A new frontier in haematology - combining pharmacokinetic with pharmacodynamic factors to improve choice and dose of drug

The issue of tailored dosing adjusted according to a range of patient-specific factors other than bodyweight or body surface area is of large and increasing clinical and financial concern. Even if it is known that dosing alterations are likely to be required for parameters such as body composition, gender and pharmacogenetics, the amount of dosing change is unknown. Thus, pharmacokinetically guided dosing is making a resurgence, particularly in areas of medicine where there are cost constraints or safety issues, such as in haematology medications. However, the evidence to support the behaviour is minimal, particularly when long-term outcomes are considered. In haematology, there are particular issues around efficacy, toxicity and overall cost. Newer targeted agents, such as the monoclonal antibody rituximab and the tyrosine kinase inhibitor imatinib, whilst clearly being highly effective, are dosed on a milligram per square metre (rituximab) or fixed dose basis (imatinib), regardless of body composition, tumour aspects or comorbidity. This review questions this practice and raises important clinical issues; specifically, the clinical potential for combined pharmacokinetically and pharmacodynamically guided dosing of new targeted agents in haematological malignancies. This pharmacokinetically and pharmacodynamically guided dosing is an emerging area of clinical pharmacology, driven predominantly by toxicity, efficacy and cost issues, but also because reasonable outcomes are being noted with more appropriately dosed older medications adjusted for patient-specific factors. Clinical trials to investigate the optimization of rituximab dose scheduling are required

The Pandora's box of novel technologies that may revolutionize lung cancer

Non-small cell lung cancer (NSCLC) is one of the most common cancers globally and has a 5-year survival rate ~20%. Immunotherapies have demonstrated long-term and durable responses in NSCLC patients, although they appear to be effective in only a subset of patients. A more comprehensive understanding of the underlying tumour biology may contribute to identifying those patients likely to achieve optimal outcomes. Profiling the tumour microenvironment (TME) has shown to be beneficial in addressing fundamental tumour-immune cell interactions. Advances in multiplexing immunohistochemistry and molecular barcoding has led to recent advances in profiling genes and proteins in NSCLC. Here, we review the recent advancements in spatial profiling technologies for the analysis of NSCLC tissue samples to gain new insights and therapeutic options for NSCLC. The combination of spatial transcriptomics combined with advanced imaging is likely to lead to deep insights into NSCLC tissue biology, which can be a powerful tool to predict likelihood of response to therapy.</p

Immune evasion via PD-1/PD-L1 on NK-cells and monocyte/macrophages is more prominent in Hodgkin lymphoma than DLBCL

Much focus has been on the interaction of PD-L1 on malignant B-cells with PD-1 on effector T-cells in inhibiting anti-lymphoma immunity. We sought to establish the contribution of NK-cells and inhibitory CD163monocytes/macrophages in Hodgkin Lymphoma (cHL) and Diffuse Large B-cell Lymphoma (DLBCL). Levels of PD-1 on NK-cells were elevated in cHL relative to DLBCL. Notably, CD3CD56CD16NK-cells had substantially higher PD-1 expression relative to CD3CD56CD16cells, and were expanded in blood and tissue, more marked in cHL than DLBCL patients. There was also a raised population of PD-L1 expressing CD163monocytes that was more marked in cHL compared to DLBCL patients. The phenotype of NK-cells and monocytes reverted back to normal once therapy (ABVD or R-CHOP) had commenced. Tumor associated macrophages (TAMs) expressed high levels of PD-L1/PD-L2 within diseased lymph nodes. Consistent with this, CD163/PD-L1/PD-L2 gene expression was also elevated in cHL relative to DLBCL tissues. An in-vitro functional model of TAM-like monocytes suppressed activation of PD-1NK-cells, which was reversed by PD-1 blockade. In line with these findings, depletion of circulating monocytes from the blood of pre-therapy cHL and DLBCL patients enhanced CD3CD56CD16NK-cell activation. We describe a hitherto unrecognised immune evasion strategy mediated via skewing towards an exhausted PD-1 enriched CD3CD56CD16NK-cell phenotype. In addition to direct inhibition of NK-cells by the malignant B-cell, suppression of NK-cells can occur indirectly by PD-L1/PD-L2 expressing TAMs. The mechanism is more prominent in cHL than DLBCL, which may contribute to the clinical sensitivity of cHL to PD-1 blockade