**11. Immune mediated pneumonitis**

One of the worrisome irAEs is the checkpoint inhibitor pneumonitis (CIP). CIP is a term used to refer to pneumonitis induced by ICI. CIP is defined as the occurrence of respiratory signs or symptoms related to new emerging inflammatory lesions viewed on chest computed tomography (CT) after ICI treatment and after exclusion of pulmonary infection, tumor progression, and other reasons [73].

The incidence of CIP was reported to be between 3% and 5% with a fatality rate between 10% and 17%. However, a higher incidence of pneumonitis was noted in patients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) and in patients treated with combination therapy [74, 75]. The median time to the onset of CIP is approximately 2.8 months post-initiation of ICI, and the overall range spans from 9 days to 19.2 months [76].

Some risk factors may predispose patients to develop pneumonitis with ICI therapy. An example of these risk factor is the type of ICI therapy. Patients receiving anti-PD-1 were found to be at increased risk of CIP as compared to patients on anti-CTLA-4 inhibitors. Other risk factors include combination therapy, cancer's primary site, and prior thoracic radiotherapy. In addition, recent literature indicates that a history of asthma and/or smoking may increase the risk of CIP [9, 77].

CIP can manifest as acute, subacute, chronic, and occult. Dyspnea, cough, and decreased activity tolerance are the most common symptoms of CIP. Sometimes, patient may present with chest pain or fever. For patients presenting with fever, the possibility of infectious pneumonia must be excluded. The main signs of CIP include elevation of inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate in most cases. In some patients, velcro crackles can be heard in the lungs on physical examination [73, 74, 76].

The grading of CIP is mainly based on the severity of signs and symptoms. Grade 1 (G1) is referred to asymptomatic or clinically observed CIP only. When common symptoms occur such as shortness of breath and cough, pneumonitis would be graded as grade 2 (G2). While grade (G3) is referred to pneumonitis manifested as severe symptoms that are limiting the activities of daily living. Finally, life-threatening difficulty in breathing would be defined as Grade 4 (G4) pneumonitis [5, 68, 70].

The main therapeutic modality for CIP is corticosteroids as recommended by guidelines on immunotherapy-related toxicity. If no remission is observed after 48 hours, the specific management approach based on the grade should be followed. G1 pneumonitis is managed by delaying the immunotherapy and monitoring symptoms every 2–3 days; in case of worsening, it should be treated as grade 2. While G2 pneumonitis is treated by withholding ICI therapy and initiating an empirical antibiotic in case infection is suspected. If there is no evidence of infection and no improvement occurred within 48 hours, prednisone should be added; if there is no improvement, it should be treated as G3. In G3 and G4 pneumonitis, ICI therapy should be permanently discontinued, and patient should be admitted to the hospital and should be covered with empirical antibiotic. In case there is

worsening or no improvement after 48 hours, IV steroids should be continued, and initiation of infliximab (or mycophenolate mofetil in case of hepatic toxicity) is recommended [5, 68, 76, 78, 79].

The decision to reintroduce the same ICI therapy in a patient who has recovered from CIP must be made based on the individual agent, the severity of the reaction, and the availability of alternative therapies. Patients with G2 pneumonitis can be re-challenged with the same ICI therapy once symptoms are resolved. However, these patients must be monitored closely and more frequently. Mainly all patients with history of CIP require careful and close monitoring because recurrent CIP has been observed in some patients even if they have not been re-challenged with ICI therapy [23, 26, 57].

### **12. Neurologic immune-related adverse events**

Some irAEs such as neurological toxicities recognition and diagnosis is very challenging [80]. There are limited reported data describing neurological manifestations associated with ICI use, with extrapolated incidence of 1–5% highlighting difficult neurotoxicity recognition and possible underreporting [81, 82].

Commonly reported immune relates neurological or neuromuscular toxicities included myasthenia gravis, peripheral neuropathy, multiple sclerosis, Guillain-Barre syndrome, immune-medicated myopathies and encephalitis/meningitis [62, 63, 81–83]. Early recognition and prompt management of immune related neurotoxicity might prevent severe and/or permanent consequences or uncommonly reported fatalities [84].

A common mechanism of irAEs include T-cell activation by the deactivation of inhibitory regulators. However, there is no clear explanation why some patients develop more immune-related neurotoxicity than others [8, 52].

Median time to onset of serious neurological irAEs, of any grade, was 45 days form ICI initiation in melanoma patients with median time to toxicity resolution of 32 days [82].

