Delivery technologies for cancer immunotherapy

Abstract

Immunotherapy has become a powerful clinical strategy for treating cancer. The number of immunotherapy drug approvals has been increasing, with numerous treatments in clinical and preclinical development. However, a key challenge in the broad implementation of immunotherapies for cancer remains the controlled modulation of the immune system, as these therapeutics have serious adverse effects including autoimmunity and nonspecific inflammation. Understanding how to increase the response rates to various classes of immunotherapy is key to improving efficacy and controlling these adverse effects. Advanced biomaterials and drug delivery systems, such as nanoparticles and the use of T cells to deliver therapies, could effectively harness immunotherapies and improve their potency while reducing toxic side effects. Here, we discuss these research advances, as well as the opportunities and challenges for integrating delivery technologies into cancer immunotherapy, and we critically analyse the outlook for these emerging areas.

Figures

Fig. 1 ∣. Paradigms in cancer nanomedicine.

a,b ∣ For decades, cancer nanomedicine has focused on the delivery of therapeutics into tumours via passive targeting mechanisms by exploiting the enhanced permeation and retention (EPR) effect mediated through leaky tumour vessels (part a) or active targeting mechanisms in which nanoparticles are functionalized with targeting ligands that specifically bind receptors on the surfaces of tumour cells (part b).c ∣ New paradigms that use nanomedicine to engage immune cells are emerging. These nanomedicines induce cytotoxic antitumour T cell responses rather than deliver drugs to the tumour. Strategies that use these new approaches include nucleic acid vaccines and the direct targeting of T cells in the circulation or ex vivo. Parts a and b are adapted with permission from REF., Elsevier. Part c is adapted from REF., Springer Nature Limited.

Fig. 2 ∣. Barriers to mRNA cancer vaccine delivery to dendritic cells.

Various non-viral vectors can be engineered to deliver mRNA to dendritic cells in vivo. These vectors need to prevent degradation of the mRNA by serum endonucleases and evade macrophage detection (which could be achieved by chemical modifications and encapsulation of nucleic acids). They also need to avoid renal clearance from the blood and prevent nonspecific interactions (by using polyethylene glycol (PEG) or through particle design). Moreover, these vectors need to extravasate from the bloodstream to reach dendritic cells in target tissues and mediate dendritic cell entry and endosomal escape. Once mRNA is in the cytosol, it is translated into the antigenic peptide, which is then processed into smaller peptide epitopes that bind to the major histocompatibility complex (MHC) class I or class II molecules. The MHCs are trafficked to the cell surface, where they present their antigenic epitopes to either CD8+ (cytotoxic) T cells or CD4+ (helper) T cells, leading to a cytotoxic T cell response or an antigen-specific antibody response, respectively. The order of the steps of mRNA entry and processing is shown by sequential numbering. Figure adapted from REFS,, Springer Nature Limited.

Fig. 3 ∣. Nanoparticles and nanoscale conjugates and delivery systems for cancer immunotherapy.

a ∣ Lipid nanoparticles typically consist of an ionizable lipid, a helper lipid, cholesterol and polyethylene glycol (PEG)–lipid. The nucleic acids are incorporated into the hydrophilic interior of the nanoparticle. b ∣ Structures of off-the-shelf lipids that have been investigated for nucleic acid delivery and, more recently, for mRNA vaccines are shown. Also included is the structure of DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine), a helper lipid that imparts efficacy to lipid nanoparticle formulations, c ∣ Structures of ionizable, lipid-like materials designed through combinatorial chemistry techniques for improved in vivo mRNA delivery with reduced toxicity. d ∣ The structure of an amphiphilic peptide–vaccine conjugate designed to bind to albumin in the bloodstream for improved delivery to lymph nodes is shown. e ∣ A matrix-binding checkpoint inhibitor conjugate that has improved retention in the peritumoural space to trigger an immune response. The checkpoint inhibitor is bound to a peptide of placental growth factor 2 (PLGF2) using an amine-to-sulfhydryl crosslinker. The PLGF2 peptide mediates binding to proteins in the extracellular matrix (ECM). DOTAP, 1,2-dioleoyl-3-trimethylammonium-propane; DOTMA, 1,2-di-O-octa-decenyl-3-trimethylammonium-propane; DSPC, 1,2-distearoyl-sn-glycero-3-phosphocholine; SMCC,sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate. Part a is adapted from REF., Springer Nature Limited. Part d is adapted from REF., Springer Nature Limited. Part e is adapted with permission from REF., Science/AAAS.

