Immune checkpoint and inflammation as therapeutic targets in pancreatic carcinoma

Table 1 Rationales of each combination therapy

Treatments	Rationales	Concerns
Checkpoint inhibitor plus cytotoxic agents	Enhance cellular immunity	Efficacy may be influenced by timing when cytotoxic agents add
	Augment dendritic cell maturation	Severe myelosupression may interrupt immune checkpoint therapy
	Reduce MDSC and Tregs
	Decreases CAF
Combination with checkpoint inhibitors	Activate tumor immunity by different mannar	ir AE will increase
	Provide synergy efficacy even in immune resistant tumor
Checkpoint inhibitor plus T cells stimulate agents	Activate tumor immunity by different mannar	Severe AE including cytokine storm may occur
	Deactive Tregs
Checkpoint inhibitor plus cancer vaccine	Increase the presentation of taas
	Enhance PD-L1 expression
Radiotherapy	Enhance cross priming of ctls	Optimal schedule and dose are not established
	Enhanse abscopal effect

MDSC: Myeloid-driven suppressor cell; CAF: Cancer-associated fibroblast; Tregs: Regulatory T cells.

Table 2 Problems of each combination therapy

Treatment	Disease	Phase	Clinical trial number	Status
Checkpoint inhibitor plus cytotoxic agents
Ipilimumab (anti-CDLA-4)	PC	1	NCT01473940	Ongoing
Gemcitabine
Nivolumab (anti-PD-1)	PC	1	NCT02309177	Ongoing
Nab-PTX ± gemcitabine
Combination with checkpoint inhibitors
Nivolumab (anti-PD-1)	TNBC, GC, PC,	1, 2	NCT01928394	Ongoing
Ipilimumab (anti-CTLA-4)	SLCL. BC, OC
MEDI4736 (anti-PD-1)	Solid tumor	1	NCT02261220	Ongoing
Tremelimumab (anti-CTLA-4)
Nivolumab (anti-PD-1)	Cervical cancer, BC, CRC, HN, GC, HCC, melanoma, NSCLC	1, 2	NCT01968109	Ongoing
BMS-986016 (anti-LAG-3)
PDR001 (anti-PD-1)	Solid tumors	1, 2	NCT02608268	Ongoing
MBG453 (anti-TIM-3)
Ipilimumab (anti-CDLA-4)	B7-H3 expressing tumors (melanoma, HN, NSCLC)	1, 2	NCT02381314	Ongoing
MGA271 (anti-B7-H3)
Pembrolizumab (anti-PD-1)	B7-H3 expressing tumors	1, 2	NCT02475213	Ongoing
MGA271 (anti-B7-H3)	(melanoma, HN, NSCLC)
Checkpoint inhibitor plus T cells stimulate agents
Nivolumab (anti-PD-1)	Solid tumors, B-cell NHL	1, 2	NCT02253992	Ongoing
Urelumab (anti-4-1 BB)
Pembrolizumab (anti-PD-1)	Solid tumors	1	NCT02179918	Ongoing
Urelumab (anti-4-1 BB)
Tremelimumab (anti-CTLA-4)	Solid tumors	1, 2	NCT02205333	Ongoing
MEDI6469 (anti-OX-40
MEDI4736 (anti-PD-L1)	Solid tumors	1, 2	NCT02205333	Ongoing
MEDI6469 (anti-OX-40)
Tremelimumab (anti-CTLA-4)	Melanoma	1	NCT01103635	Ongoing
CP-870,893 (anti-CD40)
Checkpoint inhibitor plus cancer vaccine
Ipilimumab (anti-CTLA-4) + GVAX	PC	2	Ref 58	Terminated
FOLFIRINOX followed by	PC	2	NCT01896869	Ongoing
Ipilimumab (anti-CTLA-4) + GVAX
Nivolumeb (anti-PD-1) + GVAX	PC	2	NCT02243371	Ongoing
Checkpoint inhibitor plus raditaion
Ipilimumab + radiation	Melanoma	1	NCT01557114	Terminated
	Melanoma	2	NCT016899747	Terminated
	NSCLC	2	NCT0221739	Ongoing
	Melanoma	2	NCT01970527	Ongoing

BC: Bladder cancer; CRC: Colorectal cancer; HN: Head and neck cancer; NSCLC: Non-small cell lung cancer; OC: Ovarian cancer; PC: Pancreatic cancer; SCLC: Small cell lung cancer.