Hypothesis
Immunostimulatory agonistic CD40 antibodies, in development for solid tumours, would stimulate antitumour immunity in glioma and support responses to checkpoint inhibitors.
What failed
In preclinical glioma models, systemic agonistic CD40 led to cytotoxic T-cell dysfunction and impaired the response to immune checkpoint inhibitors, even while it induced tertiary lymphoid structures.
Broken assumption
An immunostimulatory CD40 agonist can only add to, not subtract from, checkpoint-blockade efficacy.
Why
The impairment was associated with accumulation of suppressive CD11b+ B cells. In human glioma, the tertiary lymphoid structures correlated with greater T-cell infiltration, which the authors read as pleiotropic rather than purely harmful effects.
From the published paper: Hooren et al. Nature Communications, 2021. ↗CC BY