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With the advent of immunotherapy many changes have been made in cancer treatment. Particularly, it has revolutionized the treatment of metastatic renal cell carcinoma (mRCC) with immune checkpoint inhibitors (ICIs), being com monly administrated in combination with ty rosine kinase inhibitors (TKIs), other ICIs or as monotherapy1. Second line therapies in mRCC were established after several studies. Treat ment with the programmed death protein 1 (PD1) checkpoint inhibitor nivolumab alone in second line was first introduced in Checkmate 025, a randomized study that compared evero limus and nivolumab in pretreated patients (without mTOR inhibitors at first line). Primary end point was overall survival (OS), which was 5.4 months longer in the nivolumab arm (me dian 25 vs. 19.6 months)2.
The immune system is tightly regulated by a network of cells, molecules, signal pathways and receptors. ICIs prevent T lymphocytes at tenuation by blocking the binding of inhibi tory signals or enabling activating signals. This mechanism allows a more reactive immune system response against the tumor, but this disruption of immunological tolerance results in a lower response of Treg lymphocytes, a rise of auto antibodies, proinflammatory cytokines and complement activation, which explains the variety of immune related adverse events3. This mechanism of action is far from that of chemo therapy with a hugely different toxicity profile. Therefore, clinical oncologists should be aware of all the new spectrum of adverse events asso ciated with immunologic treatment.
The most common IRAEs are rash, colitis and pneumonitis4. Neurologic events are infre quent but may be serious and potentially life-threatening complications requiring immedi ate immunosuppressive therapy. These include cases of immune encephalitis which is a rapidly progressive encephalopathy caused by brain inflammation and cannot be distinguished from other encephalitis etiologies based on clinical symptoms5. Diagnosis process includes physi cal examination with new focal CNS findings, seizures not explained by a previously known seizure disorder, lumbar puncture (LP) with ce rebrospinal fluid (CSF) pleocytosis, MRI features suggestive of encephalitis6 with the suspicion of immune etiology in the context of ICI treatment. It also includes ruling out other causes such as infectious, paraneoplastic and metastatic. Auto antibodies may be present and support diagno sis, but they are not part of the early diagnos tic criteria as results can take several weeks. Standard treatment in these cases is immuno suppressive therapy, primarily with high-dose corticosteroids. If no clinical improvement is achieved, immunosuppressants such as immunoglobulins or rituximab are added. Also, antibi otic treatment is necessary from the beginning since viral or bacterial encephalitis could be fa tal without treatment.
Paraneoplastic encephalitis mimics the neu rologic symptoms but commonly precedes can cer diagnosis and does not respond to immuno suppressive treatment7. The faster treatment is initiated the better is the recovery.
Larkin et al analyzed neurologic immune related adverse event (IRAE) from 12 studies, including 3763 patients with metastatic mela noma, treated with ipilimumab plus nivolumab or nivolumab alone. The rates of severe neuro logic adverse events were 0.93%. Encephalitis was present in 6 patients (less than 0.2%), with a unique fatal event8.
Although IRAEs may be severe, they are cor related with response. The rationale for this as sociation is that blocking the inhibition of the immune system activates an hyperreactive immune system that could affect to both tumor re sponse and autoimmunity9.
We present a case of autoimmune encephalitis with treatment interruption and subsequent ma jor long-term response that even lasts till today.
Clinical case
In November of 2017, a 67-year-old woman with stage IV clear cell renal cell carcinoma on second line treatment with nivolumab, was admitted at the emergency depart ment, a week after her 18th application, with a two-week progression of a subacute confusional syndrome that add urinary incontinence and a single fever episode.
Her kidney cancer was diagnosed in February of 2014 in a localized stage so partial nephrectomy was performed. Pathology was consistent with stage 1 clear cell renal cell carcinoma Fuhrman grade 3. Pulmonary relapse was evi denced in the oncological control of March 2016, thus first line treatment with pazopanib was initiated, and due to the progression in the size of the lesions, second line with nivolumab started in January 2017 with partial response (Fig. 1). She had no history of neurological disorders, was not on any medication. Her background was being a for mer smoker, hypertension and had a mechanical aortic and a mitral valve replacement in 2015.
Physical examination at emergency entrance evi denced fever 38 degrees Celsius, Glasgow Coma Scale score of 15, minimental state of 11, apraxia, temporal and spatial disorientation, bradypsychia, perseveration, inat tention and slow speech.
No signal of motor or sensitivity affection, cranial nerves were conserved, no pyramidal or extrapyramidal signs, neck was supple, fundoscopy was normal.
