Abstract CT235: A phase I/II clinical study of an oncolytic adenovirus expressing the immunostimulatory transgenes TMZ-CD40L and 4-1BBL in advanced solid malignancies
Authors: Hahn Amanda , Irenaeus Sandra , Wenthe Jessica , Eriksson Emma , Schiza Aglaia , Dahlstrand Hanna , Olsson-Strömberg Ulla , Krause Johan , Sundin Anders , Sandin Linda , Jarblad Justyna Leja , Liljefors Maria Gustafsson , Rowinsky Eric , Loskog Angelica , Ullenhag Gustav J. 
Published: April 2023

Abstract
There is a need for therapeutics with novel mechanisms-of-action for patients with advanced solid malignancies. In this first completed part of LOKON002, a phase I/II (NCT03225989) clinical study, the safety and clinical response to LOAd703 in combination with standard-of-care (SoC), or conditioning gemcitabine chemotherapy, was investigated. LOAd703 is an oncolytic adenovirus of serotype 5/35 modified to express two immunostimulatory transgenes, trimerized membrane-bound CD40L and 4-1BBL.
In the completed part I (phase I and IIa) of the study, eligible patients with advanced pancreatic-, colorectal-, biliary- and ovarian cancer, were treated with increasing doses of LOAd703 (5 × 1010, 1 × 1011 and 5 × 1011 viral particles) using a standard 3+3 design. LOAd703 was administered intratumorally (ultrasound-guided) for up to 8 bi-weekly injections. The maximum tolerated dose tested was further evaluated in an extended dose cohort to confirm safety and assess preliminary clinical activity, and to select the best two indications for the part II of the study.
Twenty-eight patients were enrolled in part I presented herein. Fifteen of these received LOAd703 combined with SoC, and thirteen in combination with conditioning gemcitabine. The most frequently reported treatment- or procedure-related adverse events were fever (82% of patients), chills (54%) and fatigue (43%). Four patients developed transient cytokine release syndrome. Twenty-five patients fulfilled the criteria to be evaluable for efficacy, which required receiving at least 3 doses of LOAd703 and results from a CT scan week 9. 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. One of the PRs was achieved at week 25, and the patient received one additional month of chemotherapy per protocol. This patient remained treatment-free for 17 months before chemotherapy was restarted due to progression, and was still alive at last follow-up 34 months after the study registration date. The other PR was achieved at week 17, two weeks after the last LOAd703 injection; disease progression was evident at week 33 and OS was 21 months. Three patients experienced stable disease for a minimum of 25 weeks. This included a patient with advanced ovarian cancer who showed SD at least until week 40, and had an OS of 40 months. 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.
Citation Format: Amanda Hahn, Sandra Irenaeus, Jessica Wenthe, Emma Eriksson, Aglaia Schiza, Hanna Dahlstrand, Ulla Olsson-Strömberg, Johan Krause, Anders Sundin, Linda Sandin, Justyna Leja Jarblad, Maria Gustafsson Liljefors, Eric Rowinsky, Angelica Loskog, Gustav J. Ullenhag. A phase I/II clinical study of an oncolytic adenovirus expressing the immunostimulatory transgenes TMZ-CD40L and 4-1BBL in advanced solid malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT235.