Application of PD-1 Blockade in Cancer Immunotherapy

Abstract

The programmed cell death protein 1 (PD-1) pathway has received considerable attention due to its role in eliciting the immune checkpoint response of T cells, resulting in tumor cells capable of evading immune surveillance and being highly refractory to conventional chemotherapy. Application of anti-PD-1/PD-L1 antibodies as checkpoint inhibitors is rapidly becoming a promising therapeutic approach in treating tumors, and some of them have successfully been commercialized in the past few years. However, not all patients show complete responses and adverse events have been noted, suggesting a better understanding of PD-1 pathway mediated immunosuppression is needed to predict patient response and improve treatment efficacy. Here, we review the progresses on the studies of the mechanistic role of PD-1 pathway in the tumor immune evasion, recent clinical development and commercialization of PD-1 pathway inhibitors, the toxicities associated with PD-1 blockade observed in clinical trials as well as how to improve therapeutic efficacy and safety of cancer immunotherapy.

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…In 2019, the FDA approved pembrolizumab as first-line treatment of patients with stage III NSCLC that is PD-L1-positive and not amenable to surgery or chemo-radiation treatment (9,127). In addition, metastatic SCLC patients whose tumors progressed after treatment with platinumcontaining chemotherapy and at least one other systemic therapy, were approved for nivolumab treatment in 2018, an anti-PD-1 ICB, as the first immunotherapy approved for SCLC (128). Other PD-1/PD-L1 pathway-targeting ICBs approved for specific subsets of lung cancer patients include atezolizumab (NSCLC and SCLC patients) including as a first-line therapy, durvalumab (advanced NSCLC), and nivolumab (advanced NSCLC and a subset of metastatic SCLC as described above) (49,(129)(130)(131).…”

Adoptive Cell Therapy—Harnessing Antigen-Specific T Cells to Target Solid Tumours

“…Therapy based on immune checkpoint blockade (ICB) targets T cell inhibitory receptors such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4), thus leading to activation of tumour-specific T cells. Anti PD-1/PD-L1 and CTLA-4 inhibitors demonstrated remarkable therapeutic effects and were approved by FDA for treatment of different types of cancer [209,210]. Adoptively transferred T cells may upregulate PD-1 and CTLA-4 upon chronic exposure to tumour antigens, therefore combination of ACT with ICB might be a promising strategy that will improve clinical response rates.…”

Inhibition of 2-Hydroxyglutrate Elicits Metabolic-reprograming and Mutant IDH1 Glioma Immunity

“…and mIDH1 glioma bearing mice; and mIDH1 glioma bearing mice treated with AGI-5198 was assessed by liquid chromatography-mass spectrometry (UPLC-MS). AGI-5198 (40 mg/kg) was injected intraperitonially (i.p) into mice bearing mIDH1 glioma at 7,9,11,14,16,18,21,23,25 days post tumor cell implantation (dpi). Brains from untreated control mice, wtIDH1 and mIDH1 glioma bearing +/-AGI-5198 treatment were harvested for analysis at 27 dpi.…”

“…AGI-5198 (40 mg/kg) or saline was injected i.p into mice bearing mIDH1 glioma at 7,9,11,14,16,18,21,23,25 days post tumor cell implantation (dpi). A course of IR (2 Gy) was administered to mice 5 days a week for two weeks starting at 7 dpi (2, 3).…”

“…In response to 2HG inhibition, PD-L1 expression levels on mIDH1 glioma cells significantly increased to those observed in wild type IDH gliomas. Numerous preclinical solid tumor models have demonstrated that the immune checkpoint blockade of PD-1/PD-L1 interaction prevents T cell exhaustion, resulting in enhanced anti-tumor immune activity and improved MS (18). We previously demonstrated that PD-L1 checkpoint blockade as monotherapy elicited a small increase in MS in mice bearing syngeneic glioma, with only a few long term survivors (19).…”