Small molecule drugs with immunomodulatory effects in cancer

Figures & data

Table 1. Categories of small molecule compounds with immunomodulatory functions in solid tumors. Abbreviations: DC: dendritic cell, DNMT: DNA methyltransferase, HDAC: histone deacetylase complex. IDO: indoleamine-2, 3-dioxygenase, RORγt: Retinoic acid receptor-related orphan nuclear receptor gamma, TNFα: tumor necrosis factor α

Category	Mechanism of action	Examples
IDO inhibitors	Inhibit indoleamine-2, 3-dioxygenase which catalyzes L-tryptophan in kynurenine pathway	1-MT, INCB024360, NLG-919
MEK inhibitors	Inhibit catalysis of phosphorylation of tyrosine and threonine residues in ERK1/ERK2	Trametinib, selumetinib
HDAC inhibitors	Inhibit enzymatic removal of acetyl group from histones	Romidepsin, entinostat, vorinostat
DNMT inhibitors	Inhibit transfer of methyl group to DNA	Azacitidine, 5-azacitidine, decitabine.
Thalidomide analogs	Inhibit TNFα and function as T cell costimulators	Lenalidomide, pomalidomide.
Toll-like receptor agonists	Initiate T cell immunity/activation, antigen uptake/processing and DC activation	VTX-2337, SD-101.
RORγt inhibitors	Inhibit the differentiation of pro-inflammatory Th17 cells	SR2211, ML209.

Table 2. List of clinical trials of IDO inhibitors in patients with cancer (all trials listed are currently recruiting) MTD: Maximum tolerated dose

NCI Identifier	Study description	Tumor type	Phase
NCT02048709	Determine MTD and safety profile of NLG-919	Advanced solid tumors	I
NCT02077881	Indoximod + gemcitabine/nab-paclitaxel	Metastatic pancreatic cancer	I/II
NCT02166905	INCB024360 + DEC-205/NY-ESO-1 fusion protein CDX-1401 + Poly ICLC.	Ovarian/primary peritoneal/fallopian tube cancer	I/IIb
NCT02042430	Neoadjuvant INCB024360	Stage III/IV ovarian/fallopian tube/primary peritoneal cancer	II
NCT01961115	INCB024360 and vaccine therapy	Stage III-IV melanoma	II
NCT01792050	indoximod + taxane	Metastatic breast cancer	II
NCT02073123	Indoximod + ipilimumab	Stage III/IV melanoma	I/II
NCT02118285	INCB024360 + intraperitoneal allogeneic natural killer cells	Recurrent ovarian/fallopian tube/primary peritoneal cancer	I
NCT02052648	Indoximod + temozolomide	Primary brain tumors	I/II

Table 3. Selection of clinical trials of MEK inhibitors in patients with solid tumors (all trials listed are currently recruiting)

Tumor type	NCI Identifier	Study description	Patient group	Phase
Colorectal cancer	NCT02041481	MEK 162 + FOLFOX	Metastatic colorectal cancer	I
	NCT01927341	MEK162 + panitumumab	Wild-type or mutant KRAS metastatic colorectal cancer	Ib/II
	NCT01750918	Trametinib ± dabrafenib ± panitumumab ± 5FU	BRAF V600E positive	I/II
	NCT01740648	Trametinib + 5FU + radiation therapy	Neoadjuvant rectal cancer	I
	NCT02188264	Selumetinib + cyclosporine	Metastatic disease	I
Multiple	NCT01449058	MEK162 + BYL719 (PI3K inhibitor)	Advanced solid tumors	Ib
	NCT01543698	MEK162 + LGX818 (BRAF inhibitor)	Advanced solid tumors	Ib/II
	NCT01938443	Trametinib + GSK2256098 (FAK inhibitor)	Advanced solid tumors	Ib
	NCT02065063	Trametinib + palbociclib	Advanced solid tumors	I/II
	NCT02079740	Trametinib + navitoclax (Bcl2 inhibitor)	Advanced solid tumors	Ib/II
Melanoma	NCT01909453	Comparison of vemurafenib, LGX818 and LGX818 + MEK162 combination.	V600E BRAF mutated melanoma	III
	NCT01801358	MEK162 + AEB071 (PKC inhibitor)	Metastatic uveal melanoma	Ib/II
	NCT01726738	Trametinib + dabrafenib (BRAF inhibitor) and	Stage III/IV BRAF mutant melanoma	II
	NCT01781572	MEK162 + LEE011 (CDK 4/6 inhibitor)	Metastatic melanoma	Ib/II
	NCT02159066	MEK162 + LGX818 (BRAF inhibitor) followed by a rational combination of targeted therapy on progression.	Locally advanced/ metastatic melanoma	II
	NCT01763164	MEK162 vs. dacarbazine	NRAS-mutant unresectable melanoma	III
	NCT01940809	Ipilimumab ± dabrafenib ± trametinib	Inoperable/metastatic melanoma	I
Biliary tract cancer	NCT01828034	MEK162 + Gemcitabine/ cisplatin	1^st line advanced disease	I/II
	NCT02105350	MEK162 + gemcitabine/oxaliplatin.	Advanced biliary cancer	I
	NCT02151084	Gemcitabine/cisplatin ± selumetinib	Advanced biliary cancer	II
GIST	NCT01991379	MEK162 + imatinib mesylate	Untreated advanced GIST	Ib/II
NSCLC	NCT02276027	Multi-arm study of single agent AUY922, BYL719, INC280, LDK378 and MEK162.	Chinese patients with advanced NSCLC	II
	NCT01859026	MEK162 + erlotinib	NSCLC harboring KRAS/EGFR mutation	Ib/II
	NCT01146756	AZD6244 + thoracic radiotherapy.	Inoperable stage III/IV NSCLC	I
	NCT01586624	Selumetinib + vandetanib	Advanced NSCLC	I
GYN	NCT01849874	MEK162 vs. chemotherapy	Low-grade serous ovarian, fallopian tube or peritoneal cancer	III
	NCT01935973	Trametinib ± GSK2141795 (Akt inhibitor)	Recurrent endometrial cancer	II
GU	NCT01990196	Degarelix/enzalutamide ± trametinib or dasatinib	Neoadjuvant, localized prostate cancer.	II