Overview of cancer immunotherapy
The most widely studied cancer immunotherapies are PD-1/PD-L1 immune checkpoint inhibitors and chimeric antigen receptor-T cell (CAR-T) therapy. With the expanded clinical applications, some defects of cancer immunotherapies appear, such as poor permeability and long half-life, leading to limited progress in research.
Compared with most antibody drugs, small molecule drugs have better permeability, allowing them to directly target intracellular or extracellular targets to enhance anti-tumor immune response.
In addition, the relatively short half-life reduces the accumulation of small molecules in circulation, thereby reducing the risk of systemic toxicity. Due to these characteristics, small molecule drugs in cancer immunotherapy are expected to be used as a complement to antibody drugs to improve the efficacy of immunotherapy and reduce toxic reactions.
Small molecule drugs developed as promising cancer therapeutics
At present, the research on small molecule drugs for cancer immunotherapy has made some positive progress. The targets of these drugs in clinical studies are shown below (Figure 1).
PD-1 is a type I transmembrane glycoprotein of the B7/CD28 family. As a surface receptor of active T cells, it can inhibit the activation of T cells and has an immunosuppressive effect by binding to ligands located on the surface of antigen presenting cells (APCs).
However, tumor cells can utilize this inhibitory pathway to induce the expression of PD-L1 on its surface so as to inhibit T cells and achieve immune escape. Inhibiting the interaction between PD-1 and PD-L1 can reverse the immunosuppressive state and improve the killing ability of immune cells to tumor cells.
As a supplement to antibody drugs, PD-1/PD-L1 small molecule inhibitors are mostly in the early stage of development at present. There are 4 drugs in the clinical research phase, among which CA-170 is a small molecule dual inhibitor of PD-L1/VISTA that is currently under investigation for indications including lymphoma, mesothelioma, and non-small cell lung cancer.
STING is an important cohesin anchored in the endoplasmic reticulum to detect invasion of foreign DNA. STING, as a key signal transduction molecule involved in innate immune responses, plays an important role in the immunotherapy of viral infections, autoimmune diseases, and tumors mainly through the cyclic GMP-AMP synthase (cGAS)-STING signaling pathway.
After recognizing DNA in the cytoplasm, cGAS dimerizes, catalyzing the reaction of guanosine triphosphate (GTP) with ATP to produce 2′,3′-cyclic GMP-AMP (cGAMP), and subsequently activating STING, bringing a change in its conformation.
STING then uses the vesicle transport system to achieve endoplasmic reticulum transport to the Golgi matrix and recruits TANK binding kinase 1 (TBK1) in it. The interferon regulatory factor IRF-3 has been activated to induce the production of type I interferon and regulate the anti-tumor innate immune response.
At present, modulating the cGASSTING signaling pathway has become an important novel immunotherapy strategy for tumor and autoimmune diseases, and the STING regulator has also become one of the most potent anti-tumor therapeutics apart from PD-1/PD-L1 and other immune checkpoint inhibitors.
There are 11 small molecule STING agonists in the clinical study stage, and 4 of them (IMSA-101, ADU-S100, exoSTING, and MK-1454) are witnessing rapid progress.
- IDOL inhibitor
The kynurenine pathway of L-tryptophan (L-Trp) metabolism plays an important role in immune regulation. The first step is also rate-limiting, catalyzed by IDO1, IDO2, and tryptophan 2,3-dioxygenase (TDO).
Although IDO1, IDO2, and TDO catalyze the same biochemical reaction, they show significant differences in structure, tissue distribution, and substrate specificity. IDO1 is overexpressed in tumor cells and APCs, creating an immunosuppressive microenvironment for tumor cells to evade an effective immune response. TDO has similar immunosuppressive effects but is mainly expressed abnormally in liver cancer. The activity of IDO2 in catalyzing L-Trp metabolism is very low, and there is basically no abnormal expression phenomenon in the pathological state. Whether it is related to tumor immune response is still controversial.
IDO1 inhibition at the gene or cellular level activates an anti-tumor immune response in animal tumor models. In recent years, IDO1 single target inhibitors and IDO1/TDO dual target inhibitors have been considered two of the promising small molecule anti-tumor immunotherapies.
At present, there are 7 small molecule IDO1 inhibitors and 3 IDO1/TDO dual target inhibitors in clinical studies. Some drugs in rapid development are Linrodostat, Epacadostat, and Indoximod.
- A2AR antagonists
Adenosine is an immunosuppressive metabolite. In the tumor microenvironment, adenosine acts as an immunosuppressive agent by acting on A2AR expressed in immune cells, resulting in the immune escape of tumor cells and the failure of immune cells to kill them.
The CD39-CD73-A2AR is a key pathway for adenosine to regulate the immune response. Treg expresses extracellular nucleotidases (CD73, CD39), the key enzymes in the production of adenosine, which can hydrolyze ATP in tissues to form adenosine through synergistic action, thus increasing the level of adenosine in the tumor microenvironment and enhancing tumor immune escape caused by the above pathways.
CD39, CD73, and A2AR are all promising potential drug targets for anti-tumor immunotherapy. At present, there are 8 A2AR antagonists in clinical studies for tumor treatment, among which the most advanced is Ciforadenant developed by Corvus Pharmaceuticals.
- Chemokine receptor inhibitors
Chemokine receptors are a class of G-protein-coupled receptors (GPCRs) expressed on immune cells, endothelial cells, and tumor cells. Inhibition of chemokine receptors prevents macrophage infiltration and induces tumor growth arrest or apoptosis.
So far, about 20 chemokine receptors and 50 ligands have been reported in the literature. Chemokine receptors that are expected to be targets of small molecule drugs in cancer immunotherapy mainly include CXC chemokine receptor 2 (CXCR2), CXCR4, C-C chemokine receptor type 2 (CCR2), CCR4, and CCR5.
CXCR1/2 antagonist SX-682, CXCR2 antagonist AZD5069, CXCR4 antagonist Mavorixafor, CCR5 antagonist Maraviroc, CCR2/5 antagonist BMS-813160, and CCR4 inhibitor FLX 475 are under clinical development as monotherapy or combined with immune checkpoint inhibitors.
- Other small molecule drugs for cancer immunotherapy
In addition to the drugs still in development as described above, there are some relatively well-developed small molecule tumor immunotherapies including TLR agonists, TGF-p inhibitors, RORγt agonists, hematopoietic progenitor kinase 1 (HPK1) inhibitors, and ARG inhibitors.
Challenges and prospects
Many small molecule immunotherapies have entered the clinical stage, used as monotherapy or combined with antibody drugs or traditional chemotherapy drugs to further improve anti-tumor efficacy or checkpoint inhibitor resistance.
Most of these small molecule therapies have shown good safety and efficacy in early-stage clinical trials. However, the significant failure of IDOL inhibitor and pembrolizumab combination in phase III clinical trials for melanoma suggests that further exploration of tumor immune mechanisms, reliable biomarkers, and clinical design should be conducted in the future. The development of small molecule tumor immunotherapy as a complement to therapeutic antibody drugs is challenging, but also full of promises.