**2. Approved immune checkpoint inhibitors**

T cell activation is critical for normal physiology to suppress carcinogenesis. During carcinogenesis, tumor cells present neoantigens which, in complex with the major histocompatibility complex (MHC), and together with various costimulatory signals, activate naïve T cells through intracellular signals. This process is balanced by signaling through inhibitory molecules called checkpoint inhibitors on the tumor and T cells [4]. However, cancer cells have developed mechanisms to antagonize T cell activation, thereby promoting carcinogenesis. Strategies have been developed to exploit events at the checkpoint synapse to design anticancer therapeutic drugs. In **Figure 1**, the schematic diagram shows the points at which various immunotherapeutic drugs intervene in cancer progression. Currently, approved immune checkpoint drugs target CTLA-4, PD-1, PD-L1, and LAG-3 (**Table 1**). Significantly, all the approved ICIs are indicated for solid tumors, but few are effective against hematological cancers. We discuss their success and current limitations. We consider success to be associated with the overall response rate (ORR), which is generally defined as the proportion of patients who achieve a complete or partial response per RECIST (Response Evaluation Criteria in Solid Tumors) or WHO (World Health Organization) criteria.

#### **2.1 CTLA4 inhibitors**

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4 or CD152) is a membrane glycoprotein expressed exclusively on the surface of effector T cells. Despite sharing only 30% sequence similarity with the T cell surface receptor CD28, CTLA-4 has similar structural and functional properties [57]. CTLA-4 and CD28 regulate T cell responses, with CD28 having a stimulatory effect and CTLA-4 having an inhibitory effect. Both receptors bind to B7 ligands (CD80 and CD86) found on antigen-presenting cells (APCs). However, CTLA-4 has been shown to have a higher affinity for these molecules and competes for binding to common ligands [58]. CTLA-4 usually aids in maintaining self-antigen immunity by preventing T cell activation (**Figure 1A**). However, when CTLA-4 binds to B7 ligands present on cancer cells, it exerts an antagonistic effect on T cell activation and results in the evasion of immune responses. Blockade of the CTLA-4/ B7 axis invigorates T cell activation and proliferation and therefore presented a unique therapeutic opportunity for cancer patients [59].

Ipilimumab (Yervoy®) is the first immune checkpoint inhibitor that the FDA approved for the treatment of human cancers. Ipilimumab is a humanized IgG1 antibody developed by Bristol-Myers Squibb, and targets CTLA-4, thereby preventing its interaction with B7 ligands (**Figure 1B**). Ipilimumab was initially approved by the FDA for the treatment of late-stage unresectable melanomas in 2011 (**Table 1**). In 2015, it was further approved for cutaneous melanomas [5, 60]. In melanomas,

*Current Advances in Immune Checkpoint Therapy DOI: http://dx.doi.org/10.5772/intechopen.107315*

#### **Figure 1.**

*Mechanism of immune checkpoint inhibitors. (A) Immune checkpoint proteins present on T lymphocytes interact with corresponding ligands on tumor cells, which leads to an alteration in normal T cell phenotypes. The main outcome is the suppression of T cell activation and the resultant decrease in the immune response. (B) Immunotherapy targeting CTLA-4 that disrupts the binding of the B7 family and subsequent signaling. (C) Anti-PD-1 immunotherapy disrupting the interaction with PD-L1/2. (D) The PD-1 and PD-L1 pathway being inhibited by an antibody against PD-L1. (E) The dual blocking of the LAG-3/MHC II pathway and PD-1/PD-L1 pathway, using antibodies that target LAG-3 and PD-1 simultaneously. Blocking these interactions between immune checkpoint proteins and their ligands, using the targeted antibodies, results in a reversal of T cell inhibition.*

Ipilimumab exhibited an ORR of 10.9%. In 2018, Ipilimumab received approval for the treatment of renal cell carcinoma (RCC) (ORR 40.4%) and metastatic colorectal cancer (ORR 49%) in conjunction with Nivolumab [7, 61]. More recently, Ipilimumab was approved in conjunction with Nivolumab for non-small cell lung cancer (ORR 36%), malignant pleural mesothelioma (ORR 40%), and hepatocellular carcinoma (ORR 32%) in 2020 (**Table 1**) [40, 62, 63].

Although not yet approved, Tremelimumab is in the final stages of approval. Tremelimumab is a human IgG2 monoclonal antibody that also targets the CTLA-4 receptor. Following the promising results obtained from the HIMALAYA Phase III trial [64] Tremelimumab in combination with Durvalumab (STRIDE (Single T Regular Interval D) regimen) was accepted under Priority Review by the FDA for patients with unresectable hepatocellular carcinoma. The clinical trial demonstrated that patients experienced an improved median overall survival (OS) (16.4 months) and


*Current Advances in Immune Checkpoint Therapy DOI: http://dx.doi.org/10.5772/intechopen.107315*



#### **Table 1.**

*FDA-approved immune checkpoint inhibitors.*

overall response rate (20.1%) when compared to Sorafenib treatment (13.8 months and 5.1%, respectively). An approval decision in the fourth quarter of 2022 is expected. These data suggest that a combination of an ant-CTLA-4 and an anti-PD-L1 as a strategy may be a feasible approach.

