Abstract 5622: The tumor microenvironment modulates the delivery and activation of liposomal encapsulated irinotecan, MM-398.
Authors: Kalra Ashish , Kim Jaeyeon , Klinz Stephan , Paz Nancy , Reutt Joseph , Drummond Daryl , Kirpotin Dmitri , Moyo Victor , Bayever Eliel , Laivins Peter , Niyikiza Clet , Nielsen Ulrik , Fitzgerald Jonathan 
Published: August 2014

Abstract
MM-398 is a stable nanotherapeutic encapsulation of the pro-drug irinotecan with an extended plasma half-life and higher intratumoral deposition in animal models compared with free-irinotecan. MM-398 is currently in multiple clinical trials, including a Phase 3 trial for patients with advanced gemcitabine-resistant pancreatic cancer (NAPOLI-1). By using a systems pharmacology approach, we have previously identified the important determinants for MM-398 activity differentiating it from free irinotecan.
One of the critical parameters identified in the model is activity of the tumor carboxylesterase (CES) as an important correlate to the MM-398 preclinical response. Our data also shows that tumor associated macrophages (TAMs) are the dominant cell type for phagocytosis of MM-398 in the tumor microenvironment. To validate these findings we used a perturbation strategy involving manipulation of TAMs with the anti-CSF1 antibody 5A1. Depletion of macrophages with 5A1 resulted in a strong size reduction of CD11b+F4/80+ mature macrophage populations in HT29, MC38 and LLC tumor models. Furthermore, other myeloid and non-myeloid cell populations showed tumor model and mouse strain-dependent changes in population size and liposome uptake. The overall impact of 5A1-mediated macrophage depletion was a reduction of the total cellular liposomal load within the tumors. Anti-CSF1 treatment also modulated the systemic clearance of MM-398 due to changes in the macrophage populations in the liver and spleen of the animals. To capture this complex interplay of systemic and local depletion events we have expanded our mechanistically-based PK model to include separate tumor macrophage and tumor cell compartments.
The computational model also identified tumor permeability to MM-398 as a rate-limiting factor for drug deposition and in vivo activity. To assess the degree of variability in tumor permeability, we measured the levels of irinotecan and SN-38 using HPLC in six different xenograft models. A high degree of variability in irinotecan and SN-38 levels was seen across these models and between tumors from different mice bearing xenografts of the same cell lines. We then investigated the inter-relationship between tumor permeability, macrophage content, CES enzyme activity and SN-38 accumulation by assessing the levels of these markers in multiple human-derived primary xenograft models across different indications.
In summary, we demonstrated the impact of TAM modulation on overall tumor levels of irinotecan and SN-38 following treatment with liposomally encapsulated irinotecan. We outline differences in permeability of xenografts to MM-398 and the capacity to convert irinotecan into SN-38.
Citation Format: Ashish Kalra, Jaeyeon Kim, Stephan Klinz, Nancy Paz, Joseph Reutt, Daryl Drummond, Dmitri Kirpotin, Victor Moyo, Eliel Bayever, Peter Laivins, Clet Niyikiza, Ulrik Nielsen, Jonathan Fitzgerald. The tumor microenvironment modulates the delivery and activation of liposomal encapsulated irinotecan, MM-398. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5622. doi:10.1158/1538-7445.AM2013-5622