igrelimogene litadenorepvec (TILT-123) / Tilt Biotherap - LARVOL DELTA

Neutralizing antibodies and lymphocyte count as biomarkers in patients receiving oncolytic adenovirus TILT-123 and adoptive cell transfer of tumor-infiltrating lymphocytes for metastatic melanoma refractory to immune checkpoint inhibitors. (ASCO 2025) - P1 | "ICI refractory melanoma patients receiving TILT-123 and ACT-TILs without preconditioning show signs of CD8+ T cell trafficking to the tumor microenvironment. nAbs and lymphocyte count decrease can be further investigated as biomarkers."

Biomarker • Checkpoint inhibition • Clinical • IO biomarker • Metastases • Oncolytic virus • Tumor-infiltrating lymphocyte • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • CD4 • CD8 • IL2 • PD-L1

Assessment of tumors, blood, and ascites to establish correlations with treatment benefit in platinum resistant or refractory ovarian cancer patients treated with igrelimogene litadenorepvec and pembrolizumab combination therapy. (ASCO 2025) - P1/2 | "Igrelimogene litadenorepvec and pembrolizumab are therapies designed to attract, activate and/or protect lymphocyte-mediated antitumor activity. These findings suggest that having a fit immune system able to mobilize effector immune cells as well as responding to immunostimulant agents increases therapeutic success. As a disease with few therapeutic options, ovarian cancer patients often receive multiple lines of chemotherapy that might decrease the efficacy of immediate immunotherapies."

Clinical • Combination therapy • IO biomarker • Platinum resistant • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • IL2

TILT Biotherapeutics Announces Closing of USD 25 Million Series B Financing (GlobeNewswire) - "TILT Biotherapeutics...announces it has raised USD 25.6 million (EUR 22.6 million) in a Series B financing...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...Interim results from ongoing Phase 1b trials are expected to read out in H2 2026...'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.'"

Financing • New P2 trial • Platinum resistant • Ovarian Cancer

TUNINTIL-2: TNFα and IL-2 Coding Oncolytic Adenovirus TILT-123 With Lymphocyte-depleting Chemotherapy and TILs in the Treatment of Melanoma (clinicaltrials.gov) - P1 | N=9 | Recruiting | Sponsor: TILT Biotherapeutics Ltd.

New P1 trial • Melanoma • Oncology • Solid Tumor

Clinical-immunological correlates in platinum resistant or refractory ovarian cancer patients treated with chimeric oncolytic adenovirus encoding TNFa and IL-2 (TILT-123) in combination with pembrolizumab (AACR 2025) - P1/2 | "These preliminary results identify a key role of circulating lymphocyte re-distribution and humoral immune response as markers of treatment benefit. Initial phenotyping implicates IgM producing plasma cells as a potentially relevant immune cell population. Additionally we observed a correlation between the coagulation cascade and OS."

Clinical • Combination therapy • Oncolytic virus • Platinum resistant • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • IL2 • TNFA

PROTA: Oncolytic Adenovirus Coding for TNFa and IL2 (TILT-123) With Pembrolizumab or Pembrolizumab (Phase 1a and 2) and Pegylated Liposomal Doxorubicin (Phase 1b) as Treatment for Ovarian Cancer. (clinicaltrials.gov) - P1/2 | N=76 | Recruiting | Sponsor: TILT Biotherapeutics Ltd. | Trial completion date: Jun 2026 ➔ Aug 2027 | Trial primary completion date: Mar 2026 ➔ Mar 2027 | Phase classification: P1 ➔ P1/2 | N=29 ➔ 76

Enrollment change • Phase classification • Platinum resistant • Trial completion date • Trial primary completion date • Allergy • Fallopian Tube Cancer • Immunology • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor

PROTA: Oncolytic Adenovirus Coding for TNFa and IL2 (TILT-123) With Pembrolizumab or Pembrolizumab and Pegylated Liposomal Doxorubicin as Treatment for Ovarian Cancer. (clinicaltrials.gov) - P1 | N=29 | Recruiting | Sponsor: TILT Biotherapeutics Ltd. | Trial completion date: Jan 2027 ➔ Jun 2026 | Trial primary completion date: Jan 2025 ➔ Mar 2026

Platinum resistant • Trial completion date • Trial primary completion date • Allergy • Fallopian Tube Cancer • Immunology • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor

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. (PubMed, Cancer Gene Ther) - P1 | "Several T and B cell receptor segments matched those previously reported in other viral infections, suggesting possible cross-reactive immune responses. These findings emphasize that comprehensive biomarker analysis of peripheral blood should include not only cell frequencies but also transcriptional changes and distinct patterns of cellular and humoral immunity."

