Abstract
Abstract Mechanism of action studies are imperative to translating oncology therapeutics into the clinic informing testable hypotheses and potential combination partners. This often involves large and time-consuming mouse studies to test a small number of compounds in an attempt to show statistically significant benefit. Likewise, testing multiple compounds and combination partners in these systems is limited by time, cost, and a desire to reduce the number of animals used in biological research. To overcome these limitations, we utilized an implantable microdevice (IMD) developed by KiburMed to measure intra-tumoral drug responses and to differentiate the mechanism of action of multiple cytokine agents in parallel in the MC38 mouse model. After sizable tumor growth in mice and implantation of the IMD device with 9 different therapeutic candidates, MC38 mice were taken down at different time points (24 hour, 4 days,7 days) to assess response. Local tumor response in the study was measured by cyclical immunofluorescence for deep cellular response phenotyping with a panel of 32 markers for comprehensive immune cell phenotyping. Among the candidate murine surrogate compounds in the device, SAR445877 (anti-PD-1-IL-15 mutein) was tested as a monotherapy, as a combination partner with anti-PDL1 and compared against anti-PD1 monotherapy. With further validation of this novel platform, results from this work are aligned with previous studies (1) showing a murine surrogate for SAR445877 in combination with anti-PDL1 increases immune cell populations more than either single agent alone. These analyses show CD3, CD4, and CD8 were significantly increased in SAR’877 murine surrogate + anti-PDL1 compared to SAR’877 alone or anti-PD1 alone. In addition, T cells could infiltrate at a distance away from treatment release region, well into tumor core. Other significant changes in immune cell markers include increases in CD45+, CD11b, CD11c, CD20 and CD27. In conclusion, we have shown that multiple oncology therapeutics can be screened simultaneously in a small number of mice using an implantable microdevice and data obtained with this technology is consistent with that obtained from traditional mouse tumor experiments. (1) Preclinical characterization of SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein with robust anti-tumor efficacy as monotherapy and in combination with PD-L1 blockade. Marie Bernardo; Yu-an Zhang; Dan Lu; Stella Martomo; Fatima Menas; Chen Zhu; Raymond Perez; Jeegar Patel; Donald Shaffer; Xiangming Li, Cancer Res (2023) 83 (7_Supplement): 2972. *This work was supported and funded by Sanofi. Citation Format: Xiangming Li, Julien Tessier, Joon Sang Lee, Seth Garren, Virna Cortez-Retamozo, Meenu Sharma, Angela Jankowski, Erik Zarazinski, Ann Fiore, Oliver Jonas, Colin Brenan, Donald Shaffer, Angela Hadjipanayis. Spatiotemporal tumor immune modulation by localized delivery of cancer therapeutics using an implantable microdevice [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 2053.
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