**1. Introduction**

Immune evasion or the ability to evade immune recognition is one of the hallmarks of cancer growth. Cancer cells are able to spread uninhibited by avoiding detection [1] and from that prospective immunotherapy medications were developed and

revolutionized the field of oncology. They have been considered the most important development in cancer treatment over the past decade. With recent advancements in immunology and cancer biology, new classes of immunomodulatory therapy have been developed to aid tumor management [2]. Among the most important targeted pathways of this line of therapy is the inhibition of the cytotoxic T-lymphocyteassociated protein (CTLA-4) and programmed death-1 (PD-1) immune checkpoint. Numerous studies have highlighted the significantly improved survival with the use of immunomodulatory therapy in locally advanced and metastatic cancers including melanoma, lung cancer, urothelial cancer, gastric cancer, renal and hepatocellular carcinoma, and other solid tumors. Trials in other malignancies are ongoing, and undoubtedly the number of drugs in this space will grow beyond the drugs currently approved [2].

Current approved immunotherapy agents are nivolumab, pembrolizumab, cemiplimab, and dostarlimab; all which target PD-1. Moreover, atezolizumab, avelumab, and durvalumab, all of which target programmed death lingand-1 (PDL-1). While ipilimumab is the only drug that targets CTLA-4 [3]. One of the most known complication of these advances is the emergence of a new spectrum of immunerelated adverse events (irAEs). Such toxicities are known to be distinctly different from classical chemotherapy-induced adverse events [4–7].

### **2. Mechanism of immune-related adverse events**

The mechanism of irAEs remains unclear; however, it is believed to be related to the immune dysregulation caused by immune checkpoint inhibitors (ICI) [8]. Four potential mechanisms leading to the development of irAEs have been postulated. Firstly, increasing T-cell activity against antigens that are present in tumors and healthy tissues. Secondly, increasing levels of pre-existing autoantibodies. Thirdly, increasing level of inflammatory cytokines. Finally, the direct binding of an antibody against CTLA-4 with CTLA-4 expressed on normal tissues that results in enhanced complement-mediated inflammation [7, 9].

irAEs occur in nearly 90% of patients who are receiving CTLA-4 inhibitors, 70% of patients who are receiving anti-PD-1 or anti-PD-L1, and approximately all patients treated with combined therapy [10–19]. Severity of most of the reported irAEs is grade 1–2. For patients treated with CTLA-4 inhibitors, irAEs mostly involve the skin (44%), gastrointestinal tract (35%), endocrine system (6%), and liver (5%). Although severe irAEs remain rare, they can become life-threatening if not anticipated and managed appropriately [10–20].

The frequency of treatment-related adverse events in general was classified by the World Health Organization as follow: common toxicities arise at the rate of >1% (>1 in 100), uncommon toxicities of 1–0.1% (1 in 100 to 1 in 1000), rare toxicities at a rate of 0.1–0.01% (1 in 1000 to 1 in 10,000), and very rare toxicities at a rate of less than 0.01% [21].

In this chapter we will focus on selected rare or very rare irAEs, shedding the light on the other side of the coin of personalized cancer immunotherapy. We will also discuss general management approach of irAEs with an in-depth look on each one of these rare irAEs. The chapter will also cover principles of immunotherapy rechallenge post occurrence of irAEs, and the impact of irAEs incidence on the efficacy of ICI.

*The Flip of the Coin of Personalized Cancer Immunotherapy: A Focused Review on Rare… DOI: http://dx.doi.org/10.5772/intechopen.107833*

### **3. General treatment approach of immune-related adverse events**

In general, treatment is based on the severity of the observed toxicity defined according to Common Terminology Criteria for Adverse Events Version 5.0, (CTCAEs v5) [22]. For most of patients with moderate (grade 2) irAEs, treatment with ICI should be withheld and should not be resumed until toxicity becomes grade 1 or less. In addition, systemic glucocorticoid should be started if symptoms did not resolve within 1 week. For patients with severe (grade 3) or life-threatening (grade 4) irAEs, treatment with ICI should be permanently discontinued and higher doses of systemic glucocorticoid should be given. Glucocorticoids can be tapered gradually over a minimum duration of 1 month when symptoms subside to grade 1 or less. Use of other immunosuppressive agents such as infliximab, vedolizumab, mycophenolate mofetil can be considered in case of refractory toxicity to glucocorticoids [5, 20].
