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Lipid nanoparticles (LNPs) In Cancer
Immunotherapy
Immunotherapy is a type of cancer treatment that helps your immune system fight cancer.
In the past decade, cancer immunotherapy has flourished, including immunostimulatory
small molecules, immune checkpoint inhibitors (ICIs) targeting immune cells, autologous
T cells expressing chimeric antigen receptors (CARs), or natural killers (NK) cells and
mRNAs expressing tumor antigens or CARs for cancer immunotherapy. Among them,
small molecule, ICIs, and mRNA therapies are used as stand-alone treatments for many
solid tumors, such as melanoma, non-small cell lung cancer (NSCLC), and urothelial
cancer.
However, despite the promise of cancer immunotherapy, these immunotherapies also
have significant limitations: poor water solubility, immune-mediated adverse events
(IRAEs), and loss of biological activity after long-term administration limit the
immunostimulatory efficacy of small molecule therapies. Therefore, the major challenges
facing cancer immunotherapy can be attributed to the lack of delivery systems that can
bring therapeutic drugs closer to their targets. Lipid-based nanoparticles (NPs),
including liposomes, lipid nanoparticles (LNPs), and nanoemulsions (NEs), have
been developed as platforms for the delivery of multiple therapeutic
agents. Compared with other nanoscale delivery systems, LNPs maintain high solubility
in aqueous phase while minimizing systemic toxicity, which neither polymeric NPs nor
inorganic NPs can overcome in clinical applications. These advantages making LNPs
the most common type of nanomedicine approved by the FDA.
Recent advances in LNP development make it possible to deliver not only small
molecules but also mRNAs for effective anticancer immunotherapy through cytotoxic
immune cell activation, checkpoint blockade and CAR-T cell therapy.
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Components of LNPs
Lipid-based nanoparticles exhibit various types of structures. Most LNPs are nearly
spherical with one or more lipid outer layers.
Although liposomes, LNPs, and NEs may exhibit different internal structures, typical
lipid-based NPs consist of cationic lipids or ionizable lipids with tertiary or quaternary
amines to encapsulate anionic payloads. Auxiliary lipids are also used to stabilize lipid
layers and promote membrane fusion. Polyethylene glycol (PEG) lipids or surfactants are
added to improve colloidal stability for long-term storage and prevent rapid degradation of
the payload as it enters the bloodstream throughout the body. In addition, NEs includes an
oil phase, which can be triacylglycerol, diacylglycerol or monoacylglycerol, vegetable oils,
mineral oils, free fatty acids, etc.
LNPs used for immune activation of small
molecules
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Chemotherapy
There is increasing evidence that the host immune system also plays an important role in
the process of chemotherapy, ultimately leading to antitumor responses. LNPs was first
used to encapsulate chemotherapy drugs as anticancer agents. The chemotherapeutic
drug oxaliplatin led to upregulation of tumor MHCI and reduction of immunosuppressive
cells (Treg, MDSC, and TAM) in a mouse model of colorectal cancer. Interestingly, the
liposomal formulation of oxaliplatin exhibited better antitumor immunity compared to free
oxaliplatin, suggesting that precise delivery of chemotherapeutic drugs to the TME would
trigger better antitumor immunity.
Immune system agonists (small molecules, nucleic acids or
peptides)
Antigen-presenting cells (APCs) sense tumor-associated antigens or
pathogen/damage-associated molecular patterns (PAMPs/DAMPs) via pattern
recognition receptors (PRRs). Activated APC triggers proinflammatory cytokines and
chemokines to activate the adaptive immune system to kill tumor cells.
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Agonists of TLRs, NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) were
developed to induce proinflammatory immune responses that favor antitumor activity.
Pam3Csk4 is a TLR1/2 agonist using LNP with OVA mRNA. TLR7/8/9 agonists have also
been extensively studied, and encapsulation of imidazoquinoline TLR 7/8 agonists, such
as imiquimod and resiquimod, loaded into liposomal preparations have been shown to
prolong their retention in the circulation. Stimulator of interferon genes (STING) is another
PRR located in the endoplasmic reticulum, and activated STING will enhance the synergy
of type I interferons with other pro-inflammatory cytokines, thereby enhancing antitumor
immunity. Cyclic dinucleotides (CDNs) are potent STING receptor agonists that can be
encapsulated into LNPs to enhance systemic antitumor immunity.
RNA interference (RNAi) technology
RNAi technology (siRNA, shRNA, miRNA, ASO, etc.) can induce specific gene regulation
and become a new therapeutic area for infectious diseases, neurodegenerative diseases,
cancer, and other rare diseases. In addition to directly targeting specific oncogenes, RNAi
can enhance antitumor immune responses by downregulating immunosuppressive
proteins.
From tumor antigens to mRNA-based therapy
Neoantigens expressed in the mutated tumor microenvironment will allow the
development of personalized cancer vaccines with patient-specific neoepitopes.
Anti-tumor tumor antigens mainly depend on the delivery of tumor antigen peptides or
encoding mRNAs. The use of liposomes to deliver TAAs/TSA long synthetic peptides can
greatly protect them from degradation while making APCs more accessible.
The first personalized IVAC mutant group using LNPs is an RNA vaccine encoding
multiple re-epitopes, whose safety, immunogenicity, and tolerability have been evaluated
in a phase I clinical trial in melanoma patients (NCT02035956). Strong immune responses
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against vaccine antigens were observed with no adverse drug reactions and were well
tolerated. In addition, many other personalized mRNA cancer vaccines encoding different
antigens use lipid nanosystems and have reached the clinical stage (NCT03897881,
NCT02316457, NCT03313778, NCT03480152, NCT03303398).
Lipid Nanoparticles (LNPs) for cell therapy
Recently, personalized adoptive cell therapy has shown great promise in clinical trials of
hematologic neoplasms. Adoptive cell therapy includes TIL therapy, engineered T cell
receptor therapy (TCR-T), CAR-T cell therapy and NK cell therapy. Despite the great
potential of adoptive cell therapy, concerns about immune side effects and insertional
mutagenesis have also been raised due to the use of viral vectors for in vitro cell
engineering. In addition, complex manufacturing and high cost also hinder the application
of CAR-T in a wider patient population. Therefore, new in vitro transfection techniques are
needed to enable safer and more economical adoptive cell therapy.
In preclinical studies, LNPs containing encoding DNA or mRNA showed excellent efficacy
in transient transfection. LNP-based encapsulated mRNAs can be formulated by simple
and rapid mixing, therefore, the selection of LNPs for cell engineering mainly focuses on
the transfection efficiency of their payloads. In addition, LNPs are generally considered to
have low cytotoxicity, thus, the processes of gene transfection and T/NK cell activation
can be performed simultaneously.
A study reported the development of ionizable LNP-encapsulated CAR for in vitro T cell
engineering, demonstrating for the first time that LNP-engineered CAR-T in vitro has
similar tumor-killing activity to lentiviral-engineered CAR-T. LNPs/mRNA transfection
strategies are also used in NK cell engineering. The development of liposome-engineered
super NK cells containing TRAIL was first reported by Chandrasekaran et al.
TRAIL-engineered NK cells showed potent tumor-killing activity by inducing apoptosis in
tumor-draining lymph nodes in vivo.
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Conclusion
Lipid-based NPs represent the most advanced and widely used delivery vehicles for small
molecules and nucleic acids. In cancer immunotherapy, lipid-based NPs can not only
deliver small molecules and mRNAs in vivo for enormous antitumor activity, but also
enable in vitro engineered cell therapy with efficiencies comparable to other non-viral or
viral vectors. It is believed that with the emergence of more immunotherapy methods,
artificial immune cells and new nanomaterials, their combination will profoundly affect the
field of cancer immunotherapy.
As a leading PEG derivatives supplier, Biopharma PEG can provide high purity PEG
derivatives in GMP and non-GMP grades for your research of lipid nanoparticles for drug
delivery.
Reference:
1. Application of lipid-based nanoparticles in cancer immunotherapy. Front Immunol.2022; 13: 967505.
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