Ludwig Lausanne’s Melita Irving, recent PhD graduate Evangelos Stefanidis and colleagues reported in a June paper in The