Trial Watch: experimental TLR7/TLR8 agonists for oncological indications

Figures & data

Table 1. Clinical trials testing experimental TLR7 and TLR8 agonists in cancer patients*.

Target(s)	Agonist	Indication(s)	Phase(s)	Status	Route	Notes	Ref.
TLR7	852A	ALL AML CLL Lymphoma Multiple myeloma	II	Terminated	s.c.	As single agent	NCT00276159
		Breast cancer Cervical cancer Endometrial cancer Ovarian cancer	II	Completed	s.c.	As single agent	NCT00319748
		Melanoma	II	Completed	i.v.	As single agent	NCT00189332
		Melanoma	I	Completed	Topical	As single agent	NCT00091689
		Chemorefractory solid tumors	I	Completed	i.v.	As single agent	NCT00095160
	BNT411	ES-SCLC Solid tumors	I/II	Not yet recruiting	i.v.	As single agent or combined with atezolizumab and chemotherapy	NCT04101357
	DSP-0509	Advanced solid tumors	I/II	Recruiting	i.v.	As single agent or combined with pembrolizumab	NCT03416335
	LHC165	Advanced solid tumors	I	Recruiting	i.t.	As single agent or combined with PDR001	NCT03301896
	NJH395	Advanced HER2^+ solid tumors	I	Recruiting	i.v.	As single agent	NCT03696771
	Resiquimod	Actinic keratosis	II	Completed	Topical	As single agent	NCT01583816
		Brain tumors	II	Active, not recruiting	Topical	Combined with DCs pulsed with autologous tumor cell lysates	NCT01204684
		CTCL	I/II	Completed	Topical	As single agent	NCT01676831
		Melanoma	I	Completed	Topical	Combined with a peptide-based vaccine	NCT01748747
			I	Completed	Topical	Combined with a peptide-based vaccine	NCT00470379
			I/II	Active, not recruiting	Topical	Combined with a peptide-based vaccine ± poly-ICLC	NCT02126579
			II	Active, not recruiting	Topical	Combined with a peptide-based vaccine	NCT00960752
		MIBC	II	Terminated	Topical	Combined with CDX-1307, chemotherapy, GM-CSF and poly-ICLC	NCT01094496
		nBCC	I/II	Terminated	Topical	As single agent	NCT01808950
		NY-ESO-1^+ tumors	I/II	Completed	Topical	Combined with CDX-1401 ± poly-ICLC	NCT00948961
		Advanced tumors	I	Completed	Topical	Combined with a peptide-based vaccine	NCT00821652
	RO7119929	Biliary tract tumors HCC Hepatic metastases	I	Not yet recruiting	p.o.	As single agent	NCT04338685
	TQ-A3334	NSCLC	I/II	Recruiting	p.o.	As single agent or combined with anlotinib	NCT04273815
TLR7 TLR8	BDC-1001	HER2^+ advanced solid tumors	I	Recruiting	n.s.	As single agent or combined with pembrolizumab	NCT04278144
	CV8102	ACC HNSCC Melanoma SCC	I/II	Recruiting	n.s.	As single agent or combined with standard of care PD-1 blockage	NCT03291002
		HCC	I/II	Completed	i.d.	Combined with cyclophosphamide and a peptide-based vaccine	NCT03203005
	NKTR-262	Advanced/metastatic solid tumors	I/II	Recruiting	i.t.	Combined with pegylated IL2 ± nivolumab	NCT03435640
TLR8	Motolimod	Advanced solid tumors	I	Terminated	s.c.	Combined with cyclophosphamide and pegylated G-CSF	NCT02650635
			I	Completed	s.c.	Combined with cetuximab	NCT01334177
		HNSCC	I	Recruiting	i.t. s.c.	As single agent or combined with nivolumab	NCT03906526
			I	Terminated	s.c.	Combined with cetuximab ± nivolumab	NCT02124850
			I	Not yet recruiting	i.t.	Combined with nivolumab	NCT04272333
			I	Completed	n.s.	Combined with cetuximab and multimodal chemotherapy	NCT01836029
		Lymphoma	I	Terminated	i.t.	Combined with radiation therapy	NCT01289210
		Ovarian cancer	I	Completed	s.c.	Combined with paclitaxel or PLD	NCT01294293
			I/II	Active, not recruiting	s.c.	Combined with durvalumab and PLD	NCT02431559

Abbreviations: ACC, adenoid cystic carcinoma; ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CTCL, cutaneous T-cell lymphoma; DC, dendritic cell; ES-SCLC, extensive-stage small cell lung cancer; HCC, hepatocellular carcinoma; HNSCC, head and neck squamous cell carcinoma; i.d., intra derma; i.t., intra tumorem; i.v., intra venam; MIBC, muscle-invasive bladder cancer; nBCC, nodular basal cell carcinoma; n.s., not specified; NSCLC, non-small cell lung carcinoma; PLD, pegylated liposomal doxorubicin; poly-ICLC, polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose; p.o., per os; s.c., sub cutem; SCC, squamous cell carcinoma. *All clinical trials listed on http://clinicaltrials.gov/at the date of submission.

Figure 1. Current obstacles against the development of efficacious TLR7/TLR8 agonists for cancer therapy. Besides being hampered by specificity issues, the translation of currently available TLR7/TLR8 agonists to the clinic is limited by incomplete data on optimal delivery routes and administration schedules, as well as by the intrinsic issues associated with therapeutic cancer vaccines.