Abstract 5263: The impact of MRTX1133 on anti-tumor immunity in lung cancer with KRASG12D mutation
Authors: Shono Kunihiro , Watanabe Satoshi , Masuda Takaaki , Suzuki Ryo , Wakabayashi Tomoya , Sekiya Tomoki , Tanaka Susumu , Ohtsubo Aya , Tanaka Tomohiro , Nozaki Koichiro , Kondo Rie , Saida Yu , Hokari Satoshi , Yanagimura Naohiro , Arita Masashi , Ohashi Riuko , Shima Kenjiro , Kimura Yosuke , Aoki Nobumasa , Ohshima Yasuyoshi , Koya Toshiyuki , Kikuchi Toshiaki 
Published: March 2024

Abstract
Background: To date, there have been no clinical molecules that are selective for KRASG12D mutant tumors. Although immune checkpoint inhibitors (ICIs) have improved the survival for patients with lung cancer, inferior efficacy of ICIs has been reported in KRASG12D mutant NSCLC. MRTX1133 is a selective KRASG12D inhibitor, which has been investigated in early clinical studies. In this study, we aimed to reveal the immune status using preclinical murine model of KRASG12D mutated lung cancer. In addition, we investigated whether MRTX1133 effects the anti-tumor immunity in mice bearing lung cancer with KRASG12D.
Method: CCSP-rtTA/TetO-Cre mice were crossed with LSL-KRASG12D knock-in mice to obtain CCSP-rtTA/TetO-Cre/LSL-KRASG12D conditional mutant mice (KRASG12D mice). These mice were fed an autoclaved rodent diet supplemented with 0.0625% doxycycline when the mice were about 8~12 weeks old. Mice were treated with 10 mg/kg MRTX1133 in vehicle once daily by intraperitoneal injection for 4 or 8 days. After administration of MRTX1133, the lungs and spleens were harvested, and single cell suspensions were labeled with fluorophore-conjugated antibodies for FACS analyses.
Results: More regulatory T cells (Tregs) infiltrated the tumors of lung of mice treated with doxycycline for a longer period of time. The expression of immune checkpoint molecules (ICMs), including PD-L1, PD-1, TIGIT, TIM-3, LAG-3, were also upregulated on CD4+ and CD8+ T cells in the KRASG12D mice. Treatment with MRTX1133 strongly inhibited KRASG12D tumor progression, reduced the percentage of Tregs and downregulated the expression of PD-1 on CD4+ and CD8+ T cells infiltrating in lung cancers. The expression of the other ICMs remained high after MRTX1133 administration. In addition, MRTX1133 tended to increase the percentage of tumor-specific CD8+ effector T cells infiltration in lung tumors. Conclusion: T cells were exhausted in mice with KRASG12D mutant lung cancer. MRTX1133 demonstrates the therapeutic efficacy in preclinical murine KRASG12D mutated lung cancer model. This efficacy is more likely to relate not only signal inhibition but also enhances the anti- tumor immune responses. Our findings could aid in developing an alternative immunotherapy strategy in patients with KRASG12D mutant lung cancer.
Citation Format: Kunihiro Shono, Satoshi Watanabe, Takaaki Masuda, Ryo Suzuki, Tomoya Wakabayashi, Tomoki Sekiya, Susumu Tanaka, Aya Ohtsubo, Tomohiro Tanaka, Koichiro Nozaki, Rie Kondo, Yu Saida, Satoshi Hokari, Naohiro Yanagimura, Masashi Arita, Riuko Ohashi, Kenjiro Shima, Yosuke Kimura, Nobumasa Aoki, Yasuyoshi Ohshima, Toshiyuki Koya, Toshiaki Kikuchi. The impact of MRTX1133 on anti-tumor immunity in lung cancer with KRASG12D mutation [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 5263.