Advanced Liposomal Oxaliplatin Drug Delivery – Evaluation of Therapeutic Mechanisms and Synergism with Cancer Immunotherapy

Lars Ringgaard Petersen

    Research output: Book/ReportPh.D. thesisResearch

    Abstract

    Cancer is one of the most common causes of death globally. There is still a great need to advance the understanding of the heterogeneous biology of cancer to improve therapeutic outcome. Chemotherapy like oxaliplatin(oxpt) is used in various combinations with curative intent or to control disease. Cancer exists in an intricate connection with the immune system.
    This PhD thesis will investigate the use of oxpt encapsulated in liposomal nanoparticles to treat solid tumors. It involves the use of several in vivo murine tumor models and use liposome treatment as mono therapy or combination treatment with immunotherapy.
    In the first manuscript, the design of a matrix metalloproteinase (MMP) labile liposome is characterized. We show that oxpt‐containing MMP‐sensitive liposomes are homogenous and display an in vitro toxicity similar to free drug. Pharmacokinetic and biodistribution experiments in xenografted mice revealed long circulating properties and increased accumulation in tumors compared to the free drug. Efficacy experiments showed superior anti-tumor effect compared to free oxpt and conventional long‐circulating Stealth liposomes. Combination treatment of MMP‐labile oxpt‐containing liposomes with Toll‐like receptor agonist (TLR) 7/8 (R848) induced potent synergistic effects in a murine colon cancer model with a large fraction of complete responders and pro‐immunogenic tumor‐microenvironments.
    In the second manuscript, we investigate how to bypass the dose‐limiting toxicity that inhibits transition of TLR7/8 agonist R848 to the clinic. We formulated R848 in a nanogel that allows sustained release following intratumoral injection. This study identifies an improved therapeutic effect of intratumoral administration of R848 nanogel with sustained release in comparison to both systemic and intratumoral administration of the free R848 in large CT26 colorectal tumors preconditioned with MMP‐sensitive liposomal OxPt. Intratumoral delivery of nanogel TLR7 agonist R848 induced superior immunological responses that are highly encouraging towards bringing this technology forward in clinical testing.
    In the third manuscript, the mechanistic effect of liposomal delivery of oxpt on tumor TME was investigated. Different oxpt‐liposome formulations have shown markedly different anti‐tumor effect in syngeneic tumor models. We hypothesize that the infiltration of myeloid‐derived suppressor cells and the oxpt‐liposomes ability to deplete these suppressive populations are a major factor in liposome anti‐tumor efficacy. We compared CT26 and 4T1 as they have similar oxaliplatin sensitivity in vitro and similar amount of leukocytic tumor infiltration. In CT26, the largest immuno‐suppressive population is monocytic myeloid‐derived suppressor cells (Mo‐MDSC), while polymorphonuclear myeloid‐derived suppressor cells (PMN‐MDSC) dominates 4T1 tumor infiltration. We showed efficient depletion of Mo‐MDSCs, while all treatments failed to lower PMN‐MDSC levels in 4T1 and CT26. Oxpt‐liposomes was able to eradicate established CT26, while showing limited response in 4T1.
    Original languageEnglish
    PublisherDTU Nanotech
    Number of pages162
    Publication statusPublished - 2017

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