Multifunctional Lipid Bilayer Nanocarriers for Cancer Immunotherapy in Heterogeneous Tumor Microenvironments, Combining Immunogenic Cell Death Stimuli with Immune Modulatory Drugs

Abstract

In addition to the contribution of cancer cells, the solid tumor microenvironment (TME) has a critical role in determining tumor expansion, antitumor immunity, and the response to immunotherapy. Understanding the details of the complex interplay between cancer cells and components of the TME provides an unprecedented opportunity to explore combination therapy for intervening in the immune landscape to improve immunotherapy outcome. One approach is the introduction of multifunctional nanocarriers, capable of delivering drug combinations that provide immunogenic stimuli for improvement of tumor antigen presentation, contemporaneous with the delivery of coformulated drug or synthetic molecules that provide immune danger signals or interfere in immune-escape, immune-suppressive, and T-cell exclusion pathways. This forward-looking review will discuss the use of lipid-bilayer-encapsulated liposomes and mesoporous silica nanoparticles for combination immunotherapy of the heterogeneous immune landscapes in pancreatic ductal adenocarcinoma and triple-negative breast cancer. We describe how the combination of remote drug loading and lipid bilayer encapsulation is used for the synthesis of synergistic drug combinations that induce immunogenic cell death, interfere in the PD-1/PD-L1 axis, inhibit the indoleamine-pyrrole 2,3-dioxygenase (IDO-1) immune metabolic pathway, restore spatial access to activated T-cells to the cancer site, or reduce the impact of immunosuppressive stromal components. We show how an integration of current knowledge and future discovery can be used for a rational approach to nanoenabled cancer immunotherapy.

Nanocarrier Co-formulation for Delivery of a TLR7 Agonist plus an Immunogenic Cell Death Stimulus Triggers Effective Pancreatic Cancer Chemo-immunotherapy

“…Moreover, further experimentation in a robust orthotopic KPC model confirmed the ability of the dual-delivery carrier to trigger a synergistic immune response, backed by data showing improved drug delivery and tumor biodistribution. Not only do these results demonstrate the efficacy of a co-formulated drug carrier, but they expand the scope of employing a chemo-immunotherapy approach for PDAC and other cancers, as recently reviewed by us …”

“…While genetically engineered Pdx1-cre/LSL-Kras/G12D/p53R172H mice display many similarities to human PDAC (including the G12D KRAS mutation and TP53 loss, extensive desmoplasia, and an immune suppressive TME), the logistical constraints of animal breeding prompted us to use an orthotopic model instead. We have previously shown that implantation of a luciferase-expressing KPC cell line into the pancreatic tail of immunocompetent B6129SF1/J mice can be used to obtain tumor growth, with retention of human PDAC features, including a more robust stroma that resembles the heterogeneous immune landscape of the genetic animal models …”

“…Moreover, a number of TLR agonists are available for therapeutic intervention, including synthetic imidazoquinoline agonists capable of ligating endosomal TLR7 and TLR8 receptors. This approach can be used for silicasomes and liposomes …”

“…The hypothesis for the experimentation carried out in this article is that the generation of immunogenic cell death by irinotecan will be boosted by co-delivery of 3M-052, leading to improved dendritic cell activation. Adapted with permission from ref . Copyright 2022 American Chemical Society.…”

“…We demonstrate generation of a synergistic anti-PDAC immune response by improved drug delivery, including through boosting of APC activity that also involves regional lymph nodes. This is in keeping with our blueprint for synergistic nanocarriers to interfere in heterogeneous immune landscapes …”