Abstract A75: Efficacy of novel immunogene combinations for Kras and LKB1 mutant NSCLC in a humanized mouse model

Due to lack of suitability of current preclinical models for immunotherapy research, we recently developed an improved humanized mouse by reconstituting a human immune system in NSG mice by transplanting fresh human cord blood-derived CD34+ stem cells (Hu-mice). The Hu-mice show functional representation of human T, B, natural killer (NK), dendritic cells (DC), myeloid-derived suppressor cells (MDSC), and responsiveness to checkpoint blockade. TUSC2 has recently been recognized as a novel immunogene that induces apoptosis in tumor cells and promotes a wide spectrum of tumor-specific innate and adaptive immune responses. We previously reported that TUSC2 delivered systemically by nanovesicles downregulates PD-L1 expression in NSCLC and synergizes with anti-PD1 in inhibiting tumor growth in Kras-mutant syngeneic mouse models through upregulating NK and cytotoxic T cells. In this study, we aimed to evaluate the antitumor efficacy of TUSC2 in combination with standard immunotherapy on highly metastatic Kras and LKB1 mutant human lung cancer in Hu-mice. Hu-mice were challenged with A549 cells (Krasmt/LKB1-) and lung metastases were treated with TUSC2, nivolumab, or the combination. The results showed a synergistic antitumor effect with the combination. A significantly increased antitumor effect was found when TUSC2 was combined with pembrolizumab in Hu-mice. Pembrolizumab alone significantly reduced tumor burden as compared with an untreated control, whereas no antitumor effect was observed in non-Hu-mice implanted with A549 cells. The antitumor effect was correlated with significantly higher levels of CD8+ T and CD8+CD69+ active T and significantly lower levels of MDSC and regulatory T cells in the combination group. A significantly higher percentage of CD56+ NK and CD56+CD59+ active NK cells was found in the TUSC2 alone and combination groups, indicating TUSC2 related NK activation. We tested whether TUSC2 enhances efficacy to carboplatin+pembrolizumab in Hu-mice implanted with A549-luc metastatic cells. The results showed that the level of antitumor effect of carboplatin+pembrolizumab was similar to that of TUSC2 alone, but when TUSC2 was combined with carboplatin+pembrolizumab, metastases regression was significantly greater than either TUSC2 alone or carboplatin+pembrolizumab treatments. Significantly fewer or no visible tumor nodules were found in dissected lungs in the TUSC2 combination as compared with other groups. In conclusion, TUSC2 immunogene therapy in combination with pembrolizumab and carboplatin+pembrolizumab showed strong antitumor efficacy in metastatic human NSCLC in a clinically relevant humanized mouse model, supporting a clinical trial. Citation Format: Ismail M. Meraz, Mourad Majidi, Meng Feng, RuPing Shao, Min Jin Ha, Jeffrey Morris, Elizabeth J. Shpall, Jack A. Roth. Efficacy of novel immunogene combinations for Kras and LKB1 mutant NSCLC in a humanized mouse model [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A75.