Journal • Infectious Disease • Oncology • Solid Tumor

Safety and efficacy of combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus TILT-123 in metastatic melanoma. (PubMed, Cell Rep Med) - "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."

Journal • Tumor-infiltrating lymphocyte • Cutaneous Melanoma • Eye Cancer • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • Uveal Melanoma • IL2 • TNFA

Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial. (PubMed, J Immunother Cancer) - P1 | "TILT-123 therapy induced accumulation of effector lymphocytes in tumors. Peripheral lymphocyte count decrease is a promising biomarker for assessing oncolytic adenovirus therapy response."

Biomarker • IO biomarker • Journal • P1 data • Gene Therapies • Oncology • Solid Tumor • CD4 • CD8 • IL2 • TNFA

Transient lymphocyte count decrease correlates with oncolytic adenovirus efficacy in humans: mechanistic and biomarker findings from TUNIMO phase I trial (J Immunother Cancer) - P1 | N=18 | TUNIMO (NCT04695327) | Sponsor: TILT Biotherapeutics Ltd. | "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."

Biomarker • P1 data • Solid Tumor

Safety And Immunological Activity Of A Oncolytic Adenovirus Expressing TNFa And IL-2 In Combination With Pembrolizumab In Platinum-Resistant Or Refractory Ovarian Cancer Patients (ESGO 2025) - P1 | "TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFa-IRES-hIL-2) is a chimeric oncolytic adenovirus constructed to promote T-cell infiltration and activity therefore enabling ICI therapies. Doublet therapy induced systemic immune changes in blood and tumours. Further investigation continues in Phase Ib and II studies."

Clinical • Combination therapy • IO biomarker • Oncolytic virus • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • IL2 • MUC16 • TNFA

The oncolytic adenovirus TILT-123 with pembrolizumab in platinum resistant or refractory ovarian cancer: the phase 1a PROTA trial. (PubMed, Nat Commun) - P1 | "Clinical responses were associated with higher serum anti-adenovirus neutralizing antibody titer at baseline and post-treatment. The phase 1b investigating TILT-123, pembrolizumab and PEGylated liposomal doxorubicin in a similar patient population is underway."

Journal • P1 data • Fatigue • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • IL2 • TNFA

Durable complete response after combined treatment with tumor-infiltrating lymphocytes and oncolytic adenovirus (TILT-123) in a patient with metastatic mucosal melanoma. (PubMed, Immunooncol Technol) - "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. This case underscores the potential of combined immunotherapeutic approaches as a promising strategy for patients with metastatic mucosal melanoma."

Journal • Tumor-infiltrating lymphocyte • Melanoma • Mucosal Melanoma • Oncology • Solid Tumor • IL2

TILT Biotherapeutics Provides Update on International Clinical Trial Progress with Intravenous Delivery Regimen for Cancer Immunotherapies (GlobeNewswire) - "TILT Biotherapeutics...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’. 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. These findings have the potential to support future clinical development strategy...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."

New P2 trial • P1 data • Oncology • Ovarian Cancer

Single-cell analysis of peripheral blood mononuclear cells reveals therapy outcomes are associated with pre-existing immunity in patients treated with oncolytic adenovirus armed with TNF_ and IL2 (ESMO-IO 2024) - P1 | "Additionally, TILT-123 treatment enhanced B cell differentiation, promoted the diversification of both B/TCR repertoires, and supported the formation of immunological memory.Conclusions Our findings suggest that pre-existing immunity and favorable immune profiles at baseline are associated with better outcomes in response to TILT-123. These results support the potential of personalized treatment strategies to enhance therapeutic efficacy."

Clinical • Oncolytic virus • Oncology • Solid Tumor • CD8 • IL2

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 (ESMO-IO 2024) - P1 | "Macrophages in tumors increased but decreased in normal tissues suggesting the utility of the split dose regimen in attenuating anti-adenoviral normal tissue sinks. These findings support the feasibility of split-dose systemic administration of TILT-123 in future clinical trials."

