**13. Infectious immune-related adverse events**

#### **13.1 Mycobacterium tuberculosis activation/reactivation**

Extended immune response modulation as a response to ICI therapy in addition to administered corticosteroids and/or other immunosuppressants for irAEs management may increase the risk of opportunistic infections [90]. Moreover, such immune response extended manipulation may augment preexisting chronic infections or mask clinical presentations of serious infections such as cytomegalovirus-enterocolitis, pneumocystis pneumonia, infection by varicella-zoster virus, activation of latent tuberculosis, and pulmonary aspergillosis [90]. In addition to that, atypical mycobacterial infection was reported in association with anti PD-1/ anti-PD-L-1 therapy [91].

In a review of metastatic melanoma patients treated with different ICIs either anti-CTLA-4, PD-1, and/or PD-L1; the incidence of immune-medicated serious infections was estimated to be 7.3%, with an average time of onset of 135 days from the start of ICI therapy [92]. Highlighted risk factors for developing serious infections included corticosteroids and infliximab use as well as the combination of CTLA-4 inhibitor and anti-PD-1 (mainly nivolumab) [92]. On the contrary, the authors of a retrospective review of melanoma patients treated with ICI concluded that the use of pembrolizumab, an anti-PD-1, was associated with protection against serious infections [92].

Mycobacterium tuberculosis (Mtb) reactivation is an emerging infectious complication of ICI therapy that has been reported with the use of nivolumab [93], pembrolizumab [94] and atezolizumab [95].

Although there is no clear mechanism of action for Mtb reactivation associated with ICI use, preclinical studies on mice [96] and human who administered anti-PD-1 suggested an increase in CD4 T cells production of interferon alfa (INF-α) leading to further bacterial replication [97, 98]. Moreover, extended immunity response could lead to augmented cytotoxicity or extracellular destruction potentiating the growth of Mtb and facilitate disease transmission [99, 100].

A recent systematic review supported the relation between the use of anti-PD-L-1 and Mtb reactivation. Mtb reactivation was disseminated to multiple organs other than the lungs, with reported fatalities [101]. Testing cancer patients for latent Mtb prior the initiation of ICI and use of Mtb chemoprophylaxis, if tested positive, lack the evidence [95], however, is highly recommended for consideration in high-risk individuals [94].

NCCN 2022 guideline recommends baseline testing for latent/active Mtb in patients treated with anti-tumor necrosis factor alfa (TNF-α) that is indicated for the management of irAEs. Moreover, Mtb testing shall not delay the start of anti- TNF-α [5]. There is lack of evidence for the management of immune mediated Mtb reactivation, however, withholding ICI during active infection to avoid possibly excessive inflammatory response is warranted. After anti-Mtb treatment initiation, the safe timing of ICI resumption is not clearly defined. A two-week duration of anti-Mtb prior re-initiation of immunotherapy was suggested [95].

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

#### **13.2 Hepatitis B reactivation**

In relation to PD-1 pathway and hepatitis B virus (HBV), it is previously proven that upregulation of PD-1 is associated with HBV specific T cell dysfunction. In hepatocellular carcinoma patients, PD-L expression was shown to be connected to HBV load [102, 103]. Moreover, it was noted that lung cancer patients with chronic HBV infection have a significantly higher PD-L-1 expression compared to patients lacking HBV infection [104].

Patients with active infections including viral hepatitis B/C or human immunodeficiency virus (HIV) were usually excluded from ICI clinical trials [105]. Considering the possible risk of HBV reactivation for patients with chronic or resolved HBV infections, baseline hepatitis serology should be performed for all patients being treated with ICI with aspartate transaminase (AST)/alanine transaminase (ALT) and HBV deoxyribonucleic acid (DNA) being monitored closely throughout immunotherapy treatment [105– 109]. While anti-PD1 was safely administered to lung cancer patient with HBV infection [110, 111], some fatal HBV reactivation associated with durvalumab was reported [105].

### **14. Cardiac immune-related adverse events**

ICI cardiotoxicity most reported manifestations included acute coronary syndrome, arrhythmias, cardiomyopathy, and vasculitis, while myocarditis being mostly reported with high morbidity and mortality rates [112–115]. The exact mechanism of ICI cardiotoxicity is not completely understood. In animal models, ICI use shown to make cardiac cells more vulnerable to injury; this was explained that PD 1, and CTLA-4 pathways appeared to have cardioprotective effects against immune-mediated damage due to stress [116, 117].

