DNX-2440 / DNAtrix - LARVOL DELTA

The oncolytic adenovirus RGDOX sensitizes the anti-tumor efficacy of immune checkpoint blockades in murine melanoma brain metastases models (SNO 2025) - "The oncolytic adenovirus Delta-24-RGDOX (RGDOX) has been shown to function as a TME modulator in both preclinical and clinical settings...In contrast, immunosuppressive populations, such as myeloid-derived suppressor cells and M2 macrophages, were markedly reduced in both s.c. and i.c. tumors in the combination treatment group. These findings suggest the clinical translation of RGDOX with PD-1/CTLA-4 inhibition is a promising therapeutic approach for the generation of antitumor immunity against MBM."

Checkpoint block • Checkpoint inhibition • Oncolytic virus • Preclinical • Brain Cancer • Melanoma • Oncology • Solid Tumor • CD8

Ruxolitinib enhances viroimmunotherapy of gliomas: targeting JAK-guided immunosuppressive pathways (SNO 2025) - P1, P2 | "We performed gene expression analysis on 38 tumor biopsies from the Delta-24-RGD and Pembrolizumab clinical trial (NCT02798406), identifying a significant positive correlation between IFNγ and IDO1 (a main regulator of AhR activation), identifying this axis as clinically relevant. Using syngeneic glioma models, we showed that combination therapy with Delta-24-RGDOX and Ruxolitinib yielded better survival outcomes compared to monotherapy controls. In summary, this study illustrates the feasibility of combining virotherapy with drugs targeting immunosuppressive pathways in gliomas and provides a strong rationale for translating this strategy into the clinical setting."

IO biomarker • Oncolytic virus • Brain Cancer • Glioblastoma • Glioma • Solid Tumor • IDO1 • IFNG

Oncolytic adenovirus armed with immune stimulators: a promising partner for CAR T cell therapy in primary and metastatic malignant brain tumors (SNO 2025) - "Currently, we are optimizing the treatment regimen to achieve better efficacy in both mouse models. Together, these findings demonstrate the potent immunostimulatory and therapeutic activity of Delta-24-RGDOX-IL15 and its potential to synergize with CAR T cell therapy in treating advanced primary or metastatic brain tumors."

CAR T-Cell Therapy • Metastases • Oncolytic virus • Brain Cancer • Glioma • Melanoma • Oncology • Solid Tumor • CD8 • IL15 • TNFSF4

Phase I trial of single intratumoral injection of DNX-2440 oncolytic adenovirus in recurrent glioblastoma patients (SNO 2025) - "DNX-2401, an oncolytic adenovirus engineered for tumor-selective replication and enhanced infectivity, has shown efficacy in adults with recurrent glioblastoma (GBM). Intratumoral DNX-2440 administration is feasible and safe, with early signs of clinical activity. These findings support the continued exploration of oncolytic virotherapy as a platform for immunomodulation and combination strategies in GBM."

Clinical • Oncolytic virus • P1 data • Brain Cancer • Glioblastoma • Immunology • Oncology • Solid Tumor

The oncolytic adenovirus RGDOX sensitizes the anti-tumor efficacy of immune checkpoint blockades in murine melanoma brain metastases models (WFNOS 2025) - "The oncolytic adenovirus Delta-24-RGDOX (RGDOX) has been shown to function as a TME modulator in both preclinical and clinical settings...In contrast, immunosuppressive populations, such as myeloid-derived suppressor cells and M2 macrophages, were markedly reduced in both s.c. and i.c. tumors in the combination treatment group. These findings suggest the clinical translation of RGDOX with PD-1/CTLA-4 inhibition is a promising therapeutic approach for the generation of antitumor immunity against MBM."

Checkpoint block • Checkpoint inhibition • Oncolytic virus • Preclinical • Brain Cancer • Melanoma • Solid Tumor • CD8

Ruxolitinib enhances viroimmunotherapy of gliomas: targeting JAK-guided immunosuppressive pathways (WFNOS 2025) - P1, P2 | "We performed gene expression analysis on 38 tumor biopsies from the Delta-24-RGD and Pembrolizumab clinical trial (NCT02798406), identifying a significant positive correlation between IFNγ and IDO1 (a main regulator of AhR activation), identifying this axis as clinically relevant. Using syngeneic glioma models, we showed that combination therapy with Delta-24-RGDOX and Ruxolitinib yielded better survival outcomes compared to monotherapy controls. In summary, this study illustrates the feasibility of combining virotherapy with drugs targeting immunosuppressive pathways in gliomas and provides a strong rationale for translating this strategy into the clinical setting."

