Abstract 4454: TUSC2 immunogene therapy enhances efficacy of immunotherapy and targeted drugs in human non-small cell lung cancer (NSCLC) in humanized mouse models
Authors: Meraz Ismail M. , Majidi Mourad , Feng Meng , Shao RuPing , Ha Min Jin , Shpall Elizabeth J. , Roth Jack A. 
Published: September 2020

TUSC2 is a tumor suppressor gene, whose expression is reduced in almost all NSCLC. Systemic nanovesicle delivery of TUSC2 inhibits cancer cell growth through inhibition of a broad spectrum of kinases and mTOR downregulation as well as stimulation of the immune system through innate activation. We previously reported that TUSC2 downregulates PD-L1 expression in NSCLC and synergizes with anti-PD1 in inhibiting tumor growth in Kras mutant syngeneic mouse models through upregulation of NK and cytotoxic T cells. We developed an improved CD34-derived humanized mouse model (Hu-mice), with faster and higher human immune reconstitution than other available humanized mice, to evaluate immune responses in lung cancer. In this study, we tested whether TUSC2 immunogene therapy would enhance response to standard checkpoint blockade immunotherapy, chemotherapy and targeted therapies in humanized NSG mice implanted with highly metastatic Krasmt/LKB1− A549 cells. A significantly increased antitumor effect was found when TUSC2 was combined with pembrolizumab. Pembrolizumab alone reduced tumor burden as compared with an untreated control, whereas no antitumor effect was observed in non-Hu-mice implanted with A549 cells. The observed antitumor effect correlated with increased levels of CD8+ T and CD8+CD69+ active T, and decreased levels of MDSC and regulatory T cells in the combination group. A significantly higher percentages of CD56+ NK and CD56+CD69+ active NK cells were found in the TUSC2 alone and combination groups indicating TUSC2 related NK activation. Next, we tested whether TUSC2 enhances efficacy to carboplatin+pembrolizumab. The level of antitumor effect of carboplatin+pembrolizumab was similar to that of TUSC2 alone. However, 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. Immune analysis of the triple combination in CMT167 syngeneic mice showed increased infiltration of CD3+ T, CD8+ T, NK cells and significantly less Treg cells into tumor, which was associated with significant tumor inhibition by the treatments. A higher percentage of CD3+CD44+ and CD8+CD44+ memory T cells were found in tumors after carbo+aPD1+TUSC2 treatment, as compared with either Carbo+aPD1 or control groups. The antitumor activity of Carbo+aPD1+TUSC2 was further enhanced when MEKi (Trametinib) was added. Moreover, we also combined TUSC2 with the anti-angiogenic agent, bevacizumab (anti-VEGF) to enhance efficacy in the highly angiogenic 786-O renal cell carcinoma. Synergistic antitumor activity was found with the combination, which was significantly stronger than either single agent. In conclusion, the addition of TUSC2 immunogene therapy with checkpoint blockade, chemotherapy, and targeted therapies showed enhanced antitumor efficacy.

Citation Format: Ismail M. Meraz, Mourad Majidi, Meng Feng, RuPing Shao, Min Jin Ha, Elizabeth J. Shpall, Jack A. Roth. TUSC2 immunogene therapy enhances efficacy of immunotherapy and targeted drugs in human non-small cell lung cancer (NSCLC) in humanized mouse models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4454.