Phase II trial of natalizumab for the treatment of anti-Hu associated paraneoplastic neurological syndromes.

BACKGROUND: Paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS) have a very poor prognosis: more than half of the patients become bedridden and median survival is less than 12 months. Several lines of evidence suggest a pathogenic T cell-mediated immune response. Therefore, we conducted a prospective open-label phase II trial with natalizumab. METHODS: Twenty Hu-PNS patients with progressive disease were treated with a maximum of three monthly natalizumab cycles (300 mg). The primary outcome measure was functional improvement, this was defined as at least one point decrease in modified Rankin Scale (mRS) score at the last treatment visit. In addition, treatment response was assessed wherein a mRS score ≤3 after treatment was defined as treatment responsive. RESULTS: The median age at onset was 67.8 years (SD 8.4) with a female predominance (n = 17, 85%). The median time from symptom onset to Hu-PNS diagnosis was 5 months (IQR 2-11). Most patients had subacute sensory neuronopathy (n = 15, 75%), with a median mRS of 4 at baseline. Thirteen patients had a tumor, all small cell lung cancer. After natalizumab treatment, two patients (10%) showed functional improvement. Of the remaining patients, 60% had a stable functional outcome, while 30% showed further deterioration. Treatment response was classified as positive in nine patients (45%). CONCLUSIONS: Natalizumab may ameliorate the disease course in Hu-PNS, but no superior effects above other reported immunosuppressive and immunomodulatory were observed. More effective treatment modalities are highly needed. TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-000675-13/NL.

Elevated numbers of regulatory T cells, central memory T cells and class-switched B cells in cerebrospinal fluid of patients with anti-Hu antibody associated paraneoplastic neurological syndromes.

Multi-parametric flow cytometry was used to study lymphocyte subsets and dendritic cells in paired blood and CSF samples from 11 newly diagnosed patients with progressive anti-Hu antibody associated paraneoplastic neurological syndromes (Hu-PNS), 9 patients with other inflammatory neurologic disorders (IND), and 12 patients with other non-inflammatory neurologic disorders (OND). Hu-PNS patients had elevated numbers of regulatory T cells, central memory T cells, class-switched B cells and dendritic cells in their CSF. These findings support the hypothesis that the immune system is locally activated in Hu-PNS, and suggests common etiological pathways between Hu-PNS and other inflammatory central nervous system disorders.

Effector memory and late memory T cells accumulate in the blood of CMV-carrying individuals but not in their cerebrospinal fluid.

Cytomegalovirus (CMV)-carrying individuals have significantly higher levels of effector memory and late memory T lymphocytes in their blood than non-carriers. To date, it is well recognized that the central nervous system is subjected to active immunosurveillance, as evidenced by the presence of central memory T cells in cerebrospinal fluid (CSF) of healthy individuals. In order to investigate whether levels of effector memory and late memory T cells were also increased in the CSF of CMV-carrying individuals, we characterized CD4⁺ and CD8⁺ T-cell subsets in CSF and blood of both groups. Effector memory and late memory T cells were only rarely seen in CSF, which was similar in CMV carriers and non-carriers. In conclusion, there was no demonstrable difference in the numbers of CSF effector memory and late memory T cells between CMV seronegative and CMV seropositive individuals.

Three sensitive assays do not provide evidence for circulating HuD-specific T cells in the blood of patients with paraneoplastic neurological syndromes with anti-Hu antibodies.

Anti-Hu antibody-associated paraneoplastic neurological syndromes (Hu-PNSs) are severe and often precede the detection of a malignancy, usually small-cell lung cancer. In Hu-PNS, it is hypothesized that neuronal cells are destroyed by T cells targeted against HuD, a protein expressed by small-cell lung cancer cells and neurons. There is only limited evidence for the existence of HuD-specific T cells. To detect these T cells in the blood of Hu-PNS patients, we employed 3 highly sensitive assays that included T cell stimulation with dendritic cells (DCs) to specifically expand the number of any HuD-specific T cells. A total of 17 Hu-PNS patients were tested with 1 or more of the following 3 assays: (1) tetramer staining after stimulation of T cells with conventionally generated DCs (n = 9), (2) interleukin (IL)-13 enzyme-linked immunosorbent spot (ELISpot; n = 3), IL-4 and IL-5 and interferon (IFN)-γ multiplex cytokine bead array (n = 2) to assay cytokine production by T cells after stimulation with conventionally generated DCs, and (iii) IFN-γ ELISpot and tetramer staining after T cell stimulation with accelerated co-cultured DCs (n = 11). No circulating HuD-specific T cells were found. We suggest that either autoaggressive T cells in Hu-PNS are not targeted against HuD or that their numbers in the blood are too low for detection by highly sensitive techniques.