Table 1.
Current progress of biomaterials and technologies to improve engineered T cell therapies
| Application | Material & Approach | Advantages & Caveats | |
|---|---|---|---|
| Cell manufacturing |
Ex vivo nonviral CAR production |
Cationic polymers[17] / Lipid nanoparticles[18] | (+) Easier to manufacture than virus (+) Higher cell visibility than electroporation (–) Limited transfection efficiency |
| In situ CAR production | PBAE polymer nanoparticles loaded with CAR transposon[19, 20] | (+) Lower time and cost than ex vivo production (–) Off-target CAR delivery |
|
| Nonviral transgene insertion |
Transposon system[21–24] | (+) Extended transgene expression (–) Semi-random gene insertion |
|
| CRISPR-Cas9[25] | (+) Extended transgene expression (+) Site-specific gene knock-in (–) Potential immunogenicity |
||
| Predictive monitoring | Multiplexed phenotyping | Combinatorial staining[26, 27] | (+) Expand the multiplexing capacity (–) Complex staining and analysis |
| Mass barcoding (CYTOF)[28–33] | (+) Low background (+) Minimal overlap between mass labels (–) Lower sensitivity than bright fluorophores (–) Samples cannot be recovered |
||
| DNA-barcoded mAb, pMHC[34, 35] | (+) High sensitivity (+) Absolute quantification (+) Theoretically limitless multiplexing capacity (–) Complicated barcode sequence design |
||
| High throughput serial analysis |
Micro-engraved arrays[36–39] | (+) Analyze ~ 104 T cells simultaneously (–) Difficult to analyze cell-cell interaction |
|
| Single cell barcoding chip[40–45] | (+) Spatial encoding increases multiplexing (+) Valves for fluidic control (+) Capable of analyzing intracellular proteins (–) Difficult to analyze cell-cell interaction |
||
| Cell pairing by hydrodynamic traps[46–48] | (+) Precise control of cell-cell interaction (–) Low throughput |
||
| In vivo PET imaging | Radiolabeled mAb[49] | (+) Spatial and temporal analysis (+) Long circulation extends monitoring time (–) Poor tumor penetration (–) Risks of radiation-induced toxicity |
|
| Radiolabeled mAb fragments & peptides[50–53] | (+) Spatial temporal analysis (+) Good tumor penetration (+) Rapid clearance lowers risks of toxicity (–) Require repeated probe injections |
||
| In vivo activity monitoring | Synthetic biomarkers[54–63] | (+) Amplification of detection signals (+) High multiplexing capacity (+) Rapid, cost-effective workflow (–) No spatial resolution |
|
| In vivo control | TME modulation | Viral peptides[64] | (+) Easy to manufacture at GMP facilities (+) Stimulate both innate and adoptive immunity (–) Rely on intra-tumoral injection (–) Require existing antiviral immunity |
| Redirection of antiviral T cells to cancer | Tumor-targeting Ab-peptide conjugates[65, 66] | (+) Deliverable by systemic injections (–) Require existing antiviral immunity |
|
| pMHC-IgG fusion protein[67] | (+) Deliverable by systemic injections (+) No chemical conjugation needed (–) Require existing antiviral immunity |
||
| Targeted modulation | T cell backpack[68, 69] | (+) Selective drug release near T cells or in TME (–) One-time dosing only |
|
| T cell-targeting nanomaterials[70–72] | (+) Allow repeated dosing (+) Broad range of cargo types (–) Off-target delivery |
||
| Remote control | Antibody-based adaptors[73–78] | (+) Modular antigen specificity (–) Lack of spatial resolution |
|
| Microbubbles + ultrasound[79] | (+) Spatial and temporal control (–) Unproven in vivo utility |
||
| Gold nanorods + thermal gene switches[80, 81] | (+) Spatial and temporal control (–) Thermal tolerance |
Abbreviations: PBAE, poly (β-amino ester); CRISPR-Cas9, clustered regularly interspaced short palindromic repeats–CRISPR-associated protein 9; TME, tumor microenvironment; mAb, monoclonal antibody; pMHC, peptide major histocompatibility complex; IgG, Immunoglobulin G; GMP, good manufacturing practice; CYTOF, cytometry by time-of-flight; PET, positron emission tomography.