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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Adv Healthc Mater. 2021 Apr 22;10(15):e2100157. doi: 10.1002/adhm.202100157

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[2124] (+) 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)[2833] (+) 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[3639] (+) Analyze ~ 104 T cells simultaneously
(–) Difficult to analyze cell-cell interaction
Single cell barcoding chip[4045] (+) Spatial encoding increases multiplexing
(+) Valves for fluidic control
(+) Capable of analyzing intracellular proteins
(–) Difficult to analyze cell-cell interaction
Cell pairing by hydrodynamic traps[4648] (+) 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[5053] (+) Spatial temporal analysis
(+) Good tumor penetration
(+) Rapid clearance lowers risks of toxicity
(–) Require repeated probe injections
In vivo activity monitoring Synthetic biomarkers[5463] (+) 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[7072] (+) Allow repeated dosing
(+) Broad range of cargo types
(–) Off-target delivery
Remote control Antibody-based adaptors[7378] (+) 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.