Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy

Bulliard, Yannick; Andersson, Borje S.; Baysal, Mehmet A.; Damiano, Jason; Tsimberidou, Apostolia M.

doi:10.1186/s13045-023-01504-7

Journal of Hematology & Oncology

Table 1 List of factors involved in T cell memory or dysfunction evaluated in the context of adoptive cell transfer

From: Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy

Factor	Type	Adoptive transfer setting	Functional improvement in vivo (overexpression/downregulation)	References
Positive regulators of stemness for overexpression strategy in CAR-T therapy
BCL-6	Zinc finger C2H2-type BTB domain-containing TF	OVA-specific murine CD8 + T cell	Improved memory response over 4 weeks (OVA-pulsed DC) or 10 weeks (VV-OVA)	[122]
cJUN	Basic leucine zipper TF	CD19, CD22, HER2, and GD2-specific human CAR-T cells	Improved intratumoral T cell function and efficacy, particularly in low antigen density setting	[123]
cJUN	Basic leucine zipper TF	Murine CD19 CAR-T cells	No improvement compared to unmodified CAR-T cells	[84]
TCF-1	TCF/LEF TF	GP33-specific murine TCR-T cells	Greater levels of cytokine production, improved antitumor response and recall response	[131]
TCF-1	TCF/LEF TF	HER2-specific CAR-T cells	Improved expansion upon rechallenge	[128]
FOXO1	Forkhead boxes TF	HER2-specific CAR-T cells	Improved expansion upon rechallenge	[128]
BATF	Basic leucine zipper TF	Murine CD19 CAR-T cells	Improved intratumoral CAR cytokine production, decreased expression of checkpoint inhibitors and TOX, increased memory response	[84]
LEF-1	TCF/LEF TF	GD2-specific CAR-T cells	Improved antitumor response and survival	[127]
BACH2	BTB domain-containing, basic leucine zipper TF	SIY peptide-specific murine TCR-T cells	Improved antigen recall response	[79]
SOX4	SRY-box TF	SIY peptide-specific murine TCR-T cells	Improved antigen recall response	[79]
RUNX3	Runt-related TF	GP33-specific murine TCR-T cells	Improved antitumor response and survival	[130]
Positive regulators of dysfunction for downregulation strategy in CAR-T therapy
BATF	Basic leucine zipper TF	Mesothelin-specific CAR-T cells	Improved antitumor response and survival. Increased tumor infiltration, IFN-γ production and proliferation	[125]
DNMT3A	DNA/RNA methyltransferase	EphA2, HER2 and IL-13Rα2-specific CAR-T	Improved antitumor response and survival, longer persistence and greater multipotency index	[132]
SUV39H1	Lysine methyltransferase	OVA-specific murine CD8 + T cells	Improved recall response to secondary bacterial infection	[133]
NR4A1	Nuclear receptor subfamily 4 group A	OVA-specific murine CD8 + T cells	Improved antitumor response, increased IFN-γ production, and decreased expression of TIM-3 and PD-1	[91]
NR4As	Nuclear receptor subfamily 4 group A	CD19-specific murine CAR-T cells	Improved antitumor response, increased IFN-γ production, and decreased expression of TIM-3 and PD-1	[118]
TOX + TOX2	Thymocyte selection-associated high-mobility group box TFs	CD19-specific murine CAR-T cells	Improved antitumor response and survival, increased IFN-γ and TNF production, and decreased expression of TIM-3, PD-1, and LAG-3	[112]
TOX	Thymocyte selection-associated high-mobility group box TFs	GP33-specific murine TCR-T cells	No pharmacokinetic difference during acute infection. Rapid decline of blood T cell during chronic infection, despite lower level of checkpoint inhibitor expression. Lower levels of TCF-1 Monoallelic TOX deletion improves antitumor activity	[111]
		TAG-epitope-specific murine TCR-T cells	No functional or phenotypic difference after immunization Decreased infiltration of liver tumor and increased levels of apoptosis, despite lower level of checkpoint inhibitor expression	[88]
		GP33-specific murine TCR-T cells	Increased response to acute infection (transient). Survival deficit in the blood during chronic infection. Lower frequency of TCF-1 + T cells	[134]
BLIMP-1 + NR4A3	BLIMP-1: PR/SET domain family, zing fingers C2H2-type NR4A3: Nuclear receptor subfamily 4 group A	PSMA-specific CAR-T cells	Improved antitumor response and survival, increased IFN-γ, TNF, and IL-2 production, increased TCF-1 and decreased TIM-3 and PD-1 expression	[93]
ARID1A	BAF complex, AT-rich interaction domain containing	OVA- and B7-H3-specific murine CAR-T cells *ARID1A was blocked with a small molecule inhibitor	Improved antitumor response and survival and increased persistence of CD62L + T cells at day 30	[135]
ARID1A	BAF complex, AT-rich interaction domain containing	OVA-specific murine CD8 + T cells	Improved antitumor response and survival	[136]
HPK1	Mitogen-activated protein 4 kinase	CD19-, HER2-, and BCMA-specific CAR-T cells	Improved antitumor response and survival, greater tumor infiltration, increased expression of CD107a, TNF and granzyme B, and decreased expression of PD-1, TIM-3, and LAG-3	[137]
BTG1	BTG/Tob family	GD2-specific CAR-NKT cells	Improved antitumor response and survival	[138]
PD-1	V-set domain-containing immunoglobulin	CD19-, HER2-, and BCMA-specific CAR-T cells	Improved antitumor response and survival, greater tumor infiltration, increased expression of CD107a, TNF, and granzyme B, and decreased expression of PD-1, TIM-3, and LAG-3	[137]
PD-1	V-set domain-containing immunoglobulin	GP33-specific murine T cells	Decreased IFN-γ and TNF expression after stimulation with LCMV clone 13 (chronic model of viral infection) and diminished long-term proliferation	[139]

These modulators represent engineering modifications of potential interest for CAR-T cell therapeutics, with the common aim to stably imprint memory function or limit dysfunction or exhaustion

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