Abstract 5895: N17350 kills cancer cells, spares immune cells, and regresses CDX tumors from chemotherapy naive and experienced patients
Authors: Chang Cui, Ravindra Gujar, Christine Lee, Maria Fumagalli, Nicole Martinez, Hannah Liu, Nicole Grigaitis, Sonia Feau, Afshin Bahador, Alain P. Algazi, Lev Becker
Journal: Cancer Research (2024)

Abstract Background. While multiple studies have demonstrated improved clinical outcomes in patients receiving concurrent chemotherapy and immunotherapy, clinical synergy may be limited by the destructive effects of DNA-damaging chemotherapy on non-cancer cells, including key constituents of anti-tumor immunity (e.g. mature T cells). Furthermore, when first-line chemotherapy fails, subsequent lines of chemotherapy produce lower response rates. Thus, new approaches that eradicate cancer cells while preserving immune cells may be required to more efficiently induce anti-tumor immunity as monotherapy or in combination with immunotherapy. Neutrophil elastase (ELANE), a neutrophil-derived serine protease, kills a wide range of cancer cells without harming immune cells through a unique mechanism involving histone H1 and the death domain of CD95. Here, we compared N17350, an optimized biologic leveraging the ELANE pathway, and chemotherapies for their ability to kill cancer cells and preserve immune cells from primary tumors of ovarian cancer (OvCa) patients and evaluated efficacy in OvCa patient cell-derived xenografts (CDXs) and a 4T1 model of metastatic breast cancer. Methods. For in vitro studies, cancer cells and CD45+ immune cells were isolated from primary tumors of chemotherapy naïve and experienced OvCa patients. Cells were treated with N17350, oxaliplatin, or doxorubicin 24h post-isolation, and viability was quantified by calcein-AM. For in vivo studies, primary OvCa cells were injected into nude mice to create CDX models. Mice were treated with 2 doses of N17350 (400μg/100mm3, intratumoral) or carboplatin (100mg/kg, intraperitoneal), and effects on tumor growth were quantified. In 4T1 model, N17350 was compared to oxaliplatin, alone or in combination with anti-CTLA4, and effects on tumor growth and immune profile were assessed. Results. N17350 killed primary cancer cells from all OvCa patients tested but was well tolerated by CD45+ tumor immune cells from the same patients. In contrast, doxorubicin and oxaliplatin showed similar toxicity to both cell types. N17350 killed cancer cells from chemotherapy naïve and experienced patients with equal efficacy, while doxorubicin and oxaliplatin showed less efficacy in patients previously treated with chemotherapy. N17350 rapidly regressed tumors in all OvCa CDX models and exhibited markedly improved efficacy over carboplatin. In the 4T1 model, N17350 outperformed oxaliplatin in terms of regressing tumors, elevating tumor immune cells, and combining with anti-CTLA4. Conclusions. Our data demonstrate that N17350 kills OvCa tumors in vitro and in vivo while sparing CD45+ immune cells in both chemotherapy naïve and experienced patients. Together with previous data showing that N17350 induces immunogenic tumor cell death, these findings suggest that N17350 could improve clinical outcomes compared to chemoimmunotherapy. Citation Format: Chang Cui, Ravindra Gujar, Christine Lee, Maria Fumagalli, Nicole Martinez, Hannah Liu, Nicole Grigaitis, Sonia Feau, Afshin Bahador, Alain P. Algazi, Lev Becker. N17350 kills cancer cells, spares immune cells, and regresses CDX tumors from chemotherapy naive and experienced patients [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 5895.