The prevalence of reported myocarditis, in an international multicenter registry, was 1.14%, while reaching up to 2.4% with the combination of more than one ICI [118]. The median time of onset is 34 days with majority of presentations occur within 3 months of the start of ICI therapy [119]. Despite that, cardiotoxicity can still present at any time during treatment and even after discontinuation of the therapy [120, 121].

Due to the lack of typical clinical symptoms, and challenges in diagnosis and differentiation from other cardiac disease, the incidence of ICI-related myocarditis is underestimated [112, 113, 122]. Moreover, true incidence of smoldering or subclinical myocarditis is underreported as well [114].

The fatality rate of ICI-related myocarditis increases with the combination of anti-CTLA-4 inhibitors with anti-PD-1/anti-PD-L1, compared to monotherapy with anti-PD-1/anti-PD-L1 [114, 119, 123].

Although risk factors for developing ICPI-related cardiotoxicities are not fully understood, underlying autoimmune diseases is thought to be an independent risk factor [124, 125]. Other risk factors identified in an international registry included use of combination therapy of two or more ICP, CTLA-4 inhibitors, diabetes mellitus, and obesity [119, 126]. Moreover, higher prevalence of ICPI-induced myocarditis was highly reported in patients with pre-existing hypertension (60% vs. 48%, p < 0.009), tobacco use (48% vs. 17%, p < 0.001), of male gender (65% vs. 55%, p = 0.02) and patients on statin (39% vs. 29%, p = 0.04) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (32% vs. 23%, p = 0.04) [126].

As per the NCCN 2022 guideline, immediate cardiology assessment along with echocardiogram (ECG) at baseline or with any suspected immune mediated cardiotoxicity, cardiac biomarkers (troponin I or T, creatine kinase (CK), B-type natriuretic peptide (BNP) or N-terminal (NT)-pro hormone BNP (NT pro BNP) and lipid panel), Cardiac MRI (if possible), and inflammatory markers are needed for assessment and grading of cardiovascular irAEs. Cardiac catheterization and/or myocardial biopsy is considered if myocarditis is suspected [5].

Based on the American Society of Clinical Oncology (ASCO) clinical practice guideline, four categorized grading are defined based on the intensity of clinical presentation into: Grade 1 (G1) and G2 for considerably stable or minimally symptomatic patients, and G3 and G4 for unstable or very symptomatic patients [127].

Further grading criteria such as myocarditis versus pericarditis or pericardial effusion, rather than numerical grading, was applied in NCCN guideline [5].

Withholding the ICI when immune mediated myocarditis is suspected is an essential step in management while initiating further necessary workup [5, 115, 127].

Further management of confirmed ICI- induced myocarditis utilizes high dose intravenous (IV) steroids for 3–5 days. Upon follow up, and if the patient is responding and stable, IV steroids could be switched to oral form and then tapered slowly over 6–12 weeks depending on biomarkers improvement and clinical response. If no such improvement was obtained within 24–48 hours after steroids initiation, additional immunosuppressive therapies could be considered such as: mycophenolate mofetil, tacrolimus, alemtuzumab [128], and abatacept [129]. In hemodynamically unstable patients, further options are suggested including anti-thymocyte globulin (ATG), IVIG, and plasmapheresis [5, 115, 127].

It is still controversial and requires an individualized decision by multidisciplinary team to rechallenge patients who developed ICI-induced myocarditis, where single ICI is recommended upon rechallenging [127]. Severity of cardiotoxicity, status of disease, further treatment options and patient preference should be considered for rechallenging decisions [23, 26].

### **15. Summary**

It has been proven that the use of immunomodulatory therapy has significantly improved survival in locally advanced and metastatic cancers. However, the use of ICIs was associated with some adverse events. This chapter focused on selected rare or very rare irAEs including cutaneous irAEs, immune mediated hypophysitis, hematological irAEs, ophthalmic irAEs, checkpoint inhibitor pneumonitis (CIP), neurologic irAEs, infectious irAEs, and cardiac irAEs. Immune-mediated T cell activation underlines the efficacy as well as possible explanation of most irAEs. In general, treatment of irAEs is decided based on the severity of the observed toxicity which can be defined according to Common Terminology Criteria for Adverse Events Version 5.0, (CTCAEs v5). After resolution of symptoms associated with irAEs, a consultation with the irAEs designated specialists might be appropriate before deciding to rechallenge or permanently discontinue the immunotherapy.

This chapter tried to highlight the significance of identifying emerging rare and very rare irAEs while considering initial assessments and management approaches identified in various clinical practice guideline and primary literature data.