IO biomarker • Oncolytic virus • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Solid Tumor • IDO1 • IFNG

Oncolytic adenovirus armed with immune stimulators: a promising partner for CAR T cell therapy in primary and metastatic malignant brain tumors (WFNOS 2025) - P1 | "Currently, we are optimizing the treatment regimen to achieve better efficacy in both mouse models. Together, these findings demonstrate the potent immunostimulatory and therapeutic activity of Delta-24-RGDOX-IL15 and its potential to synergize with CAR T cell therapy in treating advanced primary or metastatic brain tumors."

CAR T-Cell Therapy • Metastases • Oncolytic virus • Brain Cancer • Glioma • Melanoma • Solid Tumor • CD8 • IL15 • TNFSF4

Phase I trial of single intratumoral injection of DNX-2440 oncolytic adenovirus in recurrent glioblastoma patients (WFNOS 2025) - "DNX-2401, an oncolytic adenovirus engineered for tumor-selective replication and enhanced infectivity, has shown efficacy in adults with recurrent glioblastoma (GBM). Intratumoral DNX-2440 administration is feasible and safe, with early signs of clinical activity. These findings support the continued exploration of oncolytic virotherapy as a platform for immunomodulation and combination strategies in GBM."

Clinical • Oncolytic virus • P1 data • Brain Cancer • Glioblastoma • Immunology • Solid Tumor

The oncolytic adenovirus RGDOX sensitizes the anti-tumor efficacy of immune checkpoint blockades in murine melanoma brain metastases models (WFNOS 2025) - "The oncolytic adenovirus Delta-24-RGDOX (RGDOX) has been shown to function as a TME modulator in both preclinical and clinical settings...In contrast, immunosuppressive populations, such as myeloid-derived suppressor cells and M2 macrophages, were markedly reduced in both s.c. and i.c. tumors in the combination treatment group. These findings suggest the clinical translation of RGDOX with PD-1/CTLA-4 inhibition is a promising therapeutic approach for the generation of antitumor immunity against MBM."

Checkpoint block • Checkpoint inhibition • Oncolytic virus • Preclinical • Brain Cancer • Melanoma • Oncology • Solid Tumor • CD8

Arming Oncolytic Adenoviruses with Immune Stimulators: Enhancing CAR T Cell Therapy for Malignant Primary and Metastatic Brain Tumors (SITC 2025) - "melanomas. Optimization of dosing regimens is ongoing in both tumor models to further improve outcomes.Conclusions These findings highlight the potent immunostimulatory and therapeutic properties of Delta-24-RGDOX-IL15 and support its potential to synergize with CAR T cell therapy for the treatment of advanced primary or metastatic brain tumors."

CAR T-Cell Therapy • IO biomarker • Metastases • Oncolytic virus • Brain Cancer • Glioblastoma • Glioma • Melanoma • Oncology • Solid Tumor • CD8 • IL15 • TNFSF4

Effect of armed oncolytic adenovirus on immunotherapy for primary and metastatic brain tumors. (ASCO 2025) - "Higher expression of IL-15/IL-15RA is associated with better survival in patients with melanoma. Delta-24-RGDOX-IL15 demonstrates potent oncolytic activity in both glioma and melanoma cell lines. In the intracranial brain tumor mouse model, it exhibited promising anti-tumor effects with enhanced T cell stimulation and minimal toxicity."

IO biomarker • Metastases • Oncolytic virus • Brain Cancer • Glioma • Immunology • Melanoma • Oncology • Solid Tumor • Systemic Inflammatory Response Syndrome • IL15 • TNFSF4

Targeting the AhR immunometabolic hub during viroimmunotherapy of gliomas. (SNO 2024) - P1, P2 | "Survival analysis in immunocompetent models of gliomas treated with this combined therapy showed the greatest therapeutic benefit compared to monotherapy controls. These findings highlight the critical role of AhR activation triggered by Delta-24-RGDOX and position AhR as a potential therapeutic target for enhancing the efficacy of oncolytic adenovirus therapy in GBM."

