Resistance to anti-PD1-based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. This observational study characterizes tumor CD155 ligand expression by metastatic melanoma tumors and correlates results with differences in immune cell features and response to ICB.Experimental Design: Pretreatment tumor specimens, from 155 patients with metastatic melanoma treated with ICB and from 50 patients treated with BRAF/MEK-directed targeted therapy, were assessed for CD155 expression by IHC. Intratumor T-cell features were analyzed using multiplex-immunohistofluorescence for CD8, PD1, and SOX10. Correlations were made between CD155 tumor level and bulk tumor RNA sequencing results, as well as clinical RECIST response and progression-free survival.Results: High pretreatment CD155 tumor levels correlated with high parenchymal PD1 þ CD8 þ /CD8 þ T-cell ratios (PD1 tR ) and poor response to anti-PD1 therapy. In PDL1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/ CTLA4 therapy.Conclusions: Our findings are the first to suggest that tumor CD155 supports an increase in the fraction of PD1 þ CD8 þ T cells in anti-PD1 refractory melanoma tumors and, further, that targeting the CD155 pathway might improve response to anti-PD1 therapy for patients with metastatic melanoma.

BackgroundTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, in combination with the programmed cell death-1 (PD-1) antagonist pembrolizumab.MethodsThe study was divided into two parts; parts A and B, where part A was the dose escalation part and part B was an extension part of the study. Patients with metastatic melanoma were treated with efti plus the standard dose of pembrolizumab. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect efti antibody formation and determine long-lived CD8 T cell responses and associated pharmacodynamic parameters.ResultsTwenty-four patients with melanoma received pembrolizumab and bi-weekly subcutaneous (s.c.) injections of efti at doses 1 mg, 6 mg or 30 mg/injection for up to 6 months (part A) or 30 mg/injection for up 12 months (part B). No dose-limiting toxicities were reported and the main adverse event for efti was injection site reactions. Sustained systemic exposure to the product was obtained in all patients following s.c. injections of 30 mg dose. Treatment induced an increase in activated CD8 and CD4 T cell counts, and in some of the soluble biomarkers, particularly interferon (IFN)-γ, a Th1 signature cytokine. An overall response rate (ORR) of 33% was observed in patients partly with pembrolizumab-refractory of part A and ORR of 50% was observed in patients with PD-1 naïve of part B.ConclusionsEfti was well tolerated in combination with pembrolizumab with encouraging antitumor activity. This warrants further clinical studies of this new combination therapy combining an antigen-presenting cell activator with an immune checkpoint inhibitor.

Background Malnutrition in advanced cancer patients is common but limited and inconclusive data exists on the effectiveness of nutrition interventions. Feasibility and acceptability of a novel family-based nutritional psychosocial intervention were established recently. The aims of this present study were to assess the feasibility of undertaking a randomised controlled trial of the latter intervention, to pilot test outcome measures and to explore preliminary outcomes. Methods Pilot randomised controlled trial recruiting advanced cancer patients and family caregivers in Australia and Hong Kong. Participants were randomised and assigned to one of two groups, either a family-centered nutritional intervention or the control group receiving usual care only. The intervention provided 2–3 h of direct dietitian contact time with patients and family members over a 4–6-week period. During the intervention, issues with nutrition impact symptoms and food or eating-related psychosocial concerns were addressed through nutrition counselling, with a focus on improving nutrition-related communication between the dyads and setting nutritional goals. Feasibility assessment included recruitment, consent rate, retention rate, and acceptability of assessment tools. Validated nutritional and quality of life self-reported measures were used to collect patient and caregiver outcome data, including the 3-day food diary, the Patient-Generated Subjective Global Assessment Short Form, the Functional Assessment Anorexia/Cachexia scale, Eating-related Distress or Enjoyment, and measures of self-efficacy, carers’ distress, anxiety and depression. Results Seventy-four patients and 54 family caregivers participated in the study. Recruitment was challenging, and for every patient agreeing to participate, 14–31 patients had to be screened. The consent rate was 44% in patients and 55% in caregivers. Only half the participants completed the trial’s final assessment. The data showed promise for some patient outcomes in the intervention group, particularly with improvements in eating-related distress (p = 0.046 in the Australian data; p = 0.07 in the Hong Kong data), eating-related enjoyment (p = 0.024, Hong Kong data) and quality of life (p = 0.045, Australian data). Energy and protein intake also increased in a clinically meaningful way. Caregiver data on eating-related distress, anxiety, depression and caregiving burden, however, showed little or no change. Conclusions Despite challenges with participant recruitment, the intervention demonstrates good potential to have positive effects on patients’ nutritional status and eating-related distress. The results of this trial warrant a larger and fully-powered trial to ascertain the effectiveness of this intervention. Trial registration The trial was registered with the Australian & New Zealand Clinical Trials Registry, registration number ACTRN12618001352291.