Prioritization schema for immunotherapy clinical trials in glioblastoma

Figures & data

Table 1. Prioritization “Score Card” for glioblastoma immunotherapeutics.

Target	Frequency of target expression	0–33% (1)
		34–66% (2)
		66–100% (3)
	Therapeutic targeting has benefit in other malignancy	1
	Homogeneous tumor expression	1
	Expression is sustained at recurrence	2
	Mechanism of resistance	1
	Specificity of expression in the tumor	1
Immune activation and effector response	Activating component (i.e., costimulation, TLR)	1
	Trafficking to the tumor microenvironment	1
	Maintenance of effector response within tumor	1
Agent: Preclinical	Glioma cancer stem cell activity	2
	Efficacy in preclinical model	Other model (1)
		Clonotypic (1)
		Xenograft/*GEMM (2)
	Acceptable toxicity profile	2
	Hits target (if known) in vivo	2
Agent: Clinical	Clinical activity in GBM	3
	Extreme responders	2
	Combinatorial data	2
	Acceptable phase I safety data	2

Abbreviation: *GEMM, genetically engineered murine model (of glioma).

Table 2. Priority scores for glioblastoma immunotherapeutics with published clinical data.

							Immune checkpoints				Adoptive cellular
Therapeutic approach			CDX 110	TGF-βAnti-sense	HSP-96	EGFR Ab	Anti-CTLA-4	Anti-PD-1PD-L1	Anti-IL-2Rα	CSF-1R inhibitor	DCs	NK/LAK	CMV T cell	IL13Rα2CAR	IL-12
Antigen/ Target	Expression frequency	0–33% (1)34–66% (2)66–100 (3)	1^23-25	3^126	3^105,127	2^26,128,129		1^10		1^130	3^15-17,131		3^15-17,131	3^132,133
	Benefit in other malignancy	1		1^134-136	0^14,137		1^47,138	1^48,139-144		1^59,60	1^145-147			1^148-150	1^94
	Homogeneous expression	1			1^105,127	1^26,128,129				1^57,151	1^16,17,131			1^132,133
	Persistence at recurrence	2	2^152,153	2^126		2^26,128,129		1^9			2^65	2^65
	Mechanism of resistance	1	1^152,153			1^26,128,129
	Specificity of expression in the tumor	1	1^23-25								1^23-25			1^132,133
Immune activation and effector response	Immune activation	1	1^4,5		1^127	1^154	1^155-157				1^22,31,34,35,37,38,40		1^65	1^158	1^89-91
	Trafficking to the tumor	1	1^159		1^105		1^155-157	1^8		1^58,160,161	1^22,34,35,37,40		1^65	1^158	1^89,91
	Maintenance of effector response within tumor	1			1^105		1^8,157	1^8,162			1^22,34,35,37,40			1^158	1^89
Agent:Preclinical	Anti-stem cell activity	2		2^163,164		2^165					2^166-168			2^169	2^92
	Efficacy in preclinical models	Other (1)Clone (1)Xenograft/*GEMM (2)	1^170,1712^4	1^43-452^164		1^1652^154	2^8,155,172,173	2^8,162	1^532^174	1^58,1601^58,1602^58,160	1^221^22,34,35,37,402^22	1^175-1772^178,179	1^61,65	1^1692^158	1^89,902^89,90,180
	Acceptable toxicity profile	2	2^4,159,181	2^182	2^105	2^154,183	2^47,184-190	2^48,49,139-144	2^54,174	2^58,60,160	2^22,40,98,191-195	2^62,63	2^65	2^70	2^90,93,196
	Hits target in vivo	2	2^4,197				2^8,172,173	2^8,162	2^174	2^58,160	2^22,37	2^178,179		2^158,169	2^90
Agent: Clinical	Clinical activity in GBM	3	3^27,29	3^46	3^104,105				3^54		3^22,30-35,98	3^62-64	3^60,64	3^70
	Extreme responders	2	2^29	2^45	2^104		2^198	2^48			2^22,30,31		2^60,64
	Combinatorial data	2	2^28,29		2^104	0^183,199	2^51		2^54		2^22,30-33		2^61
	Acceptable phase I safety data	2	2^159,181	2^46,200	2^105	2^183,199	2^47,138,184-190	2^48,49,139-144	2^54	2^60	2^22,30-33	2^62-64	2^65	2^70	2^94
Score			23	20	18	16	16	15	14	14	30	12	19	23	15

Abbreviation: *GEMM, genetically-engineered murine model (of glioma).

Table 3. Priority scores of glioblastoma immunotherapeutics in preclinical studies.

					Adoptive cellular
Therapeutic agent			STAT3 inhibitor	EGFRvIII × CD3 bispecific monoclonal Ab	*EGFRvIII CAR	*EGFRCAR	*IDH1 peptide vaccine	4-1BB aptamer	*Arginine	*IDO inhibitor	Adv-TK + Adv-Flt3L
Antigen/ Target	Expression frequency	0–33% (1)34–66% (2)66–100 (3)	2^72	1^23-25	1^23-25	2^26,128,129	1^85,86			3^201,202
	Benefit in other malignancy	1	1^203-211
	Homogeneous expression	1				1^26,128,129
	Persistence at recurrence	2	2^212	2^152,153	2^152,153	2^26,128,129	2^85,86
	Mechanism of resistance	1	1^212	1^152,153	1^152,153	1^26,128,129				1^202
	Specificity of expression in the tumor			1^23-25	1^23-25		1^85,86,213
Immune activation and effector response	Immune activation	1	1^111,214	1^84,215	1^69,216	1^217	1^87,218	1^172,219-221	1^109,110		1^95,96
	Trafficking to the tumor	1	1^214,222	1^84,215	1^66-68,216	1^223	1^87,218	1^224			1^95,96
	Maintenance of effector response within tumor	1	0^214	1^84,215	1^66,67,216		1^87	1^172	1^110		1^95,96
Agent: Preclinical	Anti-stem cell activity	2	2^7,79-81			2^223
	Efficacy in preclinical models	Other (1)Clone (1)*GEMM/Xenograft (2)	1^111,214 1^7,76,80,111,210,2142^112,225	2^84,215	1^66-692^66-69,216	1^2172^223	1^2182^87,218	1^219,224,2262^172,224		1^2022^8,202	1^952^96
	Acceptable toxicity profile	2	2^78,112,225	2^84,215	2^66-68,216	2^217,223	2^87,218	2^172,224,227	2^228	2^8	2^95,96
	Hits target in vivo	2	2^112,210,225	2^84,215	2^66-68,216	2^223	2^87,218			2^8	2^95,96
Score			20	14	15	17	14	8	4	11	10

Abbreviation: *GEMM, genetically-engineered murine model (of glioma).

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