Checkpoint modulation - A new way to direct the immune system against renal cell carcinoma

Figures & data

Figure 1. Stimulatory pathways of T cell activation or inhibition.

Table 1. Overview of available checkpoint modulators for cancer immunotherapy

Target pathway	Substance	Company	Reference
CTLA-4	Ipilimumab	BMS	35,36
	Tremelimumab	Pfizer	37,38
PD-1	Nivolumab (BMS-936558)	BMS	44, 47, 48
	Pembrolizumab (MK-3475)	Merck	53
	AMP-224	Amplimmune	54
	Pidilizumab (CT-011)	CureTech	55
PD-L1	MEDI4736	MedImmune/AstraZeneca	56
	MPDL3280A	Roche	57
	MSB0010718C	MerckSerono	58
	BMS-936559	BMS	43
LAG-3	IMP321	Immutep	59

Table 2. Published clinical trials of checkpoint modulators for mRCC as discussed in the review

Target pathway	Trial Design	Trial Drug	Setting all mRCC	Number	Dosing	Results	Reference
CTLA-4	Phase II	Ipilimumab	after previous IL-2	first cohort n = 21 pts.	loading dose of 3 mg/kg 1 mg/kg every 3 weeks	1 partial response	^38 NCT00057889
			after previous IL-2 or no previous treatment	second cohort n = 40 pts.	3 mg/kg every 3 weeks	5 partial responses at months 7, 8, 12, 17 and 21
	Phase I 3+3 dose escalation study	Tremelimumab	≤1 previous systemic treatment	n = 28 pts.	6 mg/kg, 10 mg/kg, or 15 mg/kg once every 12 weeks plus sunitinib 50 mg (4/2) or 37.5 mg continuously	Investigation of tremelimumab doses > 6 mg/kg plus sunitinib 37.5 mg daily were not recommended	^39 NCT00372853
PD-1	Phase Ib dose escalation study	Nivolumab	>1 previous systemic treatment	n = 33 with mRCC out of 296 pts. with soild cancers	1 mg/kg or 10 mg/kg every 2 weeks until progression (maximum up to 24 months)	objective responses in 4 of 17 patients (24%) objective responses in 5 of 16 (31%) at a dose of 10.0 mg/kg	^44 NCT00730639
PD-L1	Phase I dose escalation study	BMS-936559	>1 previous systemic treatment	n = 17 with mRCC out of 207 pts. with soild cancers	10 mg/kg every 2 weeks in 6 weeks cycles with up to 16 cycles	objective response in 2 of 17 patients (12%, all at the 10 mg/kg dose), responses lasting 4 and 17 months. stable disease in 7 (41%) lasting at least 24 weeks.	^43 NCT00729664
MHC class II	Phase I dose-escalation trial	IMP321	most pts. were pretreated with sunitinib or sorafenib	n = 21 pts.	s.c. biweekly for 6 injections with 3 to 6 pts. at 0.05, 0.25, 1.25, 6.25, and 30 mg per injection	no objective tumor response observed stable disease at 3 months in 7 of 8 evaluable patients at doses >6 mg and in 3 of 11 pts. at doses >6 mg	^59 NCT00351949

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