Table 1

Seminal preclinical nuclear-based, MRI and ultrasound studies employing direct and indirect molecular imaging for the in vivo monitoring of T cell-based immunotherapies and their immune-related components

Immune Cell	Molecular Target	Imaging agent	Labeling approach	Reporter Gene	Imaging modality	Ref
T lymphocyte	n/a	⁸⁹Zr-oxine	Direct	n/a	PET	15
T lymphocyte	n/a	¹¹¹In-oxine	Direct	n/a	SPECT	16
T lymphocyte	n/a	¹⁸F]MFBG and(¹²³I/¹²⁴I)MIBG, ¹²⁴I, ¹⁸F-FEAU, ¹²⁴I-FIAU	Indirect	hNET, hNIS, dCKDM, HSV1-tk	PET	26
T lymphocyte	n/a	¹²⁴I scFv antibody fragment	Indirect	CEA N-A3	PET	23
T lymphocyte	n/a	¹²⁴I-FIAU	Indirect	HSV1-tk, GFP	PET	43
T lymphocyte	Pan-ErbB CAR	(¹⁸F)BF₄^-	Indirect	hNIS	PET	27
T lymphocyte	CD19 CAR	(¹⁸F)DCFPyL	Indirect	tPSMA^(N9del)	PET	28
T lymphocyte	GD2 CAR	(¹⁸F)TMP	Indirect	eDHFR	PET	29
T lymphocyte	CD19 CAR	⁸⁶Y-AABD	Indirect	DAbR1	PET	30
T lymphocyte	EGFRvIII CAR	¹⁹F-PFC	Direct	n/a	MRI	75
T lymphocyte	CD19 CAR	n/a	Indirect	Heat-inducible-GFP-PGK-mCherry	MRI-guided FUS	8
T lymphocyte	OX40	⁶⁴Cu-DOTA-AbOX40	Direct	n/a	PET	77
T lymphocyte	ICOS	⁸⁹Zr-DFO-ICOS	Direct	n/a	PET	76
T lymphocyte	IL-2	(¹⁸F)FB-IL-2	Direct	n/a	PET	78
T lymphocyte	TCR	⁶⁴Cu-DOTA-KJ1-26	Direct	n/a	PET	79
T lymphocyte	CD3	⁸⁹Zr-DFO-CD3	Direct	n/a	PET	80 81
T lymphocyte	CD4	⁸⁹Zr-GK1.5 cDb	Direct	n/a	PET	82
T lymphocyte	CD8	⁸⁹Zr- malDFO-169 cDb and ⁶⁴Cu-169 cDb	Direct	n/a	PET	38 83
T lymphocyte	CD4/CD8	(¹²³I)MIBG/(¹²⁴I)FIAU	Indirect	hNET/ HSV1-tk	SPECT/ PET	22
T lymphocyte	CD8	SPIO	Direct	n/a	MRI	84
T lymphocyte	Granzyme B	⁶⁸Ga-NOTA-GZP	Direct	n/a	PET	41
T lymphocyte	IFN-gamma	⁸⁹Zr- IFN-gamma	Direct	n/a	PET	42
T lymphocyte	n/a (phosphorylated by TK₁)	(¹⁸F)FLT	Direct	n/a	PET	54 62
T lymphocyte	dGK	(¹⁸F)F-AraG	Direct	n/a	PET	85
T lymphocyte	dCK	(¹⁸F)CFA,(¹⁸F)FAC,(¹⁸F)FACB	Direct	n/a	PET	86 87
T lymphocyte	PD-1	⁶⁴Cu- PD-1, ⁶⁴Cu-DOTA- PD-1, ⁶⁴Cu-NOTA-PD-1, ⁸⁹Zr-Df-Pembrolizumab, ⁸⁹Zr-Df-Nivolumab	Direct	n/a	PET	47 48 88 89
T lymphocyte	PD-L1	^99mTc, ¹¹¹In, ¹¹¹In-DTPA, ⁸⁹Zr-DFO, ⁶⁴Cu, ⁶⁴Cu-DOTA, ⁶⁸Ga-NOTA, ¹⁸F-BMS-986192	DIrect	n/a	SPECT/PET	36 46 50 51
T lymphocyte	CTLA-4	⁶⁴Cu-DOTA- and NOTA-Ipilimumab	Direct	n/a	PET	52 53
T lymphocyte	LAG-3	^99mTcO₄^-, ⁸⁹Zr-REGN3767	Direct	n/a	SPECT, PET	55 56
T lymphocyte	TIM-3	⁶⁴Cu-NOTA-RTM3-23	Direct	n/a	PET	57
T lymphocyte	TIGIT	⁸⁹Zr- and ⁶⁴Cu-AB154	Direct	n/a	PET	58
Treg	n/a	^99mTcO₄^-	Indirect	hNIS	SPECT	33
Treg	IL-10-HLA-A2 CAR	^99mTcO₄^-	Indirect	hNIS	SPECT	34
Gamma delta T lymphocyte	n/a	⁸⁹Zr-oxine	Direct	n/a	PET	35
NK	n/a	⁸⁹Zr-oxine	Direct	n/a	PET	60
NK	n/a	(¹⁸F)FDG	Direct	n/a	PET	59
NK	n/a	¹⁹F-PFC, ¹⁹F, Ferumoxides/ Ferucarbotran	Direct	n/a	MRI	59
DC	n/a	(¹⁸F)BF₄^-	Indirect	hNIS	PET	65
DC	n/a (phosphorylated by TK₁)	(¹⁸F)FLT	Direct	n/a	PET	62
DC	n/a	¹⁹F-PFC, ¹⁹F, SPIO	Direct	n/a	MRI	61 64
DC	n/a	n/a	Indirect	Ferritin	MRI	66
Macrophages	n/a	SPION ferumoxytol	Direct	n/a	MRI	67
Monocytes/ macrophages	CD40	⁸⁹Zr-TRAF6i-HDL	Direct	n/a	PET	90
Monocytes	n/a	¹⁹F-PFC	Direct	n/a	MRI	68

