Abstract 4186: Development of an orthotopic A549 lung carcinoma model in CD34+ humanized NCG mice and response to treatment with paclitaxel and pembrolizumab

Abstract Translational in vivo models are needed to expedite the discovery of new treatments for lung cancer. One such approach is the use of humanized mouse models that enable immunotherapies targeting human immune cells to be evaluated for efficacy and tolerability. We developed an orthotopic lung carcinoma model in humanized mice (HuCD34 NCG), utilizing serial bioluminescence imaging to evaluate the activity of paclitaxel and pembrolizumab as single and combination agents. Paclitaxel, which disrupts microtuble function, and pembrolizumab, a PD-1-targeting immunotherapy, are both approved for the treatment of certain types of lung cancer. Paclitaxel kills cancer cells directly, and may also promote anti-tumor responses through enhanced presentation of tumor antigens and activation of T cells. Immunodeficient NCG mice were humanized with cord blood-derived hCD34+ stem cells from 3 donors. High levels of human cell engraftment, with expected frequencies of hCD45+ cells and other immune subsets, was observed by 14 weeks post-injection. Luciferase expressing A549 cells were implanted orthotopically into the pulmonary space of the left lobe of the lung, and animals were subsequently flux sorted into treatment groups. Tumor burden, measured by luciferase expression, increased progressively in untreated animals, and moribundity was often associated with clinical indications of respiratory distress. Treatment with paclitaxel significantly decreased the tumor burden and extended survival. In contrast, pembrolizumab did not control tumor growth or extend survival. There was no synergistic effect with the combination therapy, in fact, the addition of pembrolizumab was associated with a modest increase in tumor burden and disease progression. Comparative analysis of immune cell composition, function and persistence in lung and other tissues provided insights into the distinct pharmacodynamic responses associated with the different treatment regimens. This model establishes a robust in vivo platform to identify novel therapies for the treatment of lung cancer. Citation Format: Anya Avrutskaya, Elizabeth Rainbolt, Bincy John, Cara Clouse, Murray Stackhouse, Christopher Currie, Sydney Scatigno, Steven Bronson, Jenny Rowe, Chassidy Hall, David P. Harris. Development of an orthotopic A549 lung carcinoma model in CD34+ humanized NCG mice and response to treatment with paclitaxel and pembrolizumab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4186.