Boosting anti-tumor immunity with TILT-517 oncolytic adenovirus and checkpoint blockade in renal cell carcinoma.

Elevated levels of immune infiltration found in renal cell carcinoma are often associated with poor patient prognosis, likely due to T cell exhaustion and an immunosuppressive tumor microenvironment, which limits the efficacy of current immunotherapies. In this study, we focused on the use of Ad5/3-E2F-d24-hIL7 (TILT-517), an oncolytic adenovirus expressing interleukin-7, as a strategy to selectively lyse tumors. This approach also seeks to activate infiltrating immune cells, thereby reprogramming the immune landscape characteristic of renal cell carcinoma tumors.

Oncolytic adenovirus encoding variant interleukin-2 combined with chemotherapy enables PD-L1 inhibition in pancreatic cancer models.

Pancreatic ductal adenocarcinoma (PDAC) is a cancer with dismal prognosis due to resistance to most current therapies. Although immunotherapy has improved the treatment of many solid cancers, pancreatic cancer remains resistant to immunotherapy due to immunosuppressive tumor microenvironment, limited lymphocyte infiltration and lack of neoantigens. Oncolytic adenoviruses are a possible solution to treatment resistance in PDAC due to their ability to elicit lymphocyte trafficking and epitope spreading.

Single-cell profiling of peripheral blood mononuclear cells from patients treated with oncolytic adenovirus TILT-123 reveals baseline immune status as a predictor of therapy outcomes.

Oncolytic adenovirus Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (TILT-123, igrelimogene litadenorepvec) shows promise as a therapeutic agent capable of causing tumor regression and activating host immunity. A phase I clinical study TUNIMO (NCT04695327) assessed its safety as monotherapy in patients with various solid tumors. Through single-cell profiling of peripheral blood, we identified distinct immunological features distinguishing responders from non-responders.

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

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 oncolytic adenovirus TILT-123 with pembrolizumab in platinum resistant or refractory ovarian cancer: the phase 1a PROTA trial.

Immune checkpoint inhibitors have demonstrated modest efficacy as a monotherapy in ovarian cancer. Originally developed to improve efficacy of T-cell therapies such as immune checkpoint inhibitors and adoptive cell transfer, TILT-123 (Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a serotype chimeric oncolytic adenovirus encoding tumor necrosis factor alpha and interleukin-2. Here we report results from phase 1a of PROTA, a single-arm, multicentre dose escalation trial with TILT-123 and pembrolizumab in female patients with platinum resistant or refractory ovarian cancer (NCT05271318).

Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors.

Background: A limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection.

Overcoming effector T cell exhaustion in ovarian cancer ascites with a novel adenovirus encoding for a MUC1 bispecific antibody engager and IL-2 cytokine.

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 and immuno-oncology specifically. We have constructed an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), which is armed with a human aMUC1aCD3 T cell engager and IL-2.

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

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.

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

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.

An oncolytic adenovirus coding for a variant interleukin 2 cytokine improves response to chemotherapy through enhancement of effector lymphocyte cytotoxicity, fibroblast compartment modulation and mitotic slippage.

Pancreatic ductal adenocarcinoma (PDAC) is a highly treatment-resistant cancer. Currently, the only curative treatment for PDAC is surgery, but most patients are diagnosed with metastatic disease and thus outside the scope of surgery. The majority of metastatic patients receive chemotherapy, but responses are limited.

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

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).

Oncolytic adenovirus coding for bispecific T cell engager against human MUC-1 potentiates T cell response against solid tumors.

Immunotherapy with bispecific T cell engagers has shown efficacy in patients with hematologic malignancies and uveal melanoma. Antitumor effects of bispecific T cell engagers in most solid tumors are limited due to their short serum half-life and insufficient tumor concentration. We designed a novel serotype 5/3 oncolytic adenovirus encoding a human mucin1 antibody and the human CD3 receptor, Ad5/3-E2F-d24-aMUC1aCD3 (TILT-321).

Local delivery of interleukin 7 with an oncolytic adenovirus activates tumor-infiltrating lymphocytes and causes tumor regression.

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 to a number of adverse events. Interleukin 7 has shown promising results in clinical trials, but anti-cancer effect was limited, in part due to a low concentration of the cytokine within the tumor. We hypothesized that arming an oncolytic adenovirus with Interleukin 7, enabling high expression localized to the tumor microenvironment, would overcome systemic delivery issues and improve therapeutic efficacy.

Adenovirus Encoding Tumor Necrosis Factor Alpha and Interleukin 2 Induces a Tertiary Lymphoid Structure Signature in Immune Checkpoint Inhibitor Refractory Head and Neck Cancer.

Immune checkpoint inhibitors (ICI) have provided significant improvement in clinical outcomes for some patients with solid tumors. However, for patients with head and neck cancer, the response rate to ICI monotherapy remains low, leading to the exploration of combinatorial treatment strategies. In this preclinical study, we use an oncolytic adenovirus (Ad5/3) encoding hTNFα and hIL-2 and non-replicate adenoviruses (Ad5) encoding mTNFα and mIL-2 with ICI to achieve superior tumor growth control and improved survival outcomes.

Local therapy with an engineered oncolytic adenovirus enables antitumor response in non-injected melanoma tumors in mice treated with aPD-1.

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 on systemic antitumor response in animals receiving aPD-1 (anti-programmed cell death protein 1) therapy. Using bilateral murine melanoma models, we tested systemic tumor response to combined therapy with anti-PD-1 and an adenovirus coding for TNFa and IL-2 ("virus").

Comparison of Clinically Relevant Oncolytic Virus Platforms for Enhancing T Cell Therapy of Solid Tumors.

Despite some promising results, the majority of patients do not benefit from T cell therapies, as tumors prevent T cells from entering the tumor, shut down their activity, or downregulate key antigens. Due to their nature and mechanism of action, oncolytic viruses have features that can help overcome many of the barriers currently facing T cell therapies of solid tumors. This study aims to understand how four different oncolytic viruses (adenovirus, vaccinia virus, herpes simplex virus, and reovirus) perform in that task.