Complementary studies: Laboratory tests showed no abnormalities, with negative HIV and VDRL, TSH 0.9 (within normal range). Brain CT showed no mass, intracranial bleeding or hydrocephalus, no major vessel vascular territory infarct and MRI showed T2, FLAIR and DWI bilateral hyperintensity at posterior periventricular white matter (Fig. 2A). The EEG with occasional activity of sharp waves that were observed in centrotemporal areas in both hemispheres. A LP was performed, CSF evidenced: hyperproteinorrachy 0.6mg/L, WBC 15/μL most mononuclear cells, glucose 60, lactate acid 1.9 mmol/L.
Figure 2 A: Axial brain MRI, FLAIR sequence showing bilateral hyperintensity at posterior periventricular white matter. B: Comparison between CT at time of IRAE in Nov 2017 (a and c) with same area in Apr 2021 (b and d)
Infectious encephalitis was suspected and couldn`t be discarded in the first place so antibiotic scheme with acy clovir 600 mg/d, ampicillin 2 gr/4 hs, ceftriaxone 2 g/12 h and dexamethasone 8 mg/8h was initiated. Because of EEG alterations she was medicated with levetiracetam 500 mg/12 h.
Blood, urine, and CSF cultures results were negative, including VDRL, FTA-ABS, HSV, enterovirus, cytomega lovirus, and varicella zoster PCR in CSF. Onconeural an tibodies were studied: anti-HU, anti-RI, anti-YO, with negative results. Same as multiple other autoantibodies anti-NMDA, anti-VGKC and anti JO1.
The symptoms persisted. Without fever, negative in fectious results, not progression of cancer disease and brain MRI without metastases but compatible with in flammatory status, the suspected diagnosis was autoim mune encephalitis, then high doses of methylpredniso lone corticosteroid were administrated (1 g IV daily for 5 days) with frank improvement of neurological symp toms, and subsequent complete resolution, not requiring other immunosuppressive therapy as immunoglobulin or rituximab. Nivolumab was terminated interpretating it as the original cause of the encephalitis.
After the patient‘s discharge, subsequent CT controls showed a greater partial response of the kidney cancer lesions, which are stable without progression even after 4 years of the suspension of nivolumab, without the need for any oncological treatment (Fig. 2B).
The patient gave verbal and written consent for the article to be published
Discussion
We present a rare case of tumor regression after nivolumab suspension because of a grade IV IRAE.
In this case, the symptoms began far from the start of treatment. With negative infectious re sults, magnetic resonance imaging compatible with an inflammatory pattern, ictal activity on EEG, no progression of the disease in the brain, and excellent response to immunosuppressive therapy, the diagnosis was autoimmune en cephalitis. Absence of autoantibodies does not exclude the possibility of immune mediated dis order6.
There are many other case reports of enceph alitis as ICI adverse event, although generally they occur early on ICI treatment. Most of the patients had fatal resolution of the encephalitis, or partial response with progression of cancer disease after treatment hold10,11.
With this article we want to emphasize the low threshold of suspicion that must exist for an early recognition of the disease in patients with ICI treatment who develop alteration in mental status and the importance of a rapid establish ment of treatment that greatly improves the results. Always being careful with differential diagnoses and excluding other potentially fatal diagnoses.
This article also highlights how long the tu mor response can be in patients with metastatic renal cell carcinoma in the context of grade IV immune adverse events. After the suspension of treatment, of the multiple pulmonary metasta ses, only 2 of them persisted, which significantly reduced their size and have remained stable since then (Fig. 2B).
To the best of our knowledge this is the first case of mRCC tumor regression after stopping immunotherapy for a grade IV IRAE.
However, the better response of patients with IRAE is correlated with other reports and sup ports the idea of IRAE as biomarkers of response in patients with immunotherapy9.
Two retrospective evaluations in metastatic RCC patients treated with ICIs evidenced that patients who experienced IRAEs were associ ated with improved OS12,13.
This phenomenon was also evidenced in other tumors. A prospective biomarker study of 106 patients with advanced non-small cell lung cancer treated with ICIs evidenced that the pro portion of IRAEs was significantly higher in re sponders than nonresponders (65.2% vs. 19.3%, p < .01)14.
In conclusion, some patients previously con sidered incurable are now achieving long-term remissions with these novel therapeutics, but at the expense of frequent and sometimes se rious or even fatal IRAE. While increasing indi cations of immunotherapy, more and more pa tients are experimenting all kinds of IRAE. That’s why medical doctors should be at the vanguard, tracking signs of toxicity and treat the patient as soon as possible to rise the odds of resolution.
