Seronegative antibody‐mediated neurology after immune checkpoint inhibitors

Wilson, Roland; Menassa, David A.; Davies, AN; Michael, Sophia; Hester, Joanna; Küker, Wilhelm; Collins, Graham P.; Cossins, Judith; Beeson, David; Steven, Neil; Maddison, Paul; Rinaldi, Simon; Jacob, Saiju; Irani, Sarosh R.

doi:10.1002/acn3.547

Cited by 56 publications

(52 citation statements)

References 20 publications

(21 reference statements)

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“…7 23-25 Seronegative antibody-mediated irAEs have also been described with ICIs. Wilson et al reported novel IgG and IgM reacting to relevant tissue preparations in a patient with seronegative transverse myelitis secondary to pembrolizumab and another with seronegative myasthenia gravis due to ipilimumab-nivolumab administration, 26 suggesting that ICIs uncover previously unrecognized autoreactive antibodies. This is corroborated by Gowen et al, demonstrating that patients who later developed severe irAEs to ICIs possessed a distinct pretreatment antibody pattern extending beyond the known autoantibodies, such as antinuclear, antismooth muscle, and antithyroid antibodies.…”

Section: Case Presentationmentioning

confidence: 99%

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up

Dadu

Rodgers

Trinh

et al. 2020

J Immunother Cancer

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BackgroundImmune checkpoint inhibitors (ICIs) have produced significant survival benefit across many tumor types. However, immune-related adverse events are common including autoimmune responses against different endocrine organs. Here, a case of ICI-mediated hypoparathyroidism focusing on long-term follow-up and insights into its etiology is presented.Case and methodsA 73-year-old man developed severe symptomatic hypocalcemia after the initiation of ipilimumab and nivolumab for the treatment of metastatic melanoma. Hypoparathyroidism was diagnosed with undetectable intact parathyroid hormone (PTH). Immunoprecipitation assays, ELISAs, and cell-based functional assays were used to test the patient for antibodies against the calcium-sensing receptor (CaSR). NACHT leucine-rich repeat protein 5 (NALP5) and cytokine antibodies were measured in radioligand binding assays and ELISAs, respectively.ResultsThe patient’s symptoms improved with aggressive calcium and vitamin D supplementation. At 3 years and 3 months since the diagnosis of hypoparathyroidism, PTH was still inappropriately low at 7.6 pg/mL, and attempted discontinuation of calcium and calcitriol resulted in recurrent symptomatic hypocalcemia. Analysis for an autoimmune etiology of the patient’s hypoparathyroidism indicated that CaSR antibodies were negative before treatment and detected at multiple time points afterwards, and corresponded to the patient’s clinical course of hypoparathyroidism. CaSR antibodies purified from the patient’s serum activated the human CaSR. The patient was seronegative for NALP5 and cytokine antibodies, indicating that their hypoparathyroidism was not a manifestation of autoimmune polyendocrine syndrome type 1.ConclusionThe etiology of hypocalcemia is likely autoimmune hypoparathyroidism caused by the development of CaSR-activating antibodies that might prevent PTH release from the parathyroid.

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Section: Case Presentationmentioning

confidence: 99%

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up

Dadu

Rodgers

Trinh

et al. 2020

J Immunother Cancer

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“…32,80 Myelitis, including longitudinally extensive myelitis, has also been described, and immunotherapeutic responses can be favorable. 81,82 Peripheral nerve involvement has been reported in less than 3% of patients receiving checkpoint inhibitor therapy for cancer. 83 In some patients, manifestations have been compatible with demyelinating polyradiculoneuropathies (Guillain-Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy).…”

Section: Autoimmune Neurologic Disorders In the Era Of Checkpoint Inhmentioning

confidence: 99%

Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy

Ζεκερίδου

Lennon

2019

Mayo Clinic Proceedings

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Neurologic autoimmune disorders in the context of systemic cancer reflect antitumor immune responses against onconeural proteins that are autoantigens in the nervous system. These responses observe basic principles of cancer immunity and are highly pertinent to oncological practice since the introduction of immune checkpoint inhibitor cancer therapy. The patient's autoantibody profile is consistent with the antigenic composition of the underlying malignancy. A major determinant of the pathogenic outcome is the anatomic and subcellular location of the autoantigen. IgGs targeting plasma membrane proteins (eg, muscle acetylcholine receptor -IgG in patients with paraneoplastic myasthenia gravis) have pathogenic potential. However, IgGs specific for intracellular antigens (eg, antineuronal nuclear antibody 1 [anti-Hu] associated with sensory neuronopathy and small cell lung cancer) are surrogate markers for CD8 þ T lymphocytes targeting peptides derived from nuclear or cytoplasmic proteins. In an inflammatory milieu, those peptides translocate to neural plasma membranes as major histocompatibility complex class I protein complexes. Paraneoplastic neurologic autoimmunity can affect any level of the neuraxis and may be mistaken for cancer progression. Importantly, these disorders generally respond favorably to early-initiated immunotherapy and cancer treatment. Small cell lung cancer and thymoma are commonly associated with neurologic autoimmunity, but in the context of checkpoint inhibitor therapy, other malignancy associations are increasingly recognized.

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“…While detecting the autoantibodies can help to characterise the disorder, there have been reported cases of immune checkpoint inhibitor-related autoimmune encephalitis without detected autoantibody. In such cases it is the recognition of the clinical syndrome, its chronological association with therapy, and supportive imaging and CSF findings that enable a diagnosis 12…”

Section: Discussionmentioning

confidence: 99%

Autoimmune encephalitis associated with Ma2 antibodies and immune checkpoint inhibitor therapy

et al. 2020

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Immune checkpoint inhibitors have transformed the treatment of advanced malignancy, while increasing the risk of immune-related adverse events. A 56-year-old woman who had received nivolumab for stage 4 renal cell carcinoma subsequently developed altered behaviour, memory deficits and worsening of previously stable epilepsy. MR scan of the brain showed bilateral FLAIR (fluid-attenuated inversion recovery) hyperintensity of the mesial temporal lobes, and there were anti-Ma2 antibodies in both serum and cerebrospinal fluid. She was treated with corticosteroids but developed further clinical relapses requiring immunoglobulin and rituximab. The immune-related adverse events relating to immune checkpoint inhibitors are an emerging challenge for the neurologist. Some cases are refractory and require serial immunosuppression.

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Seronegative antibody‐mediated neurology after immune checkpoint inhibitors

Cited by 56 publications

References 20 publications

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up

Neurologic Autoimmunity in the Era of Checkpoint Inhibitor Cancer Immunotherapy

Autoimmune encephalitis associated with Ma2 antibodies and immune checkpoint inhibitor therapy

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