Liposomal Formulations to Modulate the Tumour Microenvironment and Antitumour Immune Response

Abstract

Tumours are complex systems of genetically diverse malignant cells that proliferate in the presence of a heterogeneous microenvironment consisting of host derived microvasculature, stromal, and immune cells. The components of the tumour microenvironment (TME) communicate with each other and with cancer cells, to regulate cellular processes that can inhibit, as well as enhance, tumour growth. Therapeutic strategies have been developed to modulate the TME and cancer-associated immune response. However, modulating compounds are often insoluble (aqueous solubility of less than 1 mg/mL) and have suboptimal pharmacokinetics that prevent therapeutically relevant drug concentrations from reaching the appropriate sites within the tumour. Nanomedicines and, in particular, liposomal formulations of relevant drug candidates, define clinically meaningful drug delivery systems that have the potential to ensure that the right drug candidate is delivered to the right area within tumours at the right time. Following encapsulation in liposomes, drug candidates often display extended plasma half-lives, higher plasma concentrations and may accumulate directly in the tumour tissue. Liposomes can normalise the tumour blood vessel structure and enhance the immunogenicity of tumour cell death; relatively unrecognised impacts associated with using liposomal formulations. This review describes liposomal formulations that affect components of the TME. A focus is placed on formulations which are approved for use in the clinic. The concept of tumour immunogenicity, and how liposomes may enhance radiation and chemotherapy-induced immunogenic cell death (ICD), is discussed. Liposomes are currently an indispensable tool in the treatment of cancer, and their contribution to cancer therapy may gain even further importance by incorporating modulators of the TME and the cancer-associated immune response.

Keywords: doxorubicin; immunogenic cell death; irinotecan; liposomes; mifamurtide; paclitaxel; radiotherapy; tumour microenvironment; tumour stroma; tumour vasculature; tumour-infiltrating lymphocytes.

Figure 1

Cells in the tumour microenvironment that modulate tumour growth. (A) Cells suppressing tumour growth include dendritic cells responsible for acquisition of antigens from dying tumour cells and cross-presentation; cytotoxic CD8⁺ T lymphocytes that recognise cancer cells with the tumour-associated antigens and eliminate them; and NK cells that alternatively detect cancer cells deficient in MHC I, presenting stress signatures or are opsonised and, likewise, deplete them. (B) Cells promoting tumour growth include tumour-associated endothelial cells and the corresponding tumour neovasculature; tumour-associated fibroblasts and tumour-associated adipocytes that mainly remodel the tumour’s extracellular matrix; and T_regs, tumour-associated macrophages and myeloid-derived suppressor cells all involved in various mechanisms of immune suppression.

Figure 2

Liposomal formulations used in the clinic. Commercial name and year of first approval by the authorities is provided for each of the formulations. Loaded drug and decoration of liposomal surface with PEG (in the case of Doxil™/Caelyx™ and Onivyde™) is represented in the schematics. Doxil™/Caelyx™ was the first formulation to receive approval in 1995, and consisted of PEGylated liposomal doxorubicin. Vyxeos™, approved in 2017, is, so far, the last approved liposomal formulation, and it contains a combination of two encapsulated drugs at a fixed 5:1 molar ratio of cytarabine/daunorubicin. Patisiran, a small interfering RNA (siRNA) formulation for treatment of hereditary amyloid transthyretin (ATTR) amyloidosis, will likely be approved in 2018, the year that this review was written.

Figure 3

Passive targeting of liposomal formulations by the enhanced permeability and retention (EPR) effect. (1) Liposomes are administered intravenously to cancer patients. (2) They enter the blood flow and remain in circulation for extended periods of time, due to their large particle size and improved pharmacokinetics, while the drug cargo is protected from degradation. (3, 4) Liposomes arrive at the tumour through the blood vessels. (5) They are not able to extravasate to healthy tissue because of the compact endothelial cell layer (×) that forms the capillaries. (6) However, they escape from blood circulation through the enhanced permeability of the tumour neovasculature, which is poorly formed, inflamed and “leaky”. (7) Liposomes are retained in the tumour microenvironment, since the associated lymphatic vessels are impaired. (8) The encapsulated drug is released from the accumulated liposomes into the tumour microenvironment and finally internalised by cancer cells. The arrows show the distribution of the liposomal drug from the intravenous administration to the accumulation and release into the tumour microenvironment.

Figure 4

Normalisation of tumour neovasculature by liposomal irinotecan in a mouse model of glioblastoma. After treatment with liposomal irinotecan (Irinophore C™) once weekly for 3 weeks, Verreault et al. recognised a significant reduction of the diameters of tumour blood vessels (identified by the CD31 marker, in green) in the subcutaneous glioblastoma xenograft. In contrast, the number of pericytes (NG2, in red) and the basement membrane coverage of blood vessels (collagen IV, in yellow) increased after the therapy. Taking the data together, fewer immature tumour vessels (CD31⁺, NG2⁻, and collagen IV⁻) were present in the TME after administration of liposomal irinotecan. Adapted with permission from [41]. Copyright 2011 by Verreault et al.