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Improving cancer immunotherapy through nanotechnology

Abstract

The 2018 Nobel Prize in Physiology or Medicine was awarded to pioneers in the field of cancer immunotherapy, as the utility of leveraging a patient’s coordinated and adaptive immune system to fight the patient’s unique tumour has now been validated robustly in the clinic. Still, the proportion of patients who respond to immunotherapy remains modest (~15% objective response rate across indications), as tumours have multiple means of immune evasion. The immune system is spatiotemporally controlled, so therapies that influence the immune system should be spatiotemporally controlled as well, in order to maximize the therapeutic index. Nanoparticles and biomaterials enable one to program the location, pharmacokinetics and co-delivery of immunomodulatory compounds, eliciting responses that cannot be achieved upon administration of such compounds in solution. The convergence of cancer immunotherapy, nanotechnology, bioengineering and drug delivery is opportune, as each of these fields has matured independently to the point that it can now be used to complement the others substantively and rationally, rather than modestly and empirically. As a result, unmet needs increasingly can be addressed with deductive intention. This Review explores how nanotechnology and related approaches are being applied to augmenting both endogenous leukocytes and adoptively transferred ones by informing specificity, influencing localization and improving function.

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Fig. 1: Nanotechnology can substantially improve the utility of adoptive-cell therapy.
Fig. 2: Nanoparticles can be used to modulate endogenous immune cells in situ.
Fig. 3: Co-formulation of vaccine components dramatically improves effector responses.
Fig. 4: Nanoparticle carriers are needed to deliver immunomodulatory payloads efficiently into the cytosol of immune cells.
Fig. 5: Perioperative immunotherapy represents a high-leverage context for improving the frequency and magnitude of antitumour immune responses.

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Acknowledgements

The author thanks W. Rindler for helpful comments.

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Correspondence to Michael S. Goldberg.

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M.S.G. is an inventor on patent applications related to ref.53 (Schmid et al., 2017) and ref.104 (Park et al., 2018). M.S.G. is also an employee of STIMIT.

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Nature Reviews Cancer thanks J. T. Wilson, J. Tel and the other, anonymous, reviewer for their contribution to the peer review of this work.

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Glossary

Therapeutic index

The ratio of efficacy to safety, which compares the amount of a drug that produces the therapeutic effect to the amount that causes toxicity.

Immune tolerance

A state of unresponsiveness by the immune system to antigens that allows for discrimination of self from non-self and is inappropriately fostered by tumours.

Area under the curve

(AUC). A pharmacokinetic parameter that represents total drug exposure by describing a quantitative relationship between drug concentration in the blood and time.

Immunoengineering

A burgeoning field that incorporates the tools and approaches of bioengineering, materials science, nanotechnology, drug delivery and immunology to influence the immune system — particularly, to elicit robust antitumour immune responses — in a manner not achieved by the administration of the same molecules in solution.

Pattern recognition receptors

Host sensors that can detect molecules associated with pathogens and/or cellular damage, thus inducing innate immunity, typically through the production of pro-inflammatory cytokines.

Liposomes

Spherical vesicles composed of at least one lipid bilayer that are often used to entrap and deliver therapeutics.

Enhanced permeability and retention

(EPR). A proposed effect that suggests that molecules and particles of a certain size concentrate in tumours more so than in other tissues, owing to the leaky vasculature and poor lymphatic drainage of solid tumours.

Mesoporous silica rods

A biomaterial that exhibits a high aspect ratio, enabling spontaneous assembly to form a three-dimensional microenvironment for host immune cells.

Synthetic biology

An intersection of biotechnology and molecular biology in which biological modules and systems are devised and created, with a particular emphasis on the incorporation of logic gates and other computer-like operations involving inputs, signal integration and outputs.

Lyophilization

Also known as freeze drying, a process in which water is removed from a sample under vacuum via sublimation following freezing.

Adjuvant

A molecule that augments immune responses to antigens (for example, Toll-like receptor agonists).

Neoantigens

An antigen that is created by a gene fusion or somatic mutation.

Nanodiscs

Structures comprising a lipid bilayer and amphipathic membrane-stabilizing proteins.

Immunogens

Antigens that are immunogenic, provoking a cellular and/or humoral immune response.

Aptamer

An oligonucleotide, typically identified through in vitro selection, that binds to a target of interest.

Cyclic dinucleotide pharmacophores

Molecular structures defined by a closed ring comprising two nucleotides that are recognized by the innate immune pattern recognition receptor stimulator of interferon genes (STING).

Polymersomes

Polymeric analogues of liposomes that can serve as an artificial vesicle to entrap drug-containing solutions, often affording greater control over particle stability and drug release rate.

Block copolymer

A polymer comprising two or more homopolymer blocks, connected via covalent bonds, that can confer blended or combined properties of the individual blocks.

Nanogels

Nanoparticulate forms of a hydrogel (a crosslinked hydrophilic polymer network).

Mass cytometry

Also known as cytometry by time of flight (CyTOF), a mass spectrometry-based variation of flow cytometry in which antibodies are labelled with heavy metal ions that have discrete masses, rather than with fluorophores that can have spectral overlap.

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Goldberg, M.S. Improving cancer immunotherapy through nanotechnology. Nat Rev Cancer 19, 587–602 (2019). https://doi.org/10.1038/s41568-019-0186-9

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