Tackling Cancer Resistance by Immunotherapy: Updated Clinical Impact and Safety of PD-1/PD-L1 Inhibitors

Abstract

Cancer therapy has been constantly evolving with the hope of finding the most effective agents with the least toxic effects to eradicate tumors. Cancer immunotherapy is currently among the most promising options, fulfilling this hope in a wide range of tumors. Immunotherapy aims to activate immunity to fight cancer in a very specific and targeted manner; however, some abnormal immune reactions known as immune-related adverse events (IRAEs) might occur. Therefore, many researchers are aiming to define the most proper protocols for managing these complications without interfering with the anticancer effect. One of these targeted approaches is the inhibition of the interaction between the checkpoint protein, programmed death-receptor 1 (PD-1), and its ligand, programmed death-ligand 1 (PD-L1), via a class of antibodies known as PD-1/PD-L1 inhibitors. These antibodies achieved prodigious success in a wide range of malignancies, including those where optimal treatment is not yet fully identified. In this review, we have critically explored and discussed the outcome of the latest PD-1 and PD-L1 inhibitor studies in different malignancies compared to standard chemotherapeutic alternatives with a special focus on the clinical efficacy and safety. The approval of the clinical applications of nivolumab, pembrolizumab, atezolizumab, avelumab, and durvalumab in the last few years clearly highlights the hopeful future of PD-1/PD-L1 inhibitors for cancer patients. These promising results of PD-1/PD-L1 inhibitors have encouraged many ongoing preclinical and clinical trials to explore the extent of antitumor activity, clinical efficacy and safety as well as to extend their applications.

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

“…Echinococcus multilocularis proliferation and some malignant tumours are both sharing similar features such as local immune evasion, induction of tolerance and disruption of T cell signalling, and T cell exhaustion at late stage of infection . Monoclonal antibodies targeting PD‐1 or PD‐L1 are in clinical use demonstrating high efficacy in lung, colon, head, neck and gastric cancers, in addition to renal cell carcinoma and melanoma …”

Immunomodulatory MicroRNAs in cancer: targeting immune checkpoints and the tumor microenvironment

“…For example, the overall response rate to treatment with anti-PD-1 immune checkpoint inhibitors pembrolizumab or avelumab monotherapy in patients with triple-negative breast cancer that is positive for PD-L1 is 18.5% (n = 27) and 44.4% (n = 9) [12]. Also, the cost of immunotherapeutic agents is higher than the other conventional therapies, and their use is associated with the development of some immune-related adverse effects [15]. Therefore, finding efficient biomarkers that aid in optimal patient selection is still on the top-ranked research concerns that are extensively studied.…”

“…Until now, there are no approved therapeutic agents that specifically target PD-L2. In many clinical trials, PD-1/PD-L1 inhibitors showed superior efficacy and safety compared to the traditional chemotherapeutic agents [14,15]. However, the low response rates and the development of resistance are still among the major challenges encountered by this class of anticancer agents.…”

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

“…However, although these methods have greatly increased the lifespan of many patients with malignant neoplasms, many patients with common cancer types do not respond to this treatment. Besides, inhibition of immune checkpoints causes multiple side effects, mostly autoimmune inflammatory reactions termed immune‐related adverse events …”