Mitchell B. Adamson

Tumour-infiltrating lymphocyte (TIL) therapy can be effective against metastatic melanoma, including immune checkpoint-resistant disease, but current protocols require lymphodepletion and high-dose interleukin-2 (IL-2), which can cause substantial toxicity. To overcome this limitation, we engineered a chimeric receptor, G2R, that generates an IL-2-like proliferative signal in response to granulocyte colony-stimulating factor (G-CSF), a well-tolerated cytokine widely used in oncology. Human T cells expressing G2R expanded in vitro in response to G-CSF in place of IL-2 or interleukin-15 (IL-15), and the three cytokines induced broadly similar intracellular signalling and cytokine secretion profiles. In immune-competent mice bearing established B16-F10 melanoma, adoptive transfer of G2R-expressing, tumour-reactive CD8 ⁺ T cells followed by systemic G-CSF treatment induced profound T cell expansion. This was accompanied by complete, durable tumour regression in over 75% of animals without the need for lymphodepletion, exogenous IL-2 or any other therapy. G-CSF treatment induced transient neutrophil expansion in peripheral blood but no increase in intratumoural neutrophils or macrophages. G2R-expressing memory T cells persisted long-term and could be re-expanded upon G-CSF re-treatment, enabling rejection of second tumour challenges. Thus, G-CSF can be repurposed to enable clinician-controlled anti-tumour T cell responses of profound magnitude, efficacy and durability, an approach that is readily translatable to humans.

The use of cannabis and its derivatives have increased steadily over the past few decades, prompting patients and clinicians to increasingly inquire about its health effects and safety profile. However, despite promising evidence suggesting therapeutic utilization, cannabis remains a controlled substance in most countries and is largely considered to have no medical or recreational benefit; thus, a lack of observational studies and randomized control trials exist to outline positive and negative health implications. Ultimately, this leaves patients, health-care professionals, and policymakers without necessary evidence required to make informed decisions on cannabis use. This review outlines cannabis in a clinical setting and delves into specific effects of cannabinoids on cardiovascular health and disease. It discusses positive and negative health implications associated with cannabis, mechanisms in cardiovascular disease, and reveals methods guiding cannabis use in the clinical setting. Advances in research are necessary to guide decisions regarding cannabinoid use. Countries that have federally legalized cannabis have a unique opportunity to study cardiovascular implications in an unbiased and comprehensive manner. Ultimately, as cannabis use will inevitably increase, researchers, clinicians, and policymakers must work together to ensure cannabis is utilized in a way that is therapeutically beneficial.

Continuous-flow left ventricular assist device (CF-LVAD) recipients exhibit impaired exercise capacity. Long-term continuous blood flow also elevates norepinephrine (NE) and aldosterone (Aldo) levels. However, the relationship between exercise capacity and neurohormonal activation has not been elucidated. Our study objective was to assess the association between cardiopulmonary exercise testing (CPT) measures and neurohormonal levels in CF-LVAD recipients. Symptom-limited CPT on a treadmill, using the modified Bruce protocol was performed in 15 CF-LVAD recipients. Norepinephrine and Aldo levels were measured, and the association between their levels and CPT measures were assessed. Peak VO₂ (13.6 ml/kg/min) and percent age, sex predicted VO₂ max (49.4%), and oxygen pulse (O₂ pulse) (9.0 ± 4.0 ml/beat) were low, whereas minute ventilation/carbon dioxide output (VE/VCO₂) slope (35) was elevated. In addition, VO₂ at anaerobic threshold (VO₂ AT), and O₂ pulse values negatively correlated with NE levels. Norepinephrine levels positively correlated with chronotropic responses and heart rate (HR) recovery. Aldo levels in CF-LVAD recipients were not related to any CPT measures. Continuous-flow left ventricular assist device recipients exhibited impaired exercise capacity and chronotropic incompetence (CI). Despite the association of NE levels with chronotropic responses at peak exercise, neither NE levels nor chronotropic responses predicted peak VO_2. This suggests that CI may not be the primary factor responsible for the low peak VO_2. O₂ pulse, which is a combined measure for stroke volume and peripheral oxygen extraction during exercise, was an independent predictor of peak VO₂. Future studies should examine the contribution of peripheral factors to exercise capacity limitations.