Case of anti-Zic4 antibody-mediated cerebellar toxicity induced by dual checkpoint inhibition in head and neck squamous cell carcinoma

Sunil Girish Iyer; Nidah Shabbir Khakoo; Gabriella Aitcheson; Cesar Perez

doi:10.1136/bcr-2020-235607

Case of anti-Zic4 antibody-mediated cerebellar toxicity induced by dual checkpoint inhibition in head and neck squamous cell carcinoma

BMJ Case Rep. 2020 Sep 17;13(9):e235607. doi: 10.1136/bcr-2020-235607.

Authors

Sunil Girish Iyer^#¹, Nidah Shabbir Khakoo^#², Gabriella Aitcheson², Cesar Perez^{3

4}

Affiliations

¹ Internal Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA sunil.iyer@jhsmiami.org.
² Internal Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA.
³ Oncology, University of Miami Miller School of Medicine, Miami, Florida, USA.
⁴ Oncology, Sylvester Comprehensive Cancer Center, Miami, Florida, USA.

^# Contributed equally.

Abstract

Combined checkpoint inhibition therapy targeting the programmed cell death 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 pathways has been a successful approach in the treatment of metastatic melanoma, leading to its investigation in the treatment of head and neck squamous cell carcinoma (HNSCC) with PD-L1 expression. Despite the potential for excellent responses, an increased rate of autoimmune neurological toxicity and paraneoplastic conditions has been observed when using these treatment modalities. We present the case of a patient with metastatic HNSCC treated with combination ipilimumab/nivolumab who experienced severe cerebellar ataxia with a positive screen for the anti-Zic4 antibody. This is the first case, to our knowledge, of anti-Zic4 antibody-mediated cerebellar toxicity reported in association with HNSCC. Although the patient experienced an impressive partial response with dual checkpoint inhibition, he suffered grade 4 neurotoxicity. Despite exciting advances in cancer immunotherapy, clinicians must be aware of the rare, debilitating and possibly previously undescribed paraneoplastic and autoimmune toxicities that may occur.

Keywords: cancer intervention; head and neck cancer; immunology; neurological injury; oncology.

Publication types

Case Reports

MeSH terms

Adult
Antineoplastic Combined Chemotherapy Protocols / adverse effects*
Autoantibodies / blood
Autoantibodies / immunology
B7-H1 Antigen / antagonists & inhibitors
B7-H1 Antigen / immunology
Bronchoscopy
CTLA-4 Antigen / antagonists & inhibitors
CTLA-4 Antigen / immunology
Cerebellar Ataxia / blood
Cerebellar Ataxia / diagnosis
Cerebellar Ataxia / drug therapy
Cerebellar Ataxia / immunology*
Cerebellum / diagnostic imaging
Cerebellum / immunology
Chemoradiotherapy / adverse effects
Chemoradiotherapy / methods
Cyclin-Dependent Kinase Inhibitor p16 / metabolism
Glucocorticoids / administration & dosage
Humans
Immune Checkpoint Inhibitors / adverse effects*
Immunoglobulins, Intravenous / administration & dosage
Ipilimumab / adverse effects
Lung / diagnostic imaging
Lung / pathology
Lung Neoplasms / diagnosis
Lung Neoplasms / immunology
Lung Neoplasms / secondary
Lung Neoplasms / therapy*
Magnetic Resonance Imaging
Male
Nerve Tissue Proteins / immunology
Nivolumab / adverse effects
Off-Label Use
Rituximab / administration & dosage
Squamous Cell Carcinoma of Head and Neck / immunology
Squamous Cell Carcinoma of Head and Neck / secondary
Squamous Cell Carcinoma of Head and Neck / therapy*
Transcription Factors / immunology
Treatment Outcome

Substances

Autoantibodies
B7-H1 Antigen
CD274 protein, human
CDKN2A protein, human
CTLA-4 Antigen
CTLA4 protein, human
Cyclin-Dependent Kinase Inhibitor p16
Glucocorticoids
Immune Checkpoint Inhibitors
Immunoglobulins, Intravenous
Ipilimumab
Nerve Tissue Proteins
Transcription Factors
ZIC4 protein, human
Nivolumab
Rituximab