#### **12.1 Encephalitis**

Among neurological manifestations associated with ICI use, encephalitis is considered a rare adverse event with a challenging diagnosis [82, 84]. Although, there is no clear causes of immune mediate encephalitis, around 40–70% of cases were linked to infectious etiologies [85]. On that basis, individualized diagnostic approach to immune associated encephalitis is recommended considering identified clinical presentation. Altered mental status, fever, headache, weakness, neck stiffness, sleepiness, hallucinations or seizure among other neurological sequalae of immune mediate encephalitis were reported by affected patients [82].

With no specified encephalitis grading, initial assessment for suspected immune mediated encephalitis includes neurologist consultation, brain magnetic resonance imaging (MRI), lumbar puncture, electroencephalogram (EEG) to evaluate for subclinical seizures, in addition to complete blood count (CBC), comprehensive metabolic panel (CMP) and autoimmune encephalopathy and paraneoplastic panel [5, 68].

Pertaining to encephalitis associated fatalities, permanent discontinuation of suspected ICI is generally recommended [84]. In-patient admission is warranted for grade 3–4 encephalitis. Corticosteroid trial in the form of methylprednisolone *The Flip of the Coin of Personalized Cancer Immunotherapy: A Focused Review on Rare… DOI: http://dx.doi.org/10.5772/intechopen.107833*

could be administered and then tapered over 4 weeks upon resolving of symptoms. Enhanced symptoms severity or progression over 24 hours, requires higher doses of methylprednisolone for 3–5 days with IVIG or plasmapheresis. Rituximab may be considered if minimal or no symptoms improvement was obtained after 7–14 days or in cases of positive autoimmune encephalopathy antibody [5, 68]. Additional therapy such as empirical antibiotics and antivirals could be utilized as well. Empiric antiepileptics are reasonable to address any seizure concerns [81, 84].

#### **12.2 Aseptic meningitis**

Immune related meningitis is poorly differentiated from encephalitis, mainly in metastatic cancer patients treated with ICI with newly presented seizures or impaired cognitive functions [86, 87].

Unlike, immune medicated encephalitis that is more associated with anti-PD-1 treatment, meningitis is linked particularly with ipilimumab (CTLA-4 inhibitor) use [86, 87]. National Comprehensive Cancer Network (NCCN) 2022 guideline recommended initial assessment involves brain MRI, with or without contrast, lumbar puncture when feasible while considering neurologist consultation [5]. Management of ICI induced meningitis do not significantly differ from encephalitis. Withholding ICI is recommended in mild to moderate toxicity conditions, while permanent discontinuation is required in severe case as per NCCN guideline. Corticosteroids may be considered after ruling out suspected bacterial or viral infections [5].

Rechallenging of ICI after suffering immune medicated meningitis was suggested in cases of mild to moderate toxicity grades while assuring complete symptoms resolution before re-starting immunotherapy agent [5].

#### **12.3 Myasthenia gravis**

Immune-mediated myasthenia gravis is an emerging neurologic irAE [88]. Immune-mediated myasthenia gravis induced by ICI use can occur earlier compared to other neurological irAEs (29 vs. up to 80 days) [87].

Concurrent myositis and/or myocarditis are frequently noticed along with immune associated myasthenia gravis, unlike isolated presentation of other immune related neurotoxicity [86, 87].

NCCN 2022 guideline recommend testing for erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), creatinine phosphokinase (CPK), aldolase and antistriational antibodies, pulmonary function, electromyography (EMG) and considering neurologist consultation while assessing suspected immune-mediated myasthenia gravis. Brain MRI may be considered based on presented symptoms and mainly to rule out central nervous system involvement in disease state. Acetylcholine receptor antibodies testing is not mandated for diagnosis [5].

Upon assessment of toxicity, immune mediated myasthenia graves grading is divided into moderate (grade 2) or severe (grade 3–4).

Regardless of grading, permanent discontinuation of ICI should be carried with immune mediated myasthenia gravis. In-patient care to manage patient symptoms is needed while considering intensive care unit in severe cases. In moderate grade of myasthenia gravis induced by ICI, pyridostigmine and low dose corticosteroids could be initiated. In severe cases or grades 3–4, higher doses of steroids, and initiation of IVIG or plasmapheresis are recommended. Rituximab may be adder in cases of refractory symptoms to IVIG or plasmapheresis [5, 68].

Rechallenging of ICI remains controversial after immune medicated myasthenia gravis, however data of safe re-initiation after complete resolution of symptoms is suggested [89].
