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3d
LOKON002: Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer (clinicaltrials.gov)
P1/2, N=47, Completed, Lokon Pharma AB | Active, not recruiting --> Completed
Trial completion • Oncolytic virus
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delolimogene mupadenorepvec (LOAd703)
8ms
LOAd703, an oncolytic virus-based immunostimulatory gene therapy, combined with chemotherapy for unresectable or metastatic pancreatic cancer (LOKON001): results from arm 1 of a non-randomised, single-centre, phase 1/2 study. (PubMed, Lancet Oncol)
Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing.
P1/2 data • Clinical Trial,Phase II • Journal • Oncolytic virus • Gene therapy • Metastases
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CD8 (cluster of differentiation 8) • CD40LG (CD40 ligand)
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Tecentriq (atezolizumab) • gemcitabine • albumin-bound paclitaxel • delolimogene mupadenorepvec (LOAd703)
9ms
Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer (clinicaltrials.gov)
P1/2, N=46, Active, not recruiting, Lokon Pharma AB | Trial completion date: Dec 2024 --> Aug 2024 | Trial primary completion date: Dec 2023 --> Aug 2023
Trial completion date • Trial primary completion date • Oncolytic virus
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delolimogene mupadenorepvec (LOAd703)
over1year
Immunostimulatory gene therapy targeting CD40/4-1BB in combination with chemotherapy induces an inflammatory gene profile in tumors from patients with advanced disease (AACR 2023)
In the LOKON002 phase I/II clinical trial (NCT03225989), therapy with LOAd703 (delolimogene mupadenorepvec) is investigated in combination with gemcitabine-based chemotherapy in patients with advanced cancer. In conclusion, LOAd703 therapy in combination with chemotherapy generated an inflamed tumor microenvironment in tumors that are normally seen as immunologically “cold”. Hence, LOAd703 may be able to prime tumors for immune checkpoint inhibitors or other immunotherapies, such as adoptive T or NK cell transfer.
Combination therapy • Clinical • Gene therapy • PD(L)-1 Biomarker • IO biomarker • Metastases
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CD8 (cluster of differentiation 8) • PD-1 (Programmed cell death 1) • IFNG (Interferon, gamma) • IL6 (Interleukin 6) • CXCL8 (Chemokine (C-X-C motif) ligand 8) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • CD163 (CD163 Molecule) • NCAM1 (Neural cell adhesion molecule 1) • CCR7 (Chemokine (C-C motif) receptor 7) • CD14 (CD14 Molecule) • CCL2 (Chemokine (C-C motif) ligand 2) • ITGAM (Integrin, alpha M) • CD40 (CD40 Molecule) • CD40LG (CD40 ligand) • IL15 (Interleukin 15) • TAP1 (Transporter 1) • CD80 (CD80 Molecule) • CD86 (CD86 Molecule)
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nCounter® PanCancer Immune Profiling Panel
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gemcitabine • delolimogene mupadenorepvec (LOAd703)
over1year
A phase I/II clinical study of an oncolytic adenovirus expressing the immunostimulatory transgenes TMZ-CD40L and 4-1BBL in advanced solid malignancies (AACR 2023)
Partial response (PR) was achieved in two patients with pancreatic cancer treated at the highest LOAd703 dose level in combination with gemcitabine and nab-paclitaxel. No association between adverse events and response was identified. Anti-adenoviral antibody levels (IgG), which increased in all patients, could not be related to indices of clinical benefit.Based on the safety of LOAd703 at all dose levels studied, as well as evidence of objective clinical activity in patients with advanced pancreatic cancer, further disease-directed studies of intratumoral administration of LOAd703 are warranted.
Clinical • P1/2 data • Oncolytic virus • Metastases
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CD40LG (CD40 ligand)
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gemcitabine • albumin-bound paclitaxel • delolimogene mupadenorepvec (LOAd703)
over1year
Immunostimulatory gene therapy with oncolytic viruses potentiates the effect of paclitaxel and cisplatin in ovarian cancer (AACR 2023)
Ovarian cancer is commonly treated with debulking surgery, followed by a combination of a taxane and a platinum-based chemotherapy. This effect was confirmed in vivo, in which the combination therapy had a better tumor control than the other treatment groups. A clinical trial is ongoing to confirm the effect of adding LOAd703 to different treatment regimes in ovarian cancer (NCT03225989).
Oncolytic virus • IO biomarker • Gene therapy
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CD40LG (CD40 ligand)
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cisplatin • paclitaxel • delolimogene mupadenorepvec (LOAd703)
over1year
Immunostimulatory gene therapy with an oncolytic virus expressing TMZ-CD40L and 4-1BBL induces oncolysis and show immunomodulatory capacity in soft tissue sarcoma (AACR 2023)
We are also performing multiplex analysis of proteomic changes in infected tumor cells using the OLINK® TARGET 96 assay. Finally, we willconfirm the effect of LOAd703 in vivo in a murine xenograft model for STS.
