Current Advances in Immune Checkpoint Therapy

*Bonnie L. Russell, Sibusiso T. Malindisa, Selisha A. Sooklal and Monde Ntwasa*

#### **Abstract**

Although immune checkpoint inhibitors (ICIs) have shown survival benefits for patients with metastatic cancers, some challenges have been under intense study in recent years. The most critical challenges include the side effects and the emergence of resistance. Potential opportunities exist to develop personalized immune checkpoint inhibitor therapy based on biomarker discovery. Combinational therapy involving immune checkpoint inhibitors and other forms of anticancer therapies has varied success. This chapter reviews drugs currently undergoing Phase III clinical trials and others that are FDA-approved. We take a critical look at the combinational strategies and address the ever-present challenge of resistance. Moreover, we review and evaluate the discovery of biomarkers and assess prospects for personalized immune checkpoint therapy.

**Keywords:** immune checkpoint inhibitors, PD-1, PD-L1, CTLA-4, FDA-approved, ICI resistance, combinational therapy, biomarkers

#### **1. Introduction**

Immunotherapy including the use of immune checkpoint inhibitors (ICIs) exploits the immune system's components to fight cancer progression. The use of immunotherapy on its own or in combination with conventional cancer treatments such as chemotherapy or radiation has been relatively successful in many cancers [1]. Immune checkpoint proteins are co-inhibitory receptors that are responsible for keeping the immune system in check. Cancer cells exploit these receptor proteins in order to induce tumor tolerance and T cell exhaustion [1, 2]. The FDA has approved treatments for several cancers with immune checkpoint inhibitors that target cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death 1 (PD-1), programmed cell death ligand 1 (PD-L1), and most recently, lymphocyte activation gene-3 (LAG-3). However, there are several additional molecules in clinical trials (Phases I, II, and III) that target immune checkpoint proteins as monotherapy or in combination with other ICIs or different kinds of therapy such as small molecule drugs, chemotherapy, or radiotherapy. Although some adverse reactions occur after treatment with immune checkpoint inhibitors, the main issue encountered is resistance [3]. The most promising strategy to overcome resistance is the use of

combination therapies. However, the identification of reliable biomarkers that can predict resistance and response to ICIs may assist in guiding patient selection and identifying those that will indeed benefit from treatment. Numerous biomarkers have been developed in this regard; however, current biomarkers are challenged with technical limitations. In this review, we present FDA-approved ICIs and novel ICIs in clinical trials. In addition, we address ICI resistance and the use of combinational therapy strategies to overcome it, as well as discuss some of the most extensively studied biomarkers and the limitations associated with each.