IO biomarker • Oncolytic virus • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • AHR

Anti-tumor activity of a new oncolytic adenovirus Delta-24-RGDOX-IL15 co-expressing OX40L and IL-15 (SNO 2024) - "Further studies are in progress to analyze the modifications of the tumor microenvironment induced by the addition of IL-15 to Delta-24-RGDOX. We expect this virus to be a good candidate to be combined with CAR T cell therapies."

IO biomarker • Oncolytic virus • Brain Cancer • CNS Tumor • Glioma • Melanoma • Oncology • Solid Tumor • AVEN • CD8 • IL15 • TNFSF4

Cracking the role of oncometabolites in viroimmunotherapy for pediatric malignant brain tumors (SNO 2024) - P1 | "Preliminary data using a combination of Delta-24-RGDOX and AhR inhibitors prolongs the survival of glioma-bearing mice. Collectively, our in vivo and in vitro data support the rationale to propel a future clinical trial combining Delta-24-RGDOX with AhR inhibitors for DMG."

Clinical • IO biomarker • Oncolytic virus • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Pediatrics • Solid Tumor • CD8 • IDO1 • IFNG • IL4I1 • TNFSF4

Oncolytic adenoviral infection synergizes with immune checkpoint inhibition to mediate intracranial tumor control in disparate models of melanoma brain metastases (SNO 2024) - "To counteract immunosuppressive features of the tumor microenvironment (TME), a third-generation oncolytic adenovirus (Delta-24-RGDOX) has been developed which expresses the immune stimulatory OX40 ligand (OX40L)...These findings translated in multiple in vivo models including immune cell activation and systemic antitumor immunity against uninfected MBM. Future studies are needed to explore the role of immune cell trafficking, myeloid cell modulation, T cell priming, and clonal expansion withing locally infected and the distant melanoma TME."

Checkpoint inhibition • IO biomarker • Oncolytic virus • Brain Cancer • Infectious Disease • Melanoma • Oncology • Solid Tumor • TNFSF4

Antitumor activity of CAR T cells potentiated by oncolytic adenoviruses armed with immune stimulators (SITC 2024) - "Conclusions We established syngeneic disseminated tumor models in immunocompetent mice to recapitulate clinical settings for evaluating the therapeutic effect of CAR T cells and their combination with OAs. Our data suggests Delta-24-RGDOX-IL15 is a promising candidate to be combined with CAR T cells to augment the systemic antitumor immunity against metastatic solid tumors."

CAR T-Cell Therapy • IO biomarker • Oncolytic virus • Melanoma • Oncology • Solid Tumor • HAVCR2 • IL15 • PD-1 • TNFSF4

Targeting the immunometabolic factor AhR boosts glioma viroimmunotherapy (SITC 2024) - "To improve the rate of responses, we generated Delta-24-RGDOX, an armed version of Delta-24-RGD, expressing the T-cell activator OX40-L...Ethics Approval All animal experiments were performed in accordance with The University of Texas MD Anderson Cancer Center (MDACC) Institutional Animal Care and Use Committee (IACUC) guidelines in an MDACC American Association for Accreditation of Laboratory Animal Care (AAALAC)-accredited barrier facility vivarium. Experiments were performed under protocol #00001420-RN02."

IO biomarker • Oncolytic virus • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • AHR

Modulating tumor metabolism to overcome mechanisms of resistance to viroimmunotherapy in pediatric brain tumors (SITC 2024) - P1 | "Conclusions Our findings support the rationale of combining Delta-24-RGDOX with IDO/AHR for pediatric tumors. This lays the groundwork for a potential clinical trial for DMG in the future."

Clinical • IO biomarker • Oncolytic virus • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • AHR • CD8 • IDO1 • IFNG • IL4 • IL4I1 • TNFSF4

Antitumor activity of CAR T cells potentiated by oncolytic adenoviruses armed with immune stimulators (SITC 2024) - "Conclusions We established syngeneic disseminated tumor models in immunocompetent mice to recapitulate clinical settings for evaluating the therapeutic effect of CAR T cells and their combination with OAs. Our data suggests Delta-24-RGDOX-IL15 is a promising candidate to be combined with CAR T cells to augment the systemic antitumor immunity against metastatic solid tumors."

