Zinnia P. Parra-Guillen1, Anna Dari2, Douglas Steinbach3, Xavier Woot de Trixhe2, Kathryne Taylor4, Douglas Yamada5, Nahor Haddish-Berhane3, Juan José Pérez Ruixo2, Inaki F. Troconiz1
1Pharmacometrics and Systems Pharmacology Department of Pharmaceutical Science, School of Pharmacy and Nutrition, University of Navarra, 2Janssen Research & Development, 3Johnson & Johnson Innovative Medicine, 4Lung Disease Area Stronghold, Oncology TA; Johnson & Johnson Innovative Medicine, 5Prostate Disease Area & Immunotherapy Stronghold, Oncology TA, Johnson & Johnson Innovative Medicine
Introduction: Oncolytic viruses (OVs)1,2 show promise as an oncologic therapeutic due to their ability to replicate in and kill tumor cells over normal cells. Moreover, a major advantage of OVs relies on their ability to act as a potent immunotherapeutic. The mouse surrogate of a drug product is a genetically modified HSV-1 virus with the intent of preferential replication in tumor, minimal innate antiviral immune stimulation, and multiple payload (PLs) expression to enhance antitumor efficacy. Objectives: The aim of this work is to refine a modeling framework which describes the antitumor effect of the drug product surrogate. With this, the subsequent translational efforts required to support the OV clinical development can be pursued. Methods: The analysis was based on tumor volumes (TV) collected from 12 in house studies performed in a syngeneic mouse model following bilateral MC38-5AG tumor cell implantation. One of the 2 lesions on each mouse was then intratumorally injected with, either the backbone of the mouse surrogate OV, the mouse surrogate OV with 1 PL, or the full OV mouse surrogate with multiple PLs. The non-injected lesion was used to assess abscopal effect. The doses investigated included: the vehicle, low, intermediate and high doses. A K-PD modeling approach was used to fit the data. A Simeoni model3 described the tumor growth of the lesions; 3 transit compartments with a first order elimination rate described the OV dynamics. Antitumor response was due to the direct oncolytic effect and the immune response stimulated post OV administration. PLs expression was believed a priori as a prerequisite for maximizing the antitumor response. A mixture model was included to account for the potential abscopal effect in the non-injected lesions. Results: A total of 4416 TV samples from 223 syngeneic mice were collected and included in the analysis. Data showed a complete elimination of the injected lesion reached with intermediate and high doses of the full OV mouse surrogate at ~22 days after first OV injection. However, only 3 out of 10 animals showed complete response after low dose. The model accounted for this dose dependent response using an Emax model with an OV50 of 9230 (RSE = 5.5%) pfu. In the non-injected lesion, no TV response was observed after OV injection of the low or intermediate doses; for the high dose the model estimated 20% of the animals with complete abscopal effect and 80% with partial abscopal effect. The inclusion of the backbone and full OVs in the analysis allowed the estimation of a mild direct oncolytic effect in the injected lesion (elimination rate, kkill = 0.08 (RSE = 2.4 %) 1/day). Therefore, the remaining effect leading to the complete lesion elimination was believed to be related to the activation of the immune system. Conclusions: Further refinement of a PK/PD model is required to better describe the antitumor dynamics. While clinical studies are ultimately required to fully understand and develop an OV as a therapeutic, this analysis will support the future investigation of the translational steps needed to realize more robust models.
[1] Ahamadi, Malidi, et al. Oncolytic viral kinetics mechanistic modeling of Talimogene Laherparepvec (T-VEC) a first-in-class oncolytic viral therapy in patients with advanced melanoma. CPT: Pharmacometrics & Systems Pharmacology, 2023, 12.2: 250-260. [2] Storey, Kathleen M.; LAWLER, Sean E.; JACKSON, Trachette L. Modeling oncolytic viral therapy, immune checkpoint inhibition, and the complex dynamics of innate and adaptive immunity in glioblastoma treatment. Frontiers in physiology, 2020, 11: 151. [3] Rocchetti, M., et al. Predicting the active doses in humans from animal studies: a novel approach in oncology. European journal of cancer, 2007, 43.12: 1862-1868.
Reference: PAGE 33 (2025) Abstr 11391 [www.page-meeting.org/?abstract=11391]
Poster: Drug/Disease Modelling - Oncology