, role specific effects each PRR on microenvironment treatment outcome remain unclear. Hence, aim this study was OAd.TNFa-IL2 infection PRR-mediated...
Immunotherapy with tumor-infiltrating lymphocytes (TIL) or oncolytic adenoviruses, have shown promising results in cancer treatment, when used as separate therapies. When combination, the antitumor effect is synergistically potentiated due adenovirus infection and its immune stimulating effects on T cells. Indeed, studies hamsters a 100% complete response rate animals were treated coding for TNFa IL-2 (Ad5/3-E2F-D24-hTNFa-IRES-hIL2; TILT-123) TIL therapy. In humans, one caveat virus therapy...
Checkpoint inhibitors have revolutionized cancer therapy and validated immunotherapy as an approach. Unfortunately, responses are seen in a minority of patients. Our objective is to use engineered adenoviruses designed increase lymphocyte trafficking cytokine production at the tumor, assess if they response rate checkpoint inhibition, these features been regarded predictive for responses. When Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (an oncolytic adenovirus coding TNFa IL-2, also known TILT-123) were...
The notion of developing variants the classic interleukin 2 (IL-2) cytokine has emerged from limitations observed with systemic use human IL-2 in clinic: severe adverse events accompanied by low therapeutic response rate treated patients. Modifications made receptor-binding structure leads to preferential binding variant receptors on effector anti-tumor lymphocytes over T regulatory (TReg) cells. Because their inherent immunogenicity, oncolytic adenoviruses are useful for expression...
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....
Dendritic cells (DCs) are crucial players in promoting immune responses. Logically, adoptive DC therapy is a promising approach cancer immunotherapy. One of the major obstacles immunotherapy general immunosuppressive tumor microenvironment, which hampers maturation and activation DCs. Therefore, human clinical outcomes with alone have been disappointing. In this study, we use fully serotype 3 oncolytic adenovirus Ad3-hTERT-CMV-hCD40L, expressing CD40L, to modulate microenvironment...
Intratumoral immunotherapies are entering clinical use but concerns remain regarding their effects on non-injected tumors. Here, we studied the impact of local treatment with an adenovirus coding for TNFa and IL-2 systemic antitumor response in animals receiving aPD-1 (anti-programmed cell death protein 1) therapy. Using bilateral murine melanoma models, tested tumor to combined therapy anti-PD-1 ("virus"). Virus was given intratumorally (to one two tumors only) monoclonal antibody...