Delving into the Latest Updates on Delolimogene mupadenorepvec with Synapse

Overview

Basic Info

Drug Type

Oncolytic virus

Synonyms

Target

4-1BBL x CD40L

Action

modulators

Mechanism

4-1BBL modulators(Tumor necrosis factor ligand superfamily member 9 modulators), CD40L modulators(CD40 ligand modulators)

Therapeutic Areas

NeoplasmsDigestive System DisordersEndocrinology and Metabolic Disease+ [1]

Active Indication

Biliary Tract NeoplasmsMelanomaPancreatic adenocarcinoma+ [2]

Inactive Indication

Colorectal CancerMultiple MyelomaOvarian Cancer

Originator Organization

Lokon Pharma AB

Active Organization

Lokon Pharma AB

Uppsala University Hospital

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

RegulationFast Track (United States)

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Structure/Sequence

Sequence Code 528234577

This study aims to evaluate safety and effect of combining an oncolytic adenovirus (delolimogene mupadenorepvec; LOAd703) with atezolizumab in patients with melanoma. LOAd703 will be administered intratumorally for up to 12 injections while atezolizumab will be administered intravenously for the duration of the active study visits (up to 57 weeks). The patients are then monitored for survival for maximum study participation of 48 months. The treatments will be given every 3 weeks. The patients will then be monitored for toxicity, PK, ADA, immune responses, virus shedding, tumor response by RECIST 1.1 and survival.

Start Date28 Jan 2020

Sponsor / Collaborator

Lokon Pharma AB

[+1]

NCT03555149

/ TerminatedPhase 1/2

A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Colorectal Cancer (Morpheus-CRC)

A phase Ib/II, open-label, multicenter, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in patients with metastatic colorectal cancer (mCRC) that became refractory to first- and second-line standard therapies. Eligible patients will be assigned to one of several treatment arms.

Start Date27 Sep 2018

Sponsor / Collaborator

Hoffmann-La Roche Ltd.

NCT03225989

/ CompletedPhase 1/2

Phase I/II Trial Investigating an Immunostimulatory Oncolytic Adenovirus for Cancer

This Phase I/II trial evaluates LOAd703 in patients with cancer (pancreatic, biliary, colorectal or ovarian) together with their standard of care chemotherapy or using gemcitabine immune-conditioning. LOAd703 is administered by intratumoral image-guided injections. Maximum 50 patients can be enrolled.
LOAd703 is an immunostimulatory gene therapy using an selection replication competent adenovirus as a gene vehicle. The virus is derived from serotype 5 adenovirus with the fiber from serotype 35. It expresses the transgenes trimerized membrane-bound isoleucine zipper (TMZ) TMZ-CD40L and 41BBL under control of a cytomegalovirus (CMV) promoter.

Start Date01 Mar 2018

Sponsor / Collaborator

Lokon Pharma AB

[+1]

100 Clinical Results associated with Delolimogene mupadenorepvec

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100 Translational Medicine associated with Delolimogene mupadenorepvec

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100 Patents (Medical) associated with Delolimogene mupadenorepvec

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4

Literatures (Medical) associated with Delolimogene mupadenorepvec

01 Apr 2024·The Lancet Oncology

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

Article

Author: Brenner, Malcolm K ; Jing, James ; Wenthe, Jessica ; Rowinsky, Eric K ; Hilsenbeck, Susan G ; Brisco, Amanda ; Jawaid, Salmaan ; Eriksson, Emma ; Abidi, Wasif ; Grilley, Bambi ; Loskog, Angelica S I ; Leen, Ann M ; Sandin, Linda C ; Musher, Benjamin L ; Patel, Kalpesh ; Leja-Jarblad, Justyna ; Ullenhag, Gustav J ; Wu, Mengfen ; Othman, Mohamed ; Smaglo, Brandon G

BACKGROUNDPancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma.METHODSLOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m² plus gemcitabine 1000 mg/m² (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 μL of LOAd703 at 5 × 10¹⁰ (dose 1), 1 × 10¹¹ (dose 2), or 5 × 10¹¹ (dose 3) viral particles per injection, injected endoscopically or percutaneously into the pancreatic tumour or a metastasis for six injections. The primary endpoints were safety and treatment-emergent immune response in patients who received at least one dose of LOAd703, and antitumour activity was a secondary endpoint. This study was registered with ClinicalTrials.gov, NCT02705196, arm 2 is ongoing and open to new participants.FINDINGSBetween Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8⁺ effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%) of 16 patients for whom T-cell assays could be performed. Eight (44%, 95% CI 25-66) of 18 patients evaluable for activity had an objective response.INTERPRETATIONCombining 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.FUNDINGLokon Pharma, the Swedish Cancer Society, and the Swedish Research Council.

