**4.2 Clinical application of CTLA-4 inhibitor**

In 2010, the FDA authorized ipilimumab for advanced melanoma treatment, making it the first medicine with a survival advantage for metastatic melanoma. Long-term studies have shown that antitumor immunity persists following CTLA4 inhibition, confirming the stability of this survival effect [53]. Unfortunately, findings from trials in renal cell carcinoma [54], non-small-cell lung cancer [55], small-cell lung cancer [56], and prostate cancer [57] were less effective than those reported in melanoma patients. The FDA has not yet approved tremelimumab, an IgG2 isotype CTLA4-blocking antibody, because it did not extend survival in patients with advanced melanoma. It is believed that the effectiveness of ipilimumab and tremelimumab differs due to differences in binding kinetics and the ability to mediate cytotoxicity [58].

*Perspective Chapter: Role of Immunosuppressive and Immunomodulatory Agents in Cancer DOI: http://dx.doi.org/10.5772/intechopen.109072*

#### **4.3 PD-1/PD-L1**

PD1 was initially considered to be a potential modulator of apoptosis. However, later data revealed a role in regulating hyperactivation of the immune system, like CTLA4 [59]. CTLA4 and CD28 have 20% and 15% amino acid identity, respectively [60]. CTLA4 limits T-cell activation in peripheral tissues, whereas PD1 regulates T-cell activation predominantly within lymphoid organs. Relatively, the PD1 axis performs a particular role in self-tolerance in T cells [47].

#### **4.4 Clinical application of PD-1/PD-L1 inhibitor**

Pembrolizumab and nivolumab (both IgG4), humanized and completely human anti-PD1 monoclonal antibodies (mAbs), were the first FDA-approved PD1-targeted therapies for refractory and unresectable melanoma in 2014 [61]. Pembrolizumab exceeded ipilimumab in six-month progression-free survival and overall survival [62]. Pembrolizumab was approved in 2015 for treating non-small-cell lung cancer because it increased progression-free survival by 4.3 months compared to platinum-based chemotherapeutics and was more productive than paclitaxel [63]. However, the different organs have distinct immunosuppressive microenvironments, so it's difficult to anticipate which patients may benefit. Nivolumab has since been approved for treating renal cell carcinoma, head and neck squamous cell carcinoma, urothelial carcinoma, hepatocellular carcinoma, Hodgkin lymphoma, and colorectal cancer, similar to pembrolizumab [64].

PDL1 also targeted several antibodies that have benefits for cancer treatment. Atezolizumab (an IgG4 antibody), the first PDL1-targeted humanized mAbs, was licensed to treat urothelial cancer in 2016 [65]. However, more trial results have not shown that atezolizumab has clinical efficacy in urothelial carcinoma over the standard of treatment, even though it is less toxic than conventional chemotherapy [66]. In 2017, avelumab and durvalumab, two new anti-PDL1 human mAbs, were introduced to the market [67]. As a result, similar to PD1, blocking PDL1 is successful in difficult-to-treat cancers.

#### **4.5 Clinical challenges during the blockade of immune checkpoint**

Potent immune effector mechanisms are activated by blocking a naturally occurring immunological checkpoint [68]. According to a meta-analysis study, immunerelated adverse events are expected to occur in 15–90% of patients. However, patients treated with CTLA4 and PD1 inhibitors have more severe episodes that require intervention in 15–30% of cases [69]. In addition, patients receiving anti-CTLA4 medication are at a higher risk of hypothyroidism, hepatotoxicity, and pneumonitis. In contrast, the patient that receives PD1-targeted drugs is more likely to develop hypothyroidism, hepatotoxicity, and pneumonitis [70].

Adverse events are particularly problematic in adjuvant chemotherapy because late-onset, frequently severe toxicities can impact tumor-survivor patients even after surgery only [71]. However, the toxicity of immune checkpoint inhibitors is more tolerable than that of conventional chemotherapeutics [72].

### **5. Conclusion and future perspectives**

A decade after immune checkpoint protein discovery, such as PD-1/PDL-1 and CTLA-4, still offers hope for the cure for cancer patients. Although not all patients may benefit from these medications, some of the drugs demonstrated dosedependent adverse events of mild to moderate. Unfortunately, not every cancer type responds well to the treatment, and the only options are to discontinue therapy or switch to conventional cancer treatments.

Even though several studies showing the side effects of ICI do not discourage researchers from developing the new finding, these drugs will probably be examined in adjuvant or neoadjuvant approaches, based on clinical responses in various cancer types, to increase the overall survival of many cancer patients. In addition, understanding the systemic effect mechanism caused by immunotherapy may help gain better knowledge for an effective antitumor response. Finally, combination therapy with various immunotherapy, chemotherapy, targeted medicines, radiation, and T-cell-based therapies can potentially improve the outcomes, especially in patients who have not responded well to immunotherapy-based treatments.
