Pint of Postdoc Speaker Recap - Dr. Dijana Djureinovic

“Tissue and blood analysis of patients resistant to anti-PD-1 treated with a CD40 agonist and an anti-CSF1R antibody with or without PD-1 blockade”

Dr. Dijana Djureinovic

Edited by: Aileen Fernandez

Novel treatments are needed to overcome resistance to checkpoint inhibition. In the May 2021 Pint of Postdoc series Dijana Djureinovic discussed how patients with melanoma and renal cell carcinoma who progressed on anti-PD-1 were treated with dual macrophage-targeting therapy (CD40 agonist and CSF-1R inhibitor), with or without anti-PD-1 on a phase 1 clinical trial. Best response was an unconfirmed partial response. Several proinflammatory cytokines (e.g. IL-12 and TNFα) were upregulated after treatment. To analyze treatment-associated changes of immune cells, they used digital spatial profiling on tumor tissues taken before and after treatment from four melanoma patients. Downregulation of T cell inhibitory molecules TIM3 and CTLA-4 were observed in all four patients, whereas LAG3, VISTA and FoxP3 were downregulated in three patients after treatment. T-cell activating molecules such as  GITR, OX40L and CD80 were also downregulated in most patients after treatment. Due to the low response rate and the tumor profiling data, we hypothesized that anti-CSF-1R might not only reduce immune suppressive macrophages but also the pro-inflammatory type. To test this, a mouse melanoma model (YUMMER1.7) was treated with anti-PD1, CD40a and dose escalation of anti-CSF-1R. The higher dose of anti-CSF-1R was less effective than the lower dose. Increased anti-CSF-1R led to increased levels of inflammatory cytokines (e.g. IL-6 and IP-10) 24 h post 1st treatment but decreased levels of IFN gamma in the plasma, providing a possible explanation for inferior results with higher doses of anti-CSF1R and providing justification for further clinical exploration of lower doses in humans.