01 Oct 2021·Cancer Immunology, ImmunotherapyQ2 · MEDICINE

Boosting CAR T-cell responses in lymphoma by simultaneous targeting of CD40/4-1BB using oncolytic viral gene therapy

Q2 · MEDICINE

Article

Author: Wenthe, Jessica ; Enblad, Gunilla ; Loskog, Angelica ; Lövgren, Tanja ; Labani-Motlagh, Alireza ; Naseri, Sedigheh ; Wikström, Kristina I ; Eriksson, Emma

AbstractPretreatment of B-cell lymphoma patients with immunostimulatory gene therapy using armed oncolytic viruses may prime tumor lesions for subsequent chimeric antigen receptor (CAR) T-cell therapy, thereby enhancing CAR T-cell functionality and possibly increasing response rates in patients. LOAd703 (delolimogene mupadenorepvec) is an oncolytic adenovirus (serotype 5/35) that encodes for the transgenes CD40L and 4-1BBL, which activate both antigen-presenting cells and T cells. Many adenoviruses failed to demonstrate efficacy in B-cell malignancies, but LOAd703 infect cells via CD46, which enables B cell infection. Herein, we investigated the therapeutic potential of LOAd703 in human B-cell lymphoma models, alone or in combination with CAR T-cell therapy. LOAd703 could infect and replicate in B-cell lymphoma cell lines (BC-3, Karpas422, Daudi, DG-75, U-698) and induced an overall enhanced immunogenic profile with upregulation of co-stimulatory molecules CD80, CD86, CD70, MHC molecules, death receptor Fas and adhesion molecule ICAM-1. Further, CAR T-cell functionality was boosted by stimulation with lymphoma cells infected with LOAd703. This was demonstrated by an augmented release of IFN-γ and granzyme B, increased expression of the degranulation marker CD107a, fewer PD-1 + TIM-3+ CAR T cells in vitro and enhanced lymphoma cell killing both in in vitro and in vivo xenograft models. 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.

01 Dec 2020·Cancer Gene TherapyQ2 · MEDICINE

Immunostimulatory oncolytic virotherapy for multiple myeloma targeting 4-1BB and/or CD40

Q2 · MEDICINE

Article

Author: Wenthe, Jessica ; Hellström, Ann-Charlotte ; Eriksson, Emma ; Naseri, Sedigheh ; Wiklund, Helena Jernberg ; Loskog, Angelica

AbstractMultiple myeloma (MM) is a plasma cell malignancy that is characterized by immune dysregulation. MM is commonly treated with immunomodulating agents, but still remains incurable. Herein, we proposed and evaluated immunostimulatory Lokon oncolytic adenoviruses (LOAd) for MM treatment. LOAd viruses are serotype 5/35 chimera, which enables infection of hematopoietic cells. Oncolysis is restricted to cells with a dysregulated retinoblastoma protein pathway, which is frequently observed in MM. Further, LOAd viruses are armed with human immunostimulatory transgenes: trimerized membrane-bound CD40L (LOAd700, LOAd703) and 4-1BBL (LOAd703). LOAd viruses were assessed in a panel of MM cell lines (ANBL-6, L363, LP-1, OPM-2, RPMI-8226, and U266-84). All cells were sensitive to infection, leading to viral replication and cell killing as analyzed by quantitative PCR and viability assay. Transgene expression was verified post infection with flow cytometry. Cell phenotypes were further altered with a downregulation of markers connected to MM progression (ICAM-1, CD70, CXCL10, CCL2, and sIL-2Rα) and an upregulation of the death receptor Fas. In a co-culture of immune and MM cells, LOAd viruses promoted activation of cytotoxic T cells as seen by higher CD69, CD107a, and IFNγ expression. This was most prominent with LOAd703. In conclusion, LOAd viruses are of interest for MM therapy.

