There have been recent clinical successes in targeting the immune system for the treatment of cancer. These successful methods have harnessed biologicals, including antibodies, proteins, engineered cells, and oncolytic viruses. However, small molecules targeting the immune system in cancer offer several advantages over biologicals.
Firstly, small molecules are capable of attacking intracellular targets that protein-based therapeutic agents can’t access. Moreover, they have high oral bioavailability and are able to reach high levels in the local tumor microenvironment. Small molecules can also regulate immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and dendritic cells. In other words, small molecules can regulate cell types that are not directly regulated by checkpoint blockers.
Using Small Molecules to Target Tumor Cells
Small molecules are especially useful in the mechanism of immune cell signaling, making them easily modulated with a number of different pathways showing promise as targets. Toll-like receptors (TLRs) are expressed on antigen presenting cells as part of the innate immune system, triggering a pro-inflammatory response upon ligand binding.
Agonists for TLR7 and TLR8 have been successful during pre-clinical results, resulting in the TLR7 agonist Imiquimod being approved as a topical monotherapy for basal cell carcinoma. These compounds possess antitumor effects that are mediated when dendritic cells and natural killer cells are activated to kill tumor cells and suppress T-cells (Pradere et al, 2014).
STING (stimulator of interferon genes) is a further target in the innate immune system. It functions as a pattern recognition receptor and adapter protein that mediates a TLR-independent immune response to the detection of cytoplasmic DNA. When STING gets activated by cyclic dinucleotide – after the breakdown of foreign DNA – it triggers a cascade resulting in the transcription of pro-inflammatory immune system genes.
STING agonists, including 2’,3’-cGAMP, are cyclic nucleotides with the aim of creating an immune response in the tumor microenvironment. Currently, phase 1 clinical trials are investigating intra-tumoral injection of the STING agonist ADU-S100 (Toogood, 2018).
In addition, chemokines and their receptors play a critical role in the body’s immune response in cancer. A sub-type of G-protein coupled receptors, chemokine CXC receptors are a druggable target for oncotherapy. AMD 3100 – a CXCR4 antagonist – switches the inflammatory response from a Th2 to Th1 type response in pre-clinical investigations, thus promoting a pro-inflammatory environment. What’s more, (±)-AMG 487, a CXCR3 antagonist, has been shown to inhibit lung metastasis in a mouse model of metastatic breast cancer (Walser et al, 2006).
Amino Acid Metabolism
One of the conserved pathways involved in regulating the immune response is amino acid metabolism. The indoleamine 2,3 dioxygenase (IDO) family of dioxygenases (IDO1, IDO2, and TDO) – which are responsible for the conversion of tryptophan to kynurenine and additional metabolites – have shown tremendous promise as cancer therapeutic targets. There are multiple immunosuppressive roles for IDO, and these ultimately impair immune recognition and promote tumor growth. One of the first small molecule-based strategies proposed for the induction of the immune response in cancer involved the inhibition of IDO/TDO (Mellor & Dunn, 2004).
1-Methyl-D-tryptophan, an IDO inhibitor, enhances the antitumor and antiviral immuno-response of CD8 positive T-cells in vitro. In addition, it also reduced tumor volume in mice with xenografts that overexpressed IDO (Nakamura et al, 2015). In fact, this small molecule, which also goes by the name Indoximod, is currently being studied and tested in 5 clinical trials (Toogood, 2018).
There have been a number of comprehensive reviews, which further discuss the targeting of immune response pathways with small molecules for cancer treatment. These reviews are listed below, and they outline the rationale for using small molecules and provide an update on those currently undergoing clinical trials.
- Adams et al, 2015. PMID: 26228631
- Dhanak et al, 2017. PMID: 28938090
- Kamta et al, 2017. PMID: 28459041
- Toogood, 2018. PMID: 29326017
- Adams et al (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov. 14 603.
- Dhanak et al (2017) Small-molecule targets in immuno-oncology. Cell Chem Biol. 24 1148.
- Geisse et al (2004) Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies. J Am Acad Dermatol. 50 722.
- Hogaboam et al (2005) The therapeutic potential in targeting CCR5 and CXCR4 receptors in infectious and allergic pulmonary disease. Pharmacol Ther. 107 314.
- Kamta et al (2017) Advancing cancer therapy with present and emerging immuno-oncology approaches. Front Oncol. eCollection 2017.
- Mellor & Dunn (2004) IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol. 4 762.
- Nakamura et al (2015) Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice. Int J Hematol. 102 327.
- Pradere et al (2014) The yin and yang of Toll-like receptors in cancer. Oncogene. 33 3485.
- Rytelewski et al (2014) Suppression of immunodominant antitumor and antiviral CD8+ T cell responses by indoleamine 2,3-dioxygenase. PLoS One 9 e90439.
- Toogood (2018) Small molecule immuno-oncology therapeutic agents. Bioord Med Chem Letts. Online publication ahead of print.
- Walser et al (2006) Antagonism of CXCR3 inhibits lung metastasis in a murine model of metastatic breast cancer. Cancer Res. 66 7701.
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