A randomised controlled trial of long NY-ESO-1 peptide-pulsed autologous dendritic cells with or without alpha-galactosylceramide in high-risk melanoma.

AIM: We have previously reported that polyfunctional T cell responses can be induced to the cancer testis antigen NY-ESO-1 in melanoma patients injected with mature autologous monocyte-derived dendritic cells (DCs) loaded with long NY-ESO-1-derived peptides together with α-galactosylceramide (α-GalCer), an agonist for type 1 Natural Killer T (NKT) cells. OBJECTIVE: To assess whether inclusion of α-GalCer in autologous NY-ESO-1 long peptide-pulsed DC vaccines (DCV + α-GalCer) improves T cell responses when compared to peptide-pulsed DC vaccines without α-GalCer (DCV). DESIGN, SETTING AND PARTICIPANTS: Single-centre blinded randomised controlled trial in patients ≥ 18 years old with histologically confirmed, fully resected stage II-IV malignant cutaneous melanoma, conducted between July 2015 and June 2018 at the Wellington Blood and Cancer Centre of the Capital and Coast District Health Board. INTERVENTIONS: Stage I. Patients were randomised to two cycles of DCV or DCV + α-GalCer (intravenous dose of 10 × 106 cells, interval of 28 days). Stage II. Patients assigned to DCV + α-GalCer were randomised to two further cycles of DCV + α-GalCer or observation, while patients initially assigned to DCV crossed over to two cycles of DCV + α-GalCer. OUTCOME MEASURES: Primary: Area under the curve (AUC) of mean NY-ESO-1-specific T cell count detected by ex vivo IFN-γ ELISpot in pre- and post-treatment blood samples, compared between treatment arms at Stage I. Secondary: Proportion of responders in each arm at Stage I; NKT cell count in each arm at Stage I; serum cytokine levels at Stage I; adverse events Stage I; T cell count for DCV + α-GalCer versus observation at Stage II, T cell count before versus after cross-over. RESULTS: Thirty-eight patients gave written informed consent; 5 were excluded before randomisation due to progressive disease or incomplete leukapheresis, 17 were assigned to DCV, and 16 to DCV + α-GalCer. The vaccines were well tolerated and associated with increases in mean total T cell count, predominantly CD4+ T cells, but the difference between the treatment arms was not statistically significant (difference - 6.85, 95% confidence interval, - 21.65 to 7.92; P = 0.36). No significant improvements in T cell response were associated with DCV + α-GalCer with increased dosing, or in the cross-over. However, the NKT cell response to α-GalCer-loaded vaccines was limited compared to previous studies, with mean circulating NKT cell levels not significantly increased in the DCV + α-GalCer arm and no significant differences in cytokine response between the treatment arms. CONCLUSIONS: A high population coverage of NY-ESO-1-specific T cell responses was achieved with a good safety profile, but we failed to demonstrate that loading with α-GalCer provided an additional advantage to the T cell response with this cellular vaccine design. CLINICAL TRIAL REGISTRATION: ACTRN12612001101875. Funded by the Health Research Council of New Zealand.

A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients.

Vaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected stage II-IV melanoma with intravenous autologous monocyte-derived DCs loaded with the NKT cell agonist α-GalCer and peptides derived from the cancer testis antigen NY-ESO-1. Two synthetic long peptides spanning defined immunogenic regions of the NY-ESO-1 sequence were used. This therapy proved to be safe and immunologically effective, inducing increases in circulating NY-ESO-1-specific T cells that could be detected directly ex vivo in seven out of eight patients. These responses were achieved using as few as 5 × 105 peptide-loaded cells per dose. Analysis after in vitro restimulation showed increases in polyfunctional CD4+ and CD8+ T cells that were capable of manufacturing two or more cytokines simultaneously. Evidence of NKT cell proliferation and/or NKT cell-associated cytokine secretion was seen in most patients. In light of these strong responses, the concept of including NKT cell agonists in vaccine design requires further investigation.

Preferences for psychological therapy in psychosis: trial participation, mode of treatment, and willingness to be randomised.

BACKGROUND: Psychological therapies for psychosis are well evidenced; however, service user preferences for psychological treatment and trial participation have been little researched. AIMS: To investigate preferences for psychological treatments for psychosis and trial participation decisions within a sample of people with experience of psychosis. METHOD: Hypothetical preferences were assessed in 90 individuals diagnosed with non-affective psychosis: (a) willingness/unwillingness to participate in a psychological therapy trial; (b) willingness/unwillingness to be randomised to treatment condition; (c) preference for mode of therapy; (d) reasons for preferences; (e) socio-demographic and clinical characteristics associated with preferences. RESULTS: Most participants reported willingness to participate in a therapy trial and preferred not to be randomly allocated. Reasons for preferences were diverse, and preferences were not associated with socio-demographic or clinical variables. CONCLUSIONS: The need for treatment choice in services for psychosis and further research in this area has been highlighted.

Psychosocial and neuropsychiatric predictors of subjective recovery from psychosis.

Research suggests that both psychosocial factors and neuropsychiatric factors are important predictors of outcome, but little research has examined their relative importance to self-rated recovery. We aim to investigate how such factors are associated with subjective judgements of recovery from psychosis. The participants comprised 122 individuals with experience of psychosis who completed measures of perceived recovery, as well as measures of psychological factors (including self-esteem, locus of control, and emotion) and psychiatric factors (including psychotic symptoms, neurocognition and insight). Measurement models developed using confirmatory factor analysis supported a hypothesis of separate recovery and negative emotion factors. Structural equation modelling showed that negative emotion and internal locus of control had a direct influence on self-rated recovery, and that positive symptoms and internal locus of control had an indirect effect on recovery, mediated via negative emotion. There did not appear to be any effect of insight, negative symptoms or neurocognitive functioning on either self-rated recovery or negative emotion. Psychosocial factors are more directly related to perceived recovery than neuropsychiatric factors. The implications of these findings are discussed.

Subjective judgements of perceived recovery from psychosis.

BACKGROUND: Recent conceptualisations of recovery from psychosis have recognised the importance of psychosocial aspects as well as the presence or absence of symptoms. Qualitative research and personal accounts of recovery highlight its subjective and idiosyncratic nature. This study aims to explore subjective judgements of recovery from the perspective of service users, and examine the agreement and consistency in such judgements across different measures of recovery. It also aims to investigate the relationships between subjective judgements of recovery and psychosocial factors. METHODS: A total of 122 participants with experience of psychosis completed three self-report measures of recovery judgements, as well as measures of psychological functioning (including self-esteem, optimism, anxiety and depression) and socio-demographic measures. RESULTS: Judgements about recovery from psychosis across the three measures, while showing a trend, also show within-person variability. Recovery judgements were significantly correlated with each other and with all psychological variables, but were not associated with socio-demographic variables except for age. Regression analyses showed that recovery judgements were predicted by mood, optimism and self-esteem. CONCLUSIONS: Subjective judgements of recovery were seen to be idiosyncratic, with people appearing to have different thresholds for perceived recovery. The conclusions of the existing qualitative research and first-person accounts appear generalisable to larger samples.