100 Deals associated with Delolimogene mupadenorepvec

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Melanoma	Phase 2	Sweden	Lokon Pharma AB	28 Jan 2020
Melanoma	Phase 2	United States	Lokon Pharma AB	28 Jan 2020
Multiple Myeloma	Phase 2	Sweden	Lokon Pharma AB	15 Aug 2019
Colorectal Cancer	Phase 2	Sweden	Lokon Pharma AB	01 Mar 2018
Ovarian Cancer	Phase 2	Sweden	Lokon Pharma AB	01 Mar 2018
Pancreatic adenocarcinoma	Phase 2	Sweden	Lokon Pharma AB	01 Mar 2018
Unresectable Biliary Tract Carcinoma	Phase 2	Sweden	Lokon Pharma AB	01 Mar 2018
Pancreatic Cancer	Phase 2	United States	Lokon Pharma AB	01 Nov 2016
Pancreatic Ductal Adenocarcinoma	Phase 2	United States	Lokon Pharma AB	01 Nov 2016
Biliary Tract Neoplasms	Phase 2	-	Uppsala University Hospital	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04123470 (LOKON003, ESMO2024) Manual	Phase 1/2	Melanoma	24	LOAd703ectoratezolizumab (LOAd703 (1x10^11 VP))	(ejaxelkdrx) = Most common adverse events with suspected relationship to LOAd703 were pyrexia (n=14 patients), vomiting (n=5), and chills (n=5). ozrdniandk (lfdywdrpjp ) View more	Positive	13 Sep 2024
NCT04123470 (LOKON003, ESMO2024) Manual	Phase 1/2	Melanoma	24	LOAd703ectoratezolizumab (LOAd703 (5x10^11 VP))		Positive	13 Sep 2024
NCT03225989 (ESMO2024) Manual	Phase 1/2	Advanced Malignant Solid Neoplasm	41	LOAd703 with standard of care chemotherapy	(dlzziqzaph) = associated with LOAd703 and related procedures were overall transient and of grade 1-2. The most frequent adverse events were pyrexia (76%), chills (39%), and fatigue (34%). However, three patients developed nephrotoxicity possibly related to LOAd703. ogtuhdycfo (prjnzbslgj )	Positive	13 Sep 2024
NCT02705196 (LOKON001, Pubmed)	Phase 1/2	Pancreatic carcinoma non-resectable	22	LOAd703	(ztweptifmi) = rsxkyzbaat ivxtarhktp (gskgtkiqvc ) View more	Positive	01 Apr 2024
NCT03555149 (MORPHEUS, CTgov)	Phase 1/2	Metastatic Colorectal Carcinoma	96	Regorafenib (Regorafenib (Control))	(ipuijbvsyi) = jxsmeqqhkv jfaxnwdaka (qzfpqbbern, dirtdljcke - vexrptzvid) View more	-	07 Nov 2023
NCT03555149 (MORPHEUS, CTgov)	Phase 1/2	Metastatic Colorectal Carcinoma	96	Imprime PGG+Atezolizumab+Bevacizumab (Atezolizumab + Imprime PGG + Bevacizumab)	(ipuijbvsyi) = xoffmdckxp jfaxnwdaka (qzfpqbbern, nuoafdhvrh - raqxyurzpw) View more	-	07 Nov 2023
NCT03225989 (LOKON002, AACR2023) Manual	Phase 1/2	Advanced Malignant Solid Neoplasm	28	LOAd703	(jgdtxkdzuz) = zpxysrdime xyhpdnjoht (wgghabpisf ) View more	Positive	14 Apr 2023
NCT02705196 (ASCO2022) Manual	Phase 1/2	Pancreatic Cancer	22	LOAd703+nab-paclitaxel+gemcitabine	(bmkuwgkidg) = vnpkkutshe etoxcdfert (dcuqqyhbbz ) View more	Positive	02 Jun 2022