#### **2.2 PD-1 inhibitors**

Programmed cell Death 1 (PD-1) (also known as CD279) is a co-inhibitory transmembrane protein that is expressed on antigen-stimulated T and B lymphocytes, natural killer (NK) cells, and myeloid suppressor dendritic cells (MDSCs). PD-1 is activated via antigen recognition or cytokine stimulation and results in the modulation of immune response intensity [65]. PD-1 ligands, namely, programmed death ligands 1 and 2 (PD-L1 (B7-H1) and PD-L2 (B7-DC)), are widely expressed on antigenpresenting cells. The interaction between PD-1 and its ligands results in the inhibition of lymphocyte proliferation or activation, culminating in T cell exhaustion (**Figure 1A**) [65–68]. To date, the FDA approved four PD-1 immune checkpoint inhibitors for the treatment of human cancers, namely Pembrolizumab (Keytruda®), Nivolumab (Opdivo®), Cemiplimab (Libtayo®), and Dostarlimab-gxly.

Pembrolizumab (MK-3475 or Lambrolizumab, Keytruda) is a humanized IgG4 antibody against PD-1, developed by Merck. The FDA initially approved it for the treatment of patients with unresectable or metastatic melanoma in September 2014 after the KEYNOTE-001 clinical trial (NCT01295827) [69]. These patients had to have had prior unsuccessful treatment with Ipilimumab. Pembrolizumab binds to the PD-1 receptor, thereby disrupting the PD-1 pathway and resulting in the restoration of the antitumor immune response of T lymphocyte cells (**Figure 1C**) [70–72]. Pembrolizumab has subsequently been approved for treatment predominantly as monotherapy and occasionally as part of a combinational therapy for an additional 16 cancer types (**Table 1**). The overall/objective response rates to Pembrolizumab ranges from 12 to 69% in these various cancers. The adverse reactions to Pembrolizumab include both immune-related adverse effects (irAEs) and infusion-related reactions. irAEs include encephalopathy, pneumonia, nephritis, hepatitis, myocarditis, and colitis. However, the most common adverse effects (reported in ≥20% of patients) are fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain [65, 69].

Nivolumab (Opdivo, ONO4538, MDX-1106, or BMS-936,558) is a genetically engineered, fully humanized IgG4 mAb against PD-1 developed by Bristol-Myers Squibb. Like Pembrolizumab, the FDA-approved Nivolumab for the treatment of unresectable or metastatic melanoma, which had progressed after prior treatment with

#### *Current Advances in Immune Checkpoint Therapy DOI: http://dx.doi.org/10.5772/intechopen.107315*

Ipilimumab. Nivolumab was approved in December 2014 after the CheckMate-037 trial, which tested its efficacy when combined with chemotherapy. Nivolumab selectively inhibits the interaction between the PD-1 and its ligands, PD-L1, and PD-L2. It achieves this by binding to the PD-1 receptor and interfering with the negative regulation of T lymphocyte activation and proliferation caused by the PD-1 pathway, including the antitumor immune response [73, 74]. Since Nivolumab was first approved for the treatment of melanoma in 2014 [22], it has subsequently been approved by the FDA for the treatment of an additional seven cancer types, either in monotherapy or as part of combination therapy (**Table 1**). The overall/objective response rates to Nivolumab ranges from 12 to 65% in the various cancers. Nivolumab is also the most used ICI for combination with CTLA-4 inhibitors and most recently a LAG-3 inhibitor. Serious adverse effects to Nivolumab include increased risk of severe immune-mediated inflammation in the lungs, the colon, the liver, and the kidneys, immune-mediated hypothyroidism and hyperthyroidism and autoimmune diabetes [75–77].

Cemiplimab (REGN2810, SAR439684, Libtayo) is a human IgG4 anti-PD-1 mAb developed by Sanofi/Regeneron. It was approved in September 2018 for the treatment of metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC in patients who did not qualify for surgery or radiation [32, 78]. cSCC has a high mutational burden and is therefore hard to treat. Cemiplimab binds to the PD-1 receptor and blocks its interaction with PD-L1, resulting in the upregulation of cytotoxic T cells and an increase in the antitumor activity of the immune system (**Figure 1C**) [78–80]. After its first approval in 2018, it was further approved by the FDA in 2021 for the treatment of two additional cancers, namely basal cell carcinoma and non-small cell lung cancer (**Table 1**). The overall/objective response rate to Cemiplimab ranges from 31 to 49% in the three cancer types. Reported adverse effects of Cemiplimab include severe and fatal immune-mediated adverse reactions in any organ, system, or tissue, including pneumonia, colitis, hepatitis, endocrine disorders, adverse skin reactions, nephritis, and renal dysfunction. In addition, severe infusionrelated reactions (Grade 3) can also occur. However, the most common adverse reactions are fatigue, rash, and diarrhea [65, 78, 79].

Recently, in August 2021, the FDA accelerated the approval of the novel PD-1 humanized IgG4 monoclonal antibody known as Dostarlimab-gxly (Jemperli, GlaxoSmithKline LLC) for patients with mismatch repair deficient (dMMR) recurrent or advanced solid tumors after clinical trial NCT02715284 [81]. The overall response rate was 41.6% (95% CI: 34.9, 48.6), with a 9.1% complete response rate and a 32.5% partial response rate. The most reported adverse reactions in patients with dMMR solid tumors were fatigue, anemia, diarrhea, and nausea. Most common Grade 3 or 4 adverse reactions included anemia, fatigue, increased transaminases, sepsis, and acute kidney injury. In a few patients, immune-mediated adverse reactions are associated with Dostarlimab. These include pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, and dermatologic toxicity. In 2022, Dostarlimab was preferred for treating colon cancer, as a small group of 12 patients in clinical Phase II responded positively to the drug, with a 100% complete response rate. This is a rare phenomenon in clinical trials (NCT04165772) [82]. In addition, no adverse events of Grade 3 or higher or relapse were reported. However, the FDA has not yet approved Dostarlimab for the treatment of colon cancer.