CAR T-Cell Therapy • IO biomarker • Oncolytic virus • Melanoma • Oncology • Solid Tumor • HAVCR2 • IL15 • PD-1 • TNFSF4

Exploring oncometabolite pathways in pediatric brain tumors as an actionable target to improve viroimmunotherapy (EORTC-NCI-AACR 2024) - P1 | "Our results show the activation of the tryptophan pathway as part of the tumor resistance to viroimmunotherapy. These data suggest that this immunometabolic cascade of events constitute a legitimate target leading to the feasibility of combining Delta-24-RGDOX with IDO/AhR inhibitors, providing the basis for a future clinical trial for DMG."

Clinical • Oncolytic virus • Brain Cancer • Diffuse Midline Glioma • Glioma • Oncology • Solid Tumor • CD8 • IDO1 • IFNG • IL4I1 • TNFSF4

Bifidobacterium Supplementation Alters Viroimmunotherapy Efficacy against Glioblastoma (ASM Microbe 2024) - "Current treatment advancements include Delta-24-RGDOX, an oncolytic adenovirus armed with the T-cell activator OX40L...These results highlight that this probiotic did not guarantee co-colonization by resident microbiomes. Future studies should focus on fecal matter transplant association with oncolytic viral therapy efficacy and evaluate the effect of these probiotic taxa."

Clinical • Oncolytic virus • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • Transplantation • TNFSF4

DNX-2440 for Resectable Colorectal Liver Metastasis (clinicaltrials.gov) - P1 | N=30 | Suspended | Sponsor: DNAtrix, Inc. | Trial completion date: Dec 2023 ➔ Dec 2026 | Recruiting ➔ Suspended | Trial primary completion date: Jul 2022 ➔ Jul 2026

Oncolytic virus • Trial completion date • Trial primary completion date • Trial suspension • Breast Cancer • Colon Cancer • Colorectal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Gastrointestinal Stromal Tumor • Genito-urinary Cancer • Melanoma • Oncology • Renal Cell Carcinoma • Sarcoma • Solid Tumor • Squamous Cell Carcinoma

Levels of isobutyric acid from gut butyrate-producing taxa are associated to Delta-24-RGDOX efficacy against malignant glioma (AACR 2024) - "These findings suggest that butyrate-producing bacteria coupled with higher levels of isobutyric acid may be important in the efficacy of Delta-24-RGDOX. This highlights the microbial and metabolic changes associated with oncolytic viral therapy efficacy."

Clinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • TNFSF4

Gut microbiota composition is associated with the efficacy of Delta-24-RGDOX in malignant gliomas. (PubMed, Mol Ther Oncol) - "To test this hypothesis, we evaluated the changes in gut microbiota in two mouse cohorts: (1) GSC-005 glioblastoma-bearing mice treated orally with indoximod, an immunotherapeutic agent, or with Delta-24-RGDOX by intratumoral injection and (2) a mouse cohort harboring GL261-5 tumors used to mechanistically evaluate the importance of CD4+ T cells in relation to viroimmunotherapy efficacy. The CD4+ T cell depletion was associated with gut dysbiosis, lower mouse survival, and lower antitumor efficacy of the therapy. These findings suggest that microbiota modulation along the gut-glioma axis contributes to the clinical efficacy and patient survival of viroimmunotherapy treated animals."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • CD4 • TNFSF4

THANK PHASE I TRIAL OF DNX-2440 ONCOLYTIC ADENOVIRUS IN PATIENTS WITH FIRST OR SECOND RECURRENCE OF GLIOBLASTOMA: PRELIMINARY RESULTS (EANO 2023) - "The oncolytic adenovirus DNX-2401, genetically engineered for selective replication and enhanced infectivity in tumor cells, has shown efficacy in adult patients with recurrent glioblastoma (GBM). CONCLUSIONOur current data suggest that intratumoral injection of DNX-2440 is feasible and safe, and seems to provide a clinical benefit in some patients with recurrent GBM. Furthermore, this trial illustrates the potential of oncolytic virus platforms to reshape the brain-tumor microenvironment and its interesting role in combination strategies with other immune-oncology agents for treating this disease."

Clinical • IO biomarker • Oncolytic virus • P1 data • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor