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LOAd703, an oncolyt...
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Musher, Benjamin L.Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
(author)
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/chapterEnglish2024
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Elsevier,2024
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LIBRIS-ID:oai:DiVA.org:uu-528213
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-528213URI
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https://doi.org/10.1016/S1470-2045(24)00079-2DOI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
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Background Pancreatic 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. Methods LOKON001 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/m 2 plus gemcitabine 1000 mg/m 2 (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 mu L of LOAd703 at 5 x 10 10 (dose 1), 1 x 10 11 (dose 2), or 5 x 10 11 (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. Findings Between 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. Interpretation 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.
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Added entries (persons, corporate bodies, meetings, titles ...)
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Rowinsky, Eric K.Lokon Pharm AB, Uppsala, Sweden.
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Smaglo, Brandon G.Univ Texas MD Anderson Canc Ctr, Houston, TX USA.
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Abidi, WasifBaylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Othman, MohamedBaylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Patel, KalpeshBaylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Jawaid, SalmaanBaylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Jing, JamesBaylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Brisco, AmandaUSF Hlth Morsani Coll Med, Tampa, FL USA.
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Leen, Ann M.Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Wu, MengfenBaylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Sandin, Linda C.Lokon Pharm AB, Uppsala, Sweden.
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Wenthe, JessicaUppsala universitet,Cancerimmunterapi,Lokon Pharm AB, Uppsala, Sweden(Swepub:uu)jeswe849
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Eriksson, EmmaUppsala universitet,Cancerimmunterapi,Lokon Pharm AB, Uppsala, Sweden(Swepub:uu)emmsv898
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Ullenhag, Gustav J.Uppsala universitet,Cancerimmunterapi,Uppsala Univ Hosp, Dept Oncol, Akad Sjukhuset, Uppsala, Sweden(Swepub:uu)gustulle
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Grilley, BambiBaylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Leja-Jarblad, JustynaLokon Pharm AB, Uppsala, Sweden.
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Hilsenbeck, Susan G.Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Brenner, Malcolm K.Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.
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Loskog, Angelica,1973-Uppsala universitet,Cancerimmunterapi,Lokon Pharm AB, Uppsala, Sweden(Swepub:uu)angelosk
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Baylor Coll Med, Dan L Duncan Comprehens Canc Ctr, Houston, TX 77030 USA.Lokon Pharm AB, Uppsala, Sweden.
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In:The Lancet Oncology: Elsevier25:4, s. 488-5001470-20451474-5488
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