Functional drivers of resistance to anti-CD19 CAR-T cell therapy in diffuse large B cell lymphoma

Figures & data

Table 1. Infusion product characteristics associated with response to CAR-19 therapy.

Study	Sample collection	Cell features associated with CR	Cell features associated with PD
Rossi et al. [21]	Infusion product	CD4+ and CD8+ T-cells with high PSI	Decreased T effector cells
Locke et al. [13]	Infusion product	CCR7 + CD45RA + T-cells with a negative doubling time; increased CD8+ cells	NR
Deng et al. [22]	Infusion product	CD8 + CCR7+ central memory T-cells	LAG3 + TIM3+ CD8+ T-cells
Chen et al. [42]	Pre/post CAR-T biopsies	CD8 + PD-1+ T-cells	NR
Scholler et al. [26]	Pre/post CAR-T biopsies	CD8 + PD-1+ T-cells	NR
Good et al. [24]	Post CAR-T peripheral blood	CD57 + T-bet + CAR-T cells	CD4 + CD57-Helios + Tregs
Worel et al. [23]	Peripheral blood and infusion product	Low CD3 + CD27-CD28- T-cells	CD3 + CD4+ T-helper cells

Abbreviations: CR: complete response; PD: progressive disease; Tregs: T-regulatory cells; NR: not reported.

Table 2. TME features associated with response to CAR-19 therapy.

Study	Sample collection	TME features associated with CR	TME features associated with PD
Locke et al. [13]	Infusion product	NR	High TB, myeloid activation markers, excess type 1 cytokines
Chen et al. [42]	Pre/post CAR-T biopsies	Non-CAR activated T-cells	Non-CAR lymphocytes/monocytes producing IL-6
Jain et al. [16]	Pre CAR-T biopsies	NR	Macrophage infiltration, peripheral blood M-MDSCs, high ferritin, CRP, and IL-6
Scholler et al. [26]	Pre/post CAR-T biopsies	PD1 + LAG3+/-TIM3-CD8+ cells; modest Tregs; high IL-15, IL-17, IL-18, IL-21	NR

Abbreviations: CR: complete response; PD: progressive disease; M-MDSC: monocytic myeloid derived suppressor cell; NR: not reported.

Table 3. Genomic factors associated with CAR-19 response in r/r DLBCL.

Study	Sample #, type, technique	CAR-19 Product	Genomic Markers	Associated CAR-19 Responses
Zhang et al. [30]	2, tumor, WES	BinD19 (NCT03156101)	CD19: exon 3, p.174 L > V	No response
Spiegel et al. [31]	44, tumor, IHC	Axi-cel	CD19 expression (low/absent)	Relapse
Shouval et al. [33]	82, tumor, WES	Axi-cel, liso-cel, tisa-cel	TP53: mutations or CNAs	Inferior CR & ORR
Hill et al. [35]	96, tumor, WES	Axi-cel, tisa-cel	Mutations in: MYC, BCL2, CDKN2A, KLHL6	Inferior PFS
			Mutations in: BTG2, MYD88, CD79B	Favorable PFS
Sworder et al. [15]	138, ctDNA, WES	Axi-cel	Mutations in TMEM30A, P2RY8, IRF8, TP53, CD19 CNAs in PD-L1 & PD-L2	Inferior EFS
Jain et al. [16]	49, tumors, WGS	Axi-cel	Chromothripsis, double minutes, APOBEC mutational signature, ROS damage, 3p21.31 deletion	Inferior PFS
Cherng et al. [37]	122, cfDNA, WGS	Axi-cel, liso-cel, tisa-cel	high focal CNA, 10q23.3 deletion	Inferior PFS, OS

Abbreviations: WES: whole exome sequencing; IHC: immunohistochemistry; CAN: copy number alteration; CR: complete response, ORR: overall response rate; PFS: progression-free survival; EFS: event-free survival; ROS: reactive oxygen species.

Figure 1. CAR-19 resistance is driven by infusion product, TME, and tumor-intrinsic mechanisms. Whole-genome sequencing (WGS) revealed complex LBCL genomes in association with poor CAR-19 outcomes, and a variety of studies implicate deregulation of specific genes, but functional laboratory studies are lacking. The relationship between tumor genomes and tumor microenvironments (TMEs) also remains undefined.

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