Fig. 4 ∣. Biomaterials for localized delivery of cancer immunotherapy.

a ∣ Mesoporous silica rods (MSRs) spontaneously assemble in vivo and recruit host cells for maturation. A phosphate buffered saline (PBS) dispersion of MSRs is injected into the subcutaneous tissue of mice to form a pocket. After diffusion of PBS from the pocket, in situ spontaneous assembly of MSRs, analogous to the random assembly of thrown matchsticks, results in the formation of 3D interparticle spaces into which host cells can be recruited and educated by the therapeutics delivered with the MSRs. Educated cells can then emigrate from the structure to interact with other immune cells. b ∣ In another approach, a microneedle-based transcutaneous platform loaded with self-assembled immunotherapeutic nanocarriers was used. Nanoparticle-mediated encapsulation and release of the indoleamine 2,3-dioxygenase (IDO) inhibitor 1-MT and an anti-programmed cell death 1 (PD-1) antibody from self-assembled nanoparticles are mediated through a multistep process. First, the 1-MT is conjugated to hyaluronan (HA), then this conjugate self-assembles around the anti-PD-1 antibody to form a nanoparticle for delivery. Once it has been delivered, the nanoparticle is dissociated by hyaluronidase (HAase), resulting in release of the drugs into the tumour microenvironment. These therapeutics can be delivered using microneedles as shown. c ∣ A subcutaneously delivered porous biomaterial scaffold that releases a chemoattractant recruits naive dendritic cells into its void space. Scaffold-resident dendritic cells are exposed to tumour antigens and adjuvants, resulting in increased presentation of peptides on major histocompatibility complex (MHC)–peptide complexes and phenotypic maturation. Mature dendritic cells traffic out of the scaffold to lymph nodes, where they can stimulate antitumour immunity.

Fig. 5 ∣. Delivery approaches for T cell-based immunotherapy.

a ∣ Therapeutic T cell engineering via surface-conjugated synthetic nanoparticles. Nanoparticles can be stably conjugated to the surfaces of T cells via cell surface thiols for improved adoptive T cell therapy. b ∣ Programming T cells in situ via DNA nanocarriers. A schematic of the T cell-targeted DNA nanocarrier used to programme T cells, including fabrication of the poly(β-amino ester) (PBAE) nanoparticles for encapsulation of DNA, is shown. Nanoparticles are then coated with polyglutamic acid (PGA) to shield the positive charge and functionalized with an anti-CD3 antibody to mediate binding to T cells in the bloodstream. A nuclear localization signal (NLS) and a microtubule-associated sequence (MTAS) can be added to target the DNA to the nucleus. c ∣ Strategies for synthetic artificial antigen-presenting cell (aAPC) design. A representation of a classic micro-aAPC with surface-bound signal 1 (anti-CD3 antibody, major histocompatibility complex (MHC) multimer and other components; shown in blue) and signal 2 (anti-CD28 antibody, anti-4-1BB antibody and other components; shown in grey) molecules to initiate T cell expansion and activation is shown. Nanoscale aAPCs are less efficient T cell activators but may outperform micro-aAPCs in vivo owing to their transport properties. Recent findings suggest that ellipsoidal nano-aAPCs activate T cells more efficiently than spherical nano-aAPCs owing to increased contact surface area. CAR, chimeric antigen receptor; PEG, polyethylene glycol. Part a is adapted from REF., Springer Nature Limited. Part b is adapted from REF., Springer Nature Limited. Part c is adapted with permission from REF., Elsevier.