Solid tumour immunotherapy — Oncolytic VSV-mIFNβ combined with EGFRvIII CAR T cells

Intranodal injections of tumour-antigen-loaded autologous CD1c+ and plasmacytoid dendritic cells after surgery would lengthen recurrence-free survival in resected stage IIIB/C melanoma.

In the randomised MIND-DC trial (148 patients, 99 nDC vs 49 placebo), 2-year recurrence-free survival was 36.8% with nDCs versus 46.9% with placebo (p = 0.31); median RFS 12.7 vs 19.9 months (HR 1.25), and overall survival did not differ.

Why it matched: same research area · mechanism: Adaptive immunity & tolerance · failed the same way: Held in the model species, not beyond it

Low-dose IL2 raises regulatory T cells, which reverse protein loss in the urine in animal models of nephrotic syndrome, so it would lower protein loss in children whose nephrotic syndrome resists all other drugs.

In 5 boys given six monthly cycles, IL2 raised regulatory T cells in some, but protein in the urine and kidney function did not change at any point. One child had an asthma attack after the first dose.

Why it matched: mechanism: Inflammation & innate immunity · mechanism: Adaptive immunity & tolerance · failed the same way: Held in the model species, not beyond it

MERTK in endothelial cells maintains barrier function and restrains neutrophil transendothelial migration, so deleting it specifically in endothelium should aggravate inflammatory lung injury.

Knocking MERTK down in primary human pulmonary microvascular endothelial cells increased neutrophil transmigration and dextran leak and disrupted adherens junctions and basal Rac1 activity, and global Mertk-null mice recruited more neutrophils and leaked more Evans blue during Pseudomonas aeruginosa pneumonia. But inducible endothelium-specific Mertk-null mice showed no difference from controls in either neutrophil migration into inflamed lungs or vascular permeability.

Why it matched: mechanism: Inflammation & innate immunity · failed the same way: Held in the model species, not beyond it

An LVS mutant that stimulates human antigen-presenting cells better than wild type would make a better tularemia vaccine, so in vitro screening of antigen-presenting-cell interaction could rationally pre-select candidates before animal work.

Strain 13B47 raised proinflammatory cytokine secretion from dendritic cells and macrophages, increased costimulatory molecule expression and activated T cells more efficiently than wild-type LVS, and a clean deletion allele reproduced those in vitro properties, yet vaccination with it did not improve survival after challenge with a virulent type A Francisella strain; the mutant was attenuated for growth in vivo and failed to stimulate comparable T cell responses in the lung.

Why it matched: mechanism: Inflammation & innate immunity · mechanism: Adaptive immunity & tolerance

The neutrophils that flood the airways in severe RSV infection would contribute to controlling the virus, to lung inflammation, or to how sick the host becomes.

In RSV-infected mice, antibody depletion of neutrophils did not substantially change type I interferons, IL-6, TNF-alpha or IL-1beta, nor viral load. Neither depleting neutrophils nor boosting them with CXCL1 changed peak disease severity measured by weight loss.

Why it matched: mechanism: Inflammation & innate immunity · failed the same way: Held in the model species, not beyond it