Small-Molecule Immuno-Oncology Therapy: Advances, Challenges and New Directions

Abstract

Oncology immunotherapy has gained significant advances in recent years and benefits cancer patients with superior efficacy and superior clinical responses. Currently over ten immune checkpoint antibodies targeting CTLA-4 and PD-1/PD-L1 have received regulatory approval worldwide and over thousands are under active clinical trials. However, compared to the rapid advance of Monoclonal Antibody (mAb), studies on immunotherapeutic small molecules have far lagged behind. Small molecule immunotherapy not only can target immunosuppressive mechanisms similar to mAbs, but also can stimulate intracellular pathways downstream of checkpoint proteins in innate or adaptive immune cells that mAbs are unable to access. Therefore, small molecule immunotherapy can provide an alternative treatment modality either alone or complementary to or synergistic with extracellular checkpoint mAbs to address low clinical response and drug resistance. Fortunately, remarkable progress has achieved recently in the pursuit of small molecule immunotherapy. This review intends to provide a timely highlight on those clinically investigated small molecules targeting PD-1/PD-L1, IDO1, and STING. The most advanced IDO1 inhibitor epacadostat have been aggressively progressed into multiple clinical testings. Small molecule PD-1/PD-L1 inhibitors and STING activators are still in a premature state and their decisive application needs to wait for the ongoing clinical outcomes. Since no small molecule immunotherapy has been approved yet, the future research should continue to focus on discovery of novel small molecules with distinct chemo-types and higher potency, identification of biomarkers to precisely stratify patients, as well as validation of many other immune-therapeutic targets, such as LAG3, KIRs, TIM-3, VISTA, B7-H3, and TIGIT.

Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn–AhR–AQP4 signaling pathway

“…18,19 Some IDO1 inhibitors have been developed and applied in antitumor therapy in preclinical and clinical trials. 50 Although IDO1 inhibitors have not demonstrated antitumor activity as single agents in orthotopic glioma animals, a unique synergy when combined with radiotherapy, temozolomide, or anti-programmed cell death protein 1 antibody has been noted. [28][29][30][51][52][53] TDO inhibitors have not been tested in glioma animals.…”

Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer

“…All these IDO1 inhibitors were shown to be safe and well-tolerated (158)(159)(160)(161). Epacadostat is the clinically most advanced IDO1 inhibitor and has been shown to inhibit tumor growth in mice models (162).…”

“…Unfortunately, a recent trial with combined administration of epacadostat with pembrolizumab found no superiority over pembrolizumab alone (169). Despite this setback, several ongoing trials investigate the effect of other (also structurally new) IDO1 inhibitors in combination with different immunotherapies (162).…”

Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance

“…Enhancement of the anti-tumor response of neutrophils can also be achieved by targeting signaling partners downstream of the inhibitory receptors. Even better, combination of ligand-receptor interaction disruption and simultaneous blockade of a protein functioning downstream, could have a substantial impact ( 234 , 235 ). Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) are two important regulators of immune cell responses.…”