7.2 Small Molecule Immune Modulators
Modulating the immune system through small molecules offers several unique advantages as follows: (1) oral bioavailability; (2) penetration of physiological barriers and easier exposure within the tumor microenvironment; (3) diverse and well-understood formulation and dosing options to alleviate pharmacokinetic and/or pharmacodynamics challenges and enabling titration of drug exposure.Another compelling advantage of small-molecule drugs is the lower in cost.Thus, the development of small-molecule drug is complementary and potentially synergistic with large biological molecules, and is now coming into spotlights in the field of immunotherapy.The rationale for using small-molecule drugs targeting some of the key intracellular proteins or activities as immuno-therapies in cancer, including amino acid catabolism, T cell immune checkpoint proteins, NK cell sensitization effect, and pattern recognition receptors.We offer considerations regarding the future promise of their utility both as single agents and in combination with other cancer medicines.
NK (natural killer) cells play a crucial role in the surveillance of malignant cells, whose activity are not required the prior sensitization of special antigens, but dependent on the regulatory balance of inhibitory and activating receptors.Among these, the natural-killer group 2 member D (NKG2D)receptor and its ligands is one of the most characterized interaction pairs.And the engagement of ligands on tumor cells represent a promising therapeutic strategy against cancer.Most of NKG2D ligands inducers are concentrated upon histone deacetylase (HDAC) inhibitor, such as sodium valproate (VPA), trichostatin A (TSA) and entinostat.In addition, some chemotherapy agents like cisplatin or proteasome inhibitor MG132 were also reported to be able to induce the expression of NKG2D ligands.Besides, a natural product matrine was also demonstrated to up-regulate the expression of NKG2D ligands.But none of the NKG2D ligands inducers are under clinical tests.More basic research upon NK cell and lead compounds are needed to promote this process [6].
Innate immune responses play an important role against cancer during the process of tumorigenesis.And through a series of knockout mice and other ancillary studies, researchers found that the STING pathway is the main bridge to this spontaneous antitumor immunity.STING is an ER-associated trans-membrane protein, acting as a novel nucleic acid sensor, which is activated not only by pathogen-derived nucleic acids, but also self-DNA released by host apoptotic or necrotic cells detected by dendritic cells.After the activation of STING signaling, the production of type I IFNs will lead to a powerful immune cascade like inflammatory cytokines and other elements [7].
The use of STING agonist as a cancer treatment is disclosed in the patent US20160287623 (Pub.Date October 6, 2016).Natural STING ligands are cyclic dinucleotides.Currently, at least two STING agonists, ADU-S100/MIW815 and MK1454 are in early-stage clinical trials.ADU-S100 is a synthetic cyclic dinucleotide STING agonist, which is an effective stimulator for the induction of IFN-β in vitro in human peripheral blood mononuclear cells (PBMCs).The clinical trials for MK-1454 are ongoing by alone or in combination with pembrolizumab in participants with advanced/metastatic solid tumors or lymphomas.No detail results were posted [8].(https://www.daowen.com)
Toll-like receptors (TLRs) are type I transmembrane proteins that function as microbial pattern recognition molecules, which are expressed on antigen-presenting cells.The activation of TLRs stimulated by pathogen-associated molecular patterns leads to a rapid innate immune response, and induces appropriate adaptive immune responses.The family of TLRs may be considered the seminal immuno-oncology targets if Coley’s toxins are supposed to be the original immunotherapy for cancer [9].
Generally, endogenous ligands for TLRs are derived from viruses or bacteria, as well as a variety of non-classical molecular patterns including double-stranded RNA and polynosinic: polycytidylic acid (poly I:C) (TLR3), lipopolysaccharide (TLR4), and un-methylated CpG oligodeoxynucleotides(TLR9).Clinical trials of TLR agonists for cancer indications have examined agonists of endosomal TLRs (TLR3, TLR7, TLR8 and TLR9) and utilized as either vaccine adjuvants or monotherapy.The anti-tumor effects of TLR7 and TLR8 agonists are primarily by mediating the activation of dendritic cells and natural killer cells, and suppressing activation of Treg cells.Small-molecule heterocyclics, such as imidazoquinolines are recognized as nucleoside agonists by TLR7 and TLR8.And imiquimod is the first approved LR7 and TLR8 agonist by the US FDA in 1997 for the treatment of genital warts, and for the topical treatment of basal cell carcinoma in 2004.Several synthetic oligodeoxynucleotides agonists for TLR9 such as IMO-2055, CPG 7909 and MGN1703, are currently in development for the treatment of colorectal cancer, NSCLCs and renal cell carcinoma [10].
Once engaged, TLRs will trigger a strong pro-inflammatory cytokine response following by a stimulation of immune surveillance, which could be important for the elimination of cancer.Due to high polarity, presence of charged species or poor hydrolytic stability for TLRs ligands, there are no any clinically evaluated oral small-molecule TLRs agonists.Therefore, more research about TLRs agonists are needed for exploitation of orally bioavailable drug-like analogs.