Clinical • Metastases • Oncolytic virus • Oncology • Solid Tumor

Immunoprofiling and correlative analysis from PROTA: a phase I trial combining an oncolytic adenovirus encoding TNFα and IL2 with pembrolizumab for platinum-resistant or refractory ovarian cancer (SITC 2024) - P1 | "Background 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 study was approved in USA by FDA under the IND# 027209. Consent Written informed consent was obtained from all patients in this study for publishing the results as a abstract, manuscript, presentation or similar scientific communication."

IO biomarker • Oncolytic virus • P1 data • Oncology • Ovarian Cancer • Refractory Ovarian Cancer • Solid Tumor • CD4 • CD8 • GZMB • IL2 • NCAM1 • TNFA

KEYNOTE-E46: Oncolytic Adenovirus TILT-123 With Pembrolizumab as Treatment for Refractory Non-Small Cell Lung Cancer (clinicaltrials.gov) - P1 | N=22 | Recruiting | Sponsor: TILT Biotherapeutics Ltd. | Trial completion date: Oct 2025 ➔ May 2026 | Trial primary completion date: Oct 2024 ➔ Jan 2026

Checkpoint inhibition • Combination therapy • Oncolytic virus • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors. (PubMed, J Exp Clin Cancer Res) - P1 | "TILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation."

IO biomarker • Journal • Metastases • Oncolytic virus • Immunology • Oncology • Solid Tumor • IL2 • TNFA

Fully intravenous delivery regimen of oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) in patients with advanced solid cancers (ESMO 2024) - P1 | "Fully intravenous delivery of TILT-123 was safe, resulting in tumor transduction and immunological effects in metastases. Further studies utilizing this regimen are mandated."

Clinical • Metastases • Oncolytic virus • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Liposarcoma • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Rectal Cancer • Sarcoma • Solid Tumor • IL2 • TNFA

TILT Biotherapeutics Presents Clinical Data on TILT-123 After Fully Intravenous Delivery Regimen at ESMO 2024 (GlobeNewswire) - P1 | N=18 | TUNIMO (NCT04695327) | Sponsor: TILT Biotherapeutics Ltd. | "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...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."

P1 data • Oncology • Solid Tumor

PROTA: A phase I clinical trial combining an oncolytic adenovirus encoding for TNFa and IL-2 with pembrolizumab for the treatment of platinum-resistant or -refractory ovarian cancer. (ASCO 2024) - P1 | "Combination of TILT-123 and pembrolizumab is safe and appears to induce disease control in a difficult-to-treat patient population. Investigation of TILT-123, pembrolizumab and pegylated liposomal doxorubicin is ongoing in similar patients."

Clinical • Oncolytic virus • P1 data • Anemia • Fallopian Tube Cancer • Hematological Disorders • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor • IL2 • TNFA

Intravenous delivery of oncolytic adenovirus TILT-123 results in systemic tumor transduction and accumulation of lymphocytes. (ASCO 2024) - P1 | "In summary, intravenous injection of TILT-123 results in persistence of the virus in peripheral blood for up to 7 days. Tumor transduction was observed in 75% of patients in three Phase I trials on day 8 post TILT-123 systemic administration. These data suggest that TILT-123 could be developed as an intravenous therapy."

Oncolytic virus • Melanoma • Oncology • Ovarian Cancer • Sarcoma • Solid Tumor • IFNG • IL2 • TNFA

PROTA: Oncolytic Adenovirus Coding for TNFa and IL2 (TILT-123) With Pembrolizumab or Pembrolizumab and Pegylated Liposomal Doxorubicin as Treatment for Ovarian Cancer. (clinicaltrials.gov) - P1 | N=29 | Recruiting | Sponsor: TILT Biotherapeutics Ltd. | Trial completion date: Mar 2026 ➔ Jan 2027 | Trial primary completion date: Jun 2024 ➔ Jan 2025

Trial completion date • Trial primary completion date • Allergy • Fallopian Tube Cancer • Immunology • Oncology • Ovarian Cancer • Peritoneal Cancer • Refractory Ovarian Cancer • Solid Tumor