Anti–Interleukin-6 and Janus Kinase Inhibitors for Severe Neurologic Toxicity of Checkpoint Inhibitors

Abstract

Background and ObjectivesTo describe the marked clinical and biological responses of a targeted treatment with anti–interleukin-6 (IL-6)–receptor antibody and Janus kinase (JAK) inhibitors in a patient with a severe, corticoresistant CNS toxicity of immune-checkpoint inhibitor (ICI) therapy.MethodsA 58-year-old man was admitted for subacute paraparesis, urinary retention, and ascending paresthesia. He was under treatment with ipilimumab and nivolumab for metastatic melanoma. Spine MRI disclosed multiple T2-hyperintense, contrast-enhancing longitudinally extensive lesions. A diagnosis of ICI-related acute transverse myelitis was made.ResultsICIs were immediately discontinued, and the patient received high-dose glucocorticoids plus 1 session of plasma exchange, but he did not improve. Based on the marked elevation of CSF IL-6 (505 pg/mL), a second-line targeted therapy with anti-IL-6-receptor tocilizumab (8 mg/kg/mo for 3 infusions) plus JAK inhibitor ruxolitinib (50 mg/d) was administered. Patient neurologic status started to improve shortly after, with corresponding radiologic resolution. At 9 months, the patient was able to walk independently, presenting only slight residual disability while remaining in oncologic partial response.DiscussionOur case suggests that some patients with severe, corticoresistant CNS immune-related toxicities of ICIs may benefit from cytokine blockade. Cytokine measurement in serum and CSF might help in selecting patients for personalized treatment strategies.

A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics

“…We have applied and validated the nSMOL assay for more than 40 mAbs including 2 Fc fusion proteins 8,9,21,[46][47][48] . The exquisite specificity of mAbs and availability of 6 CDR legions (3 from each heavy and light chains) enables robust selection of the signature peptide as we and others have demonstrated 30 .…”

“…This feature curtails errors introduced through sample dilution and during the process of extrapolation of mAb concentration from the standard curve, while such errors are difficult to mitigate in ELISA (e.g., a linear standard curve is typically accompanied by narrower dynamic range whereas wider dynamic range ends up with a sigmoidal standard curve). Although others successfully measured mAbs using the nSMOL assay 47,52,53 and we demonstrated the minimal inter-operator variabilities in measuring bevacizumab with the nSMOL assay 49 , we have built and validated a prototype for an automated nSMOL platform using an automated liquid handler in our effort to further address inter-operator variabilities (manuscript in preparation). We also showed reasonable inter-instrument/platform variabilities from the LC-MS when conducting the nSMOL assays.…”

A rapid and universal liquid chromatograph-mass spectrometry-based platform, refmAb-Q nSMOL, for monitoring monoclonal antibody therapeutics

“…Major advantages of the refmAb-Q nSMOL assay stem from its backbone, the nSMOL assay. We have applied and validated the nSMOL assay for more than 40 mAbs including 2 Fc fusion proteins 8,9,21,[47][48][49] . The exquisite specificity of mAbs and availability of 6 CDR legions (3 from each heavy and light chains)…”

“…This feature curtails errors introduced through sample dilution and during the process of extrapolation of mAb concentration from the standard curve, while such errors are difficult to mitigate in ELISA (e.g., a linear standard curve is typically accompanied by narrower dynamic range whereas wider dynamic range ends up with a sigmoidal standard curve). Although others successfully measured mAbs using the nSMOL assay 48,53,54 and we demonstrated the minimal inter-operator variabilities in measuring bevacizumab with the nSMOL assay 50 , we have built and validated a prototype for an automated nSMOL platform using an automated liquid handler in our effort to further address inter-operator variabilities (manuscript in preparation).…”

Paraneoplastic Autoimmune Neurological Syndromes and the Role of Immune Checkpoint Inhibitors

“…1 (3)) suppresses pro-inflammatory cascades and has shown to ameliorate neurologic symptoms and relapse rates in patients with NMOSD refractory to multiple immunosuppressive therapies [ 135 – 137 ]. Tocilizumab has improved neurological symptoms in a patient with ICI-related steroid-refractory transverse myelitis with high levels of IL-6 in the CSF [ 138 ] and demonstrated efficacy in patients with ICI-mediated cerebritis [ 139 ]. Satralizumab is a modified anti-IL-6R antibody with a pH-dependent antibody-antigen binding which prolongs the elimination half-life of the drug and has been recently FDA-approved for the treatment of NMOSD [ 140 ].…”