1. Tumor Adjacent IL2 Cytokine Factories Eradicates Ovarian Cancer in Mice Through Cytotoxic T-cell Activation with Safe and Predictable Dosing in Non-human Primates
- Author
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Guillaume Carmona, Amanda Nash, Maria Jarvis, Ryan Newman, Jake Schladenhauffen, Samira Aghlara-Fotovat, Andrea Hernandez, Shirin Nouraein, Sudip Mukherjee, Andrew Hecht, Yufei Cui, Jared Lee, Peter Rios, David Zhang, Chunyu Xu, Rahul Sheth Sheth, Weiyi Peng, Jose Oberholzer, Oleg Igoshin, Amir Jazaeri, and Omid Veiseh
- Subjects
Immunology ,Immunology and Allergy - Abstract
Recombinant IL-2 has been approved for the treatment of melanoma and renal cancer. However, IL-2 therapy is limited by its short half-life in circulation and the associated toxicities that emerge as a result of high systemic exposure. To overcome these limitations, we developed a localized cytokine LOCOcyteTM platform composed of allogeneic and engineered cells which produce potent immune effector molecules for local delivery with temporal regulation of activity. Administration of AVB-001 in mice and non-human primates demonstrated that IL2 local concentration (IP space) was 100x higher than the systemic concentration. Additional studies in mice demonstrated dose-dependent levels of IL2 in the intraperitoneal cavity in mice. Treatment of peritoneal tumors in mice using a single administration of AVB-001 provided sustained eradication of peritoneal tumors in an ovarian cancer mouse model. Our data in mice confirmed local increases in activation (CD25+CD8+) (8.6 fold) and proliferation (Ki67+CD8+)(3.4 fold) of cytotoxic T cells within the IP space in comparison to sham mice. Finally, a single administration of AVB-001 led to therapeutic levels of IL2 in the IP space in NHP and produced local and systemic T cell biomarker profiles that predict efficacy, AVB-001 was well tolerated by all animals with no abnormal clinical observations during the study. Our findings demonstrate that the LOCOcyteTM platform has a dose-dependent PK/PD effect, is safe and efficacious in animal models and enables itself to deliver a diverse set of cytokines alone or in combination which is presently explored. Combined, our pre-clinical results provide a rationale for testing AVB-001 in ovarian cancer patients.
- Published
- 2022