BI, Boehringer Ingelheim; BMS, Bristol-Myers Squibb; CAR, chimeric antigen receptor; CEA, carcinoembryonic antigen; DC, dendritic cell; dCK, Deoxycytidine kinase; Df or DFO, Deferoxamine; dGK, Deoxyguanosine; DOTA, 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid; eDHFR, Escherichia Coli dyhydrofolate reductase; EGFRvIII, Epidermal Growth Factor Receptor variant III; [¹⁸F]BF₄, Tetrafluoroborate; [¹⁸F]CFA, [¹⁸F]Clorafabine; [¹⁸F]DCFPyL, Piflufolastat fluorine ¹⁸F; [¹⁸F]FAC, 1-(2’-deoxy-2’-¹⁸F-fluoroarabino-furanosyl) cytosine; [¹⁸F]F-AraG, 2’-deoxy-2’-¹⁸F-fluoro-9β-D-arabinofuranosyl-guanine; [¹⁸F]FB-IL-2, N-(4-¹⁸F fluorobenzoyl_interleukin-2; [¹⁸F]FDG, [¹⁸F]fluorodeoxyglucose; [¹⁸F]FHBG, 9-(4-(18)F-Fluoro 3[hydroxymethyl]butyl)guanine; [¹⁸F]FIAU, 2’-deoxy-2’-[¹⁸F]-fluoro-1-beta-D-arabinofuranosyl-5-iodouracil; [¹⁸F]FLT, [¹⁸F]fluorothymidine; (¹⁸F)TMP, (¹⁸F)fluoropropyl-trimethoprin; FUS, Focused Ultrasound; ⁶⁸Ga-NOTA-hGZP, ⁶⁸Gallium-1,4,7-Triazacyclononane-1,4,7-triacetic acid-human biotin βAla-GGG-IEPD-CHO; GRm13Z40, Interleukin-13 zetakine Receptor Alpha 2-targeted CAR; hNET, human norepinephrine transporter; hNIS, human sodium iodide symporter; [¹²⁴I]FIAU, ¹²⁴I-2’-fluoro-deoxy-1-beta-D-arabinofuranosyl-5-iodouracil; ^[123I^]MIBG, ^[123I^]metaiodobenzylguanidine; n/a, not available; NK, natural killer; PET, positron emission tomography; PFC, Perfluorocarbon; P28z, PSMA-targeted CD28z CAR ; SPECT, single photon emission computed tomography ; SPION, superparamagnetic iron oxide nanoparticle; TRAF6, tumor necrosis factor receptor-associated factor 6; ⁸⁶Y-AABD, ⁸⁶Yttrium (S)-2-(4-acrylamidobenzyl)-DOTA.