Oncolytic virus • IO biomarker • Gene therapy • Immunomodulating
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CD40LG (CD40 ligand)
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delolimogene mupadenorepvec (LOAd703)
over2years
A phase I/II study of LOAd703, a TMZ-CD40L/4-1BBL-armed oncolytic adenovirus, combined with nab-paclitaxel and gemcitabine in advanced pancreatic cancer. (ASCO 2022)
Funded by: Pharmaceutical/Biotech Company. Combining intratumoral injections of LOAd703 with standard nPG chemotherapy was safe and feasible. The target response rate at the highest dose level was met, and treatment-emergent immune responses were observed. A follow-up clinical trial combining LOAd703, nPG, and the anti-PDL-1 inhibitor atezolizumab is underway.
P1/2 data • Oncolytic virus
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CD40LG (CD40 ligand)
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Tecentriq (atezolizumab) • gemcitabine • albumin-bound paclitaxel • delolimogene mupadenorepvec (LOAd703)
over2years
Induction of tumor cell apoptosis & immunogenic cell death by CD40L-armed oncolytic adenoviruses (AACR 2022)
Here we have evaluated the anti-tumor effects of trimerized membrane-bound (TMZ)-CD40L-armed LOAd700 and TMZ-CD40L/4-1BBL-armed LOAd703 in a variety of solid tumors to understand the underlying tumor modulating mechanisms. Upregulation of cell surface calreticulin as well as the death receptors TRAIL-R1 and -R2 indicated generation of a more immunogenic phenotype of cancer cells. Thus, our findings suggest that CD40L-armed LOAd viruses could be inducers of apoptosis and immunogenic cell death in a variety of cancer types with an augmented effect in cancer cells expressing the CD40 receptor.
Oncolytic virus • IO biomarker
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CASP3 (Caspase 3) • TNFRSF10A (TNF Receptor Superfamily Member 10a) • CALR (Calreticulin) • CASP7 (Caspase 7) • CD40LG (CD40 ligand) • TNFRSF10B (TNF Receptor Superfamily Member 10b) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
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LOAd700 • delolimogene mupadenorepvec (LOAd703)
over2years
LOAd732 - a novel oncolytic adenovirus with enhanced immunostimulatory properties and resistance to immunosuppression (AACR 2022)
LOAd703, encoding trimerized (TMZ)-CD40L and 4-1BBL, is under clinical investigation in solid tumors...The addition of the immunosuppressing cytokines did not affect LOAd732 capacity to expand the antigen-specific T cells.In conclusion, LOAd732 infected DCs express activation markers and co-stimulatory molecules and produce cytokines necessary for the initiation of an immune response. Moreover the DCs are functional and can expand antigen-specific T cells and protect them from TGF-β and IL-10 suppression.
Oncolytic virus • IO biomarker
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CD8 (cluster of differentiation 8) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • CD70 (CD70 Molecule) • IL2 (Interleukin 2) • ICAM1 (Intercellular adhesion molecule 1) • IL10 (Interleukin 10) • CD14 (CD14 Molecule) • CSF2 (Colony stimulating factor 2) • TGFB1 (Transforming Growth Factor Beta 1) • CD40LG (CD40 ligand) • IL15 (Interleukin 15) • IL21 (Interleukin 21) • IL4 (Interleukin 4) • CD86 (CD86 Molecule) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
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delolimogene mupadenorepvec (LOAd703)
almost3years
Immune priming using DC- and T cell-targeting gene therapy sensitizes both treated and distant B16 tumors to checkpoint inhibition. (PubMed, Mol Ther Oncolytics)
Herein, we investigated whether the adenoviral gene vehicle mLOAd703 carrying both DC- and T cell-activating genes can lead to inflammation in a B16-CD46 model and thereby overcome resistance to checkpoint inhibition therapy...This response was even more pronounced after combining the virus with checkpoint therapy, in particular with anti-PD-L1 and anti-TIM-3, leading to further reduced tumor growth in injected lesions. Moreover, anti-PD-L1 combination also facilitated abscopal responses in non-injected lesions.
