Enhancing Checkpoint Inhibitor Therapy in Solid Tissue Cancers: The Role of Diet, the Microbiome & Microbiome-Derived Metabolites.

Host immunity plays a central role in the regulation of anti-tumour responses during checkpoint inhibitor therapy (CIT). The mechanisms involved in long lasting remission remain unclear. Animal studies have revealed that the microbiome influences the host immune response. This is supported by human studies linking a higher microbial richness and diversity with enhanced responses to CIT. This review focuses on the role of diet, the microbiome and the microbiome-derived metabolome in enhancing responses to current CIT in solid tissue cancers. The Western diet has been associated with dysbiosis, inflammation and numerous metabolic disorders. There is preliminary evidence that lifestyle factors including a high fibre diet are associated with improved responses to CIT via a potential effect on the microbiota. The mechanisms through which the microbiota may regulate long-term immunotherapy responses have yet to be determined, although bacterial-metabolites including short chain fatty acids (SCFAs) are recognized to have an impact on T cell differentiation, and may affect T effector/regulatory T cell balance. SCFAs were also shown to enhance the memory potential of activated CD8 T cells. Many therapeutic approaches including dietary manipulation and fecal transplantation are currently being explored in order to enhance immunotherapy responses. The microbiome-derived metabolome may be one means through which bacterial metabolic products can be monitored from the start of treatment and could be used to identify patients at risk of poor immunotherapy responses. The current review will discuss recent advances and bring together literature from related fields in nutrition, oncology and immunology to discuss possible means of modulating immunity to improve responses to current CIT.

Microbiome-derived metabolome as a potential predictor of response to cancer immunotherapy.

Cancer immunotherapy with checkpoint blockade has become standard of care treatment for numerous cancer types. Despite this, robust predictive biomarkers are lacking. There is increasing evidence that the host microbiome is a predictor of immunotherapy response, although the optimal host microbiome has not been defined. Metabolomics is a new area of medicine that aims to analyze the metabolic profile of a biological system. The microbiome-derived metabolome (fecal and serum) represents the end products of microbial metabolism and these may be functionally more important than the distinct bacterial species that comprise a favorable microbiome. Short-chain fatty acids (SCFA) are metabolites produced by gut microbiota and have a role in T cell homeostasis, including differentiation of regulatory T cells. Recent studies have confirmed differential expression of SCFA for immunotherapy responders compared with non-responders. We propose that the microbiome metabolome, with a focus on SCFA may be a novel predictive biomarker for immunotherapy efficacy.

Intravenous high-dose interferon with or without maintenance treatment in melanoma at high risk of recurrence: meta-analysis of three trials.

Resected stage IIB-IIIC malignant melanoma has a poor prognosis with a high risk of relapse and death. Treatment with adjuvant interferon alfa-2b (IFN-α-2b) is associated with improved relapse-free and overall survivals (OS), but the most appropriate dose and duration of treatment are unknown. In this article, we present an individual patient data random effects meta-analysis of melanoma patients from the U.K., Greek, and Chinese randomized trials. All patients were randomized either to IFN-α-2b 15-20 MIU/m(2) IV daily 5 days per week for 4 weeks (IV) or to the same regimen followed by IFN-α-2b 9-10 MIU/m(2) administered three times per week for 48 weeks (IV and SC). Allowing for dose interruptions and reductions, an equivalent total dose of IFN-α-2b was delivered in all three studies. We assessed whether IV was noninferior to IV and SC in terms of relapse-free survival (RFS) and investigated tumor and patient characteristics that impacted on outcomes. Median follow-up of 716 stage IIB-IIIC patients was 5.4 years. Noninferiority of IV compared to IV and SC could not be conferred for RFS (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.89-1.52; noninferior P = 0.17). Stage (P < 0.0001), site (acral vs. other, P < 0.0001), and Breslow thickness (P = 0.02) were significant predictors of RFS. The HR for death was 1.13 for IV compared to IV and SC, (95% CI 0.91-1.39). Stage (P < 0.0001) and Breslow thickness (P = 0.001) were significant independent predictors of OS. The available data suggest that where adjuvant high-dose interferon is being considered there is no evidence to deviate from the year long regimen described in the Eastern Cooperative Oncology Group and Intergroup studies.

Clinical presentation of melioidosis in Queensland, Australia.

A retrospective study was performed on culture-positive patients (n = 57) with melioidosis presenting to the Townsville Hospital to define the epidemiology of the disease in Queensland, Australia. Mortality was 25% (n = 14) with a 9% (n = 5) relapse rate. At presentation, primary organs involved included the lungs (58%; n = 33), genitourinary system (11%; n = 6), skin and soft tissue (9%; n = 5), bone and joints (4%; n = 2), central nervous system (4%; n = 2), mycotic aneurysm (2%; n = 1) and peritonitis (2%; n = 1). No focus of infection could be identified in 12% of cases (n = 7). There was no significant difference in the clinical presentation of melioidosis in Queensland compared with the Northern Territory. Regional trends in the clinical presentation of melioidosis in Australia compared with Southeast Asia were confirmed. Risk factors for disease included diabetes (42%), excess alcohol consumption (42%), chronic lung disease (26%), immunosuppressive drug use (12%), renal disease (11%), malignancy (7%) and autoimmune disease (5%). No risk factors were identifiable in 18% of cases. The presence of multiple risk factors for melioidosis was not significantly associated with increased mortality (P > 0.05).

Effect of cryopreservation on the immunogenicity of umbilical cord blood cells.

Cryopreservation is the accepted method for long-term storage of cord blood (CB) cells. We evaluated the effects of using different cooling rates (1, 5, 7.5 and 10 degrees C/min) on CB cell allostimulatory and alloproliferative function, antigen expression and clonogenic potential. Significant decreases (P<0.001-0.003) in viable cell recovery observed between fresh CB cells and CB cells cryopreserved at each cooling rate tested. Reductions in clonogenic potential of CB cells cryopreserved at cooling rates of 1, 5, 7.5 and 10 degrees C/min were 44%, 76%, 88% and 93% respectively, compared to fresh controls. FACS analysis indicated no changes in percentages CD34+ cells or lymphocytes. Two sets of mixed lymphocyte reactions were carried out for each CB sample. It was observed that allostimulatory and alloproliferative function varied following cryopreservation at different cooling rates (1 and 5 degrees C/min). Interestingly, there was a significant decrease (P<0.001-0.04) in the alloproliferative function of six of the seven CB samples following cryopreservation using a cooling rate of 5 degrees C/min. Cooling rates between 1 and 5 degrees C/min may provide immunomodulation of CB with maintenance of haematopoietic progenitor cells function.