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Table 1 Summary of described technologies and challenges they address

From: Tuning CARs: recent advances in modulating chimeric antigen receptor (CAR) T cell activity for improved safety, efficacy, and flexibility

Category

CAR Control Technologies

Challenges Addressed

Mechanisms

1. Elimination of therapeutic cells

HSV-TK

iC9

FADD

CD20/Rituximab

EGFRt/Cetuximab

Cytosine deaminase

Death signalobody, SFas

Uridine metabolic switch

Safety

Incorporated genetic mechanism for on-demand cell elimination

2. Regulation of CAR gene expression

Tet-ON

Res controlled CAR

Zinc finger TF-based switch system

LINTAD

ReCoM

Photothermal switch CAR

FUS-CAR system

HiCAR

HypoxiCAR

SynNotch logic CAR

Safety

Efficacy

Flexibility

Spatiotemporal control of CAR abundance limits off-tumor activity

Prevent T cell exhaustion

Controlling CAR expression location or using AND-logic provides access to more target antigens

3. Inducible CAR protein degradation

SWIFF-CAR

Lenalidomide-induced CAR degradation

PROTAC-mediated CAR degradation

Safety

Temporal regulation of CAR protein activity and abundance

4. Inducible formation of a functional CAR or inducible CAR disassembly

ON-switch split CAR

DARRIC

AvidCAR

Lenalidomide ON switch split CAR

Lipocalin-based ON-switch CAR

FKBP/FRB-mcCAR

LiCAR

CRASH-IT switch CAR

STOP-CAR

Minocycline TetCAR

CondCAR OFF-switch CAR

Safety

Efficacy

Temporal regulation of CAR protein activity and abundance

Prevent T cell exhaustion

5. Inhibitory CARs

iCAR

Double-Arm CAR

iKP (KIR2-PD1) CAR

Tmod2 CAR

NASCAR

anti-HLA-DR iCAR

Safety

Efficacy

Flexibility

Limited off-tumor CAR activity

Improved precision of antigen targeting

More target antigens available (NOT-logic)

6. Modular universal adaptor CAR platforms

FcR-based ADCC CAR

Anti-FITC CAR

BBIR CAR

mSA2 CAR

AdCAR

PNE specific CARs

Convertible CAR

Cp-Fab CAR

SpyCatcher CAR

SNAP-CAR

UniCAR

RevCAR

SUPRA CAR

bsCAR

Safety

Efficacy

Flexibility

Dose-dependent control of CAR abundance

Simultaneous targeting of multiple antigens available

Modular design for easy antigen retargeting

  1. Category: corresponds to the respective review section. CAR Control Technologies: a list of technologies described in the section. Challenges Addressed: this column provides information about three challenges related to CAR cell control that were addressed with the described technologies. Mechanism: a short description of how each challenge was addressed using the described technologies