Journal • Checkpoint inhibition
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • TNFA (Tumor Necrosis Factor-Alpha) • ITGAE (Integrin Subunit Alpha E)
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delolimogene mupadenorepvec (LOAd703)
over3years
Systemic immunity upon local oncolytic virotherapy armed with immunostimulatory genes may be supported by tumor-derived exosomes. (PubMed, Mol Ther Oncolytics)
The exosomes from CD40L/4-1BBL-expressing tumor cells, or the viruses themselves, could stimulate robust dendritic cell (DC) activation with an enhanced level of major histocompatibility complex (MHC) and costimulatory molecules. Hence, exosomes after OV infection can locally activate immune responses at the tumor site and encounter immune cells such as DCs.
Journal • Oncolytic virus
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CD40LG (CD40 ligand)
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delolimogene mupadenorepvec (LOAd703)
over3years
[VIRTUAL] Exosomes derived from tumor cells treated with immunostimulatory oncolytic virotherapy exert immune activation instead of immunosuppression (AACR 2021)
To investigate the role of exosomes derived from OV-treated tumors, human melanoma Mel526 cells were infected by delolimogene mupadenorepvec -LOAd703 - which is an adenoviral serotype 5/35 OV armed with costimulatory molecules CD40L and 4-1BBL...In conclusion, tumor-derived exosomes released by OV-infected tumor cells can cargo the immunostimulatory transgenes expressed by the OVs and are then converted from immunosuppressive to immune activating exosomes as shown by their capacity to activate immune cells such as dendritic cells. Exosomes that cargo immunostimulatory transgenes from OV-infected tumor cells may support the systemic immunity gained by OVs after local intratumoral delivery.
Oncolytic virus • PD(L)-1 Biomarker • IO biomarker
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CD40LG (CD40 ligand) • CD86 (CD86 Molecule) • HSP90AA1 (Heat Shock Protein 90 Alpha Family Class A Member 1Heat Shock Protein 90 Alpha Family Class A Member 1)
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delolimogene mupadenorepvec (LOAd703)
over3years
Boosting CAR T-cell responses in lymphoma by simultaneous targeting of CD40/4-1BB using oncolytic viral gene therapy. (PubMed, Cancer Immunol Immunother)
In addition, LOAd703-infected lymphoma cells upregulated the secretion of several chemokines (CXCL10, CCL17, CCL22, CCL3, CCL4) essential for immune cell homing, leading to enhanced CAR T-cell migration. In conclusion, immunostimulatory LOAd703 therapy is an intriguing approach to induce anti-lymphoma immune responses and to improve CAR T-cell therapy in B-cell lymphoma.
Journal • CAR T-Cell Therapy • PD(L)-1 Biomarker • IO biomarker
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PD-1 (Programmed cell death 1) • IFNG (Interferon, gamma) • CXCL10 (Chemokine (C-X-C motif) ligand 10) • HAVCR2 (Hepatitis A Virus Cellular Receptor 2) • CD70 (CD70 Molecule) • ICAM1 (Intercellular adhesion molecule 1) • CCL2 (Chemokine (C-C motif) ligand 2) • GZMB (Granzyme B) • CCL22 (C-C Motif Chemokine Ligand 22) • CD40 (CD40 Molecule) • CD40LG (CD40 ligand)
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IFNG expression
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delolimogene mupadenorepvec (LOAd703)
over4years
[VIRTUAL] Abscopal effect using intratumoral oncolytic virotherapy (LOAd703) is enhanced by anti-PD-1 or anti-PD-L1 (AACR-II 2020)
The abscopal effect was further increased by combining mLOAd703 with anti-PD-1 or anti-PD-L1. LOAd703 (i.t.) is currently in clinical development with and without PD-L1.
PD(L)-1 Biomarker • IO biomarker
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CD8 (cluster of differentiation 8) • IFNG (Interferon, gamma) • CD40LG (CD40 ligand)
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delolimogene mupadenorepvec (LOAd703)
over4years
Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and/or CD40. (PubMed, Cancer Gene Ther)
Further, LOAd viruses are armed with human immunostimulatory transgenes: trimerized membrane-bound CD40L (LOAd700, LOAd703) and 4-1BBL (LOAd703). This was most prominent with LOAd703. In conclusion, LOAd viruses are of interest for MM therapy.
Journal
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CXCL10 (Chemokine (C-X-C motif) ligand 10) • CD70 (CD70 Molecule) • ICAM1 (Intercellular adhesion molecule 1) • CCL2 (Chemokine (C-C motif) ligand 2) • CD40LG (CD40 ligand)
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LOAd700 • delolimogene mupadenorepvec (LOAd703)
over6years
New P1/2 trial
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Avastin (bevacizumab) • Tecentriq (atezolizumab) • Stivarga (regorafenib) • Sarclisa (isatuximab-irfc) • idasanutlin (RG7388) • etrumadenant (AB928) • Imprime PGG (odetiglucan) • delolimogene mupadenorepvec (LOAd703) • selicrelumab (RG7876)