More commonly known as an inhibitory cytokine, high doses of IL-10 have been shown to lead to the activation and survival of antigen stimulated CD8 T cells. According to a study published in the Journal of Clinical Oncology, the investigators in this first-in-human, phase 1 clinical trial of IL-10 (AM0010), demonstrate antitumor activity and therapy tolerability in a pretreated population. The primary endpoint of the study was to establish safety, tolerability and the maximum tolerated dose. This goal appears to have been met, with a low incidence of adverse events, most of which were temporary or reversible. The dose-escalation study was followed by a renal cell cancer dose-expansion cohort.
By Sam LaBrie
Developing precision medicines for COPD is an important goal, as the disease is the third most common cause of death in the developed world and there are relatively few effective therapies. A recent study published in PLOS, Common Genetic Polymorphisms Influence Blood Biomarkers Measurements in COPD, explores the massive datasets from two cohorts, SPIROMICS and COPDGene, in a search for biomarkers linked to various aspects of COPD. Scientists combined single nucleotide polymorphisms (SNPs) and a custom MAP (Multi-Analyte Profile) of Myriad RBM’s serum biomarker assays to identify protein quantitative trait loci (pQTLs), i.e. genetic features that are correlated with variations in protein expression).
Data analysis revealed 527 SNPs that are associated with 38 protein biomarkers (pQTLs). For 13 of these proteins, the pQTL could explain >10% of the variation in expression levels seen in the 2 cohorts, with the strongest influence being ~75% of the change in expression of vitamin D binding protein. Several of the pQTLs show significant associations with disease phenotypes, including the pQTL linked to sRAGE, which has been previously associated with emphysema. A striking finding was that SNPs in the ABO blood group region of the genome are strongly associated with many protein biomarker levels. Interestingly, the ABO blood group and COPD have been linked in earlier studies, confirming that ABO status should be taken into consideration for future COPD studies.
The authors conclude that multi-omics studies like this one are important for understanding complex diseases like COPD.
Let your kids get dirty; it’s good for them!
In the current issue of the New England Journal of Medicine researchers explore the mechanism behind the effect of endotoxin exposure on asthma and allergies in children. The researchers used Myriad RBM’s TruCulture® tubes to collect and stimulate whole blood in order to study differences in the innate and adaptive immune response in Amish and Hutterite children. The authors also investigated cellular changes and allergy biomarkers in serum. Amish and Hutterite people are similar in genetic make-up and lifestyle, but differ in exposure to microbial antigen which has been shown to be protective for asthma and allergies in other studies.
The results show that Amish children, who –through their families’ dairy farms– are more exposed to endotoxins then their Hutterite counterparts, have a reduced incidence of asthma and allergies coinciding with lower serum IgE levels. Stimulating the innate immune system with LPS resulted in lower cytokine release in Amish then Hutterite children, but there were no differences when using a T cell specific stimulant. This data and changes in immune cell populations suggests that lower asthma incidence in children exposed to microbial antigen and their endotoxin is mediated by changes in innate immunity.
Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma
The data presented in this paper shows baseline and on-treatment biomarkers from a phase 1b study of the PD-1 inhibitor nivolumab in renal cell carcinoma. The study examined immune changes in the microenvironment of the tumor, such as types of tumor infiltrating cells and gene expression and show that they correlate with gene expression and protein biomarkers in peripheral blood. The results suggest induction of a Th1 response locally and correlating T cell chemotactic proteins in the periphery, both of which were dose independent.
Our sales and marketing team represented Myriad RBM at the Biomarkers and Diagnostics World Congress in Philadelphia with a booth on the vendor floor. In addition to hearing the latest in the world of biomarker development, we had a chance to chat to current customers and introducing new ones to our biomarker testing services.
Of particular interest to us, was the luncheon presentation on Monday which compared different immunoassay platforms and their sensitivity in regard to IL-6. The talk by Pacific Biomarkers’ Maribeth Raines, compared IL-6 assays on the Ciraplex platform to R&D Systems’ standard ELISA, Meso Scale Discovery’s QuickPlex, and Singulex’s Erenna and showed that the ULTRA IL-6 assay had the best sensitivity between .016 and .03 pg/ml. Notably absent in the study was Quanterix’ Simoa assay, which in our hands at 0.0046 pg/ml reproducibly has a lower limit of quantification than any of the assays mentioned.
The luncheon presentation on Wednesday was sponsored by Myriad RBM and featured Dr Tasha Sims from Regeneron talking about the VELOUR trial, which enrolled FOLFIRI treated patients with metastatic colorectal cancer and studied the effects of anti-VEGF treatment plus FOLFIRI vs FOLFIRI only. The protein biomarker data from baseline samples suggests that some markers may be predictive in that patients with high levels of inflammatory molecules, including IL-8, MIF, and also VEGF/VEGF-R2, -R3 respond better to anti-VEGF treatment then those with low levels. Other markers may be prognostic, based on the observation that patients with elevated angiogenic factors such as NRP-1 and Ang-2 or specific pro-inflammatory markers like CRP seem to have poor outcome overall. The speaker emphasized the need for further studies on this topic. Genentech’s Andy Williams, Ph.D. talked about diagnostic strategies for cancer immune therapies. He touched on first generation methods like PD-L1 IHC and then proposed new strategies including predictive biomarkers, gene expression, mutational load, multiplex IHC and blood markers. He explained three different possible immune states of a tumor: an ‘immune desert’ (no T cells present), excluded infiltrate (T cells present solely in the periphery, but excluded from the tumor), and pre-existing immunity (T cells present in the tumor, but not active). The three results call for different treatment options; immune desert requires chemotherapy to generate new antigens to induce a T cell response, exclusion can be treated with anti-VEGF factors, and the presence of anergic T cells calls for anti-PD-L1 to remove the immune blockade. T cell gene expression signatures correlate with IHC findings. The interesting question for us is: Can we reliably detect these different immune states in the periphery? With the development of more ultra-sensitive assays like Simoa mentioned above, it may be possible to detect immune signatures even when diluted in peripheral blood. Blood based biomarkers are more easily accessible then tumor tissue and avoid some problems related to tumor biopsies.