Three’s a charm

Tumors whose infiltrating T cells are exhausted respond poorly to immunotherapies like PD-1 blockade. In a July paper in the Journal of Clinical Investigation, researchers led by Ludwig MSK’s Jedd Wolchok and Taha Merghoub identified a potentially novel approach to overcome this problem without compounding autoimmune side effects. The strategy focuses on antigen presenting cells (APCs), scouts of the innate immune system that present antigens to T cells to activate them. Jedd, Taha and their colleagues treated a single melanoma tumor in mice bearing multiple tumors with two agents that cooperatively activate APCs—monophosphoryl lipid A and a stimulatory antibody against the protein CD40. They also gave the mice systemic injections of an anti-PD-1 antibody, which reinvigorates exhausted killer T cell responses against tumors. They found that the combination therapy led to a depletion of exhausted T cells in tumors and elicited potent anti-tumor T cell responses that induced regressions of untreated tumors as well. The mice did not respond to anti-PD-1 therapy alone. The combination treatment also spared non-malignant tissues. Notably, gene expression patterns in the treated mice resembled those seen in patients who respond well to anti-PD-1 therapy. The team is now planning clinical trials of the regimen.

This article appeared in the November 2019 issue of Ludwig Link. Click here to download a PDF (1 MB).


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