Nanomaterials for T-cell cancer immunotherapy

Purpose: T-cell-based immunotherapies have shown clinical success in B-cell malignancies, but broad implementation is limited by insufficient T-cell expansion, poor trafficking into solid tumours, T-cell exhaustion in hostile tumour microenvironments, and loss of target antigen expression. Nanomaterials may uniquely overcome these barriers through rational design.

Hypothesis: No formal experimental hypothesis. Central thesis: rationally designed nanomaterials can enhance T-cell expansion in vivo, improve T-cell penetration into solid tumours, reverse immune suppression, and prevent antigen escape, thereby improving T-cell cancer immunotherapy.

Aims: Provide an overview of nanomaterials used to overcome clinical barriers to T-cell-based immunotherapies. - Discuss nanomaterials for in vivo T-cell expansion via targeted delivery, backpacking, and nanomaterial-based vaccines. - Review nanomaterials that improve T-cell engagement with solid tumours by overcoming physical barriers and immune-suppressive microenvironments. - Discuss nanomaterials to prevent target antigen loss, including nanomaterial-based bispecific T-cell engagers (NBiTEs). - Provide future outlook at the interface of cancer immunotherapy and nanomaterial design.

Delivery system: Nanomaterials: polymeric nanoparticles (poly(beta-amino ester), PLGA, PLGA-PEG), liposomes, iron nanomaterials, nanogels, multilamellar liposomal vesicles, calcium phosphate liposomes, alginate scaffolds, nickel-titanium thin films, polystyrene nanomaterials, exosomes. - Cargo/payloads: plasmid DNA encoding CAR and piggyBac transposase, cytokines (IL-2-Fc, IL-15 superagonist), TGF-β inhibitors (SB525334, SD-208, SB505124), STAT3/STAT5 inhibitor imatinib, anti-CD137 and anti-PD-L1 antibodies, PI3K inhibitor PI-3065 plus T-cell stimulator 7DW8-5, A2a adenosine receptor antagonist SCH-58261, photothermal agent indocyanine green, α-mangostin plus LIGHT plasmid, mRNA encoding CLDN6, bispecific antibodies. - Targeting/functionalization: anti-CD3ε F(ab′)2, anti-CD90, anti-PD-1, anti-CD137, anti-PD-L1, HER2, CD20, calreticulin, EGFR, CD3, peptide ligands, amphiphile CAR T-cell ligands. - T-cell therapy classes discussed: CTLs, TILs, TCR-T cells, CAR T cells.

Approach: Review of preclinical and clinical literature. Preclinical models include mouse melanoma, leukaemia, colon cancer, breast cancer, ovarian cancer, pancreatic cancer, and EGFRvIII+ glioma. Clinical stage examples include a phase 1 trial of IL-15 superagonist nanogel backpacking for solid tumours and lymphomas, and a phase 1 projected study for in vivo CAR T-cell generation via polymeric nanomaterial. Most discussed systems remain preclinical.

Key methods: T-cell expansion, proliferation, persistence, and memory/effector populations. - Tumour infiltration and penetration. - Exhaustion markers and immune-suppressive pathway inhibition. - Tumour growth inhibition, survival, and relapse in post-resection models. - Toxicity and off-target delivery. - Antibody potency and binding affinity for NBiTEs. - Cellular viability assays and in vivo imaging/biodistribution.

Key results: IL-2-Fc fusion-protein-modified liposomes delivered to the surface of >95% of adoptively transferred T cells, inducing enhanced T-cell proliferation in tumour-bearing mice. - IL-15 superagonist nanogel backpacked onto CAR T cells produced a 16-fold increase in T-cell expansion versus free IL-15Sa, with limited systemic toxicity. - Lipid nanomaterial mRNA vaccine (CARVac) encoding CLDN6 completely inhibited tumour growth in lymphodepleted mice when combined with a sub-therapeutic dose of CLDN6-CAR T cells. - Liposomal NBiTE co-conjugated with HER2 and CD20 antibodies showed a 25-fold increase in antibody potency in a cell viability assay and enhanced tumour growth inhibition versus free antibodies. - T-cell-functionalized alginate scaffold showed no tumour relapse in a post-resection breast cancer model, whereas intravenous T cells, locally administered T cells, and locally administered T cells with IL-15Sa/antibodies all relapsed. - Micropatterned nickel-titanium thin films (TFN) delivered CAR T cells with well-organized loading and enhanced central memory/effector T-cell populations without exhaustion in ovarian cancer models. - In vivo CAR T-cell generation via polymeric nanomaterial resulted in CAR expression and expansion in a mouse leukaemia model, though the nanomaterial was also found in ~5.9% of non-T blood cells, raising off-target toxicity concerns.

Interpretation: Nanomaterials have immense potential to address the major clinical barriers facing T-cell immunotherapies. They can enhance T-cell expansion, improve solid tumour penetration, modulate the immune-suppressive tumour microenvironment, and prevent antigen escape, supporting continued development of nanomaterial-based T-cell cancer immunotherapies.

Limitations: Review article; no primary data. - Most discussed systems remain preclinical; clinical data are limited. - Off-target delivery and potential toxicity remain concerns (e.g., ~5.9% non-T blood cell delivery). - Cytokine burst release, nanomaterial biodegradability, and clearance need further optimization. - Solid tumour penetration remains an obstacle even with local delivery. - Scaffolds may have random pore networks and unpredictable loading/release kinetics. - NBiTEs face short circulation times and binding affinity limitations. - Antigen escape and tumour heterogeneity remain difficult challenges. - Scale-up, manufacturing, and regulatory pathways for nanomaterial-based T-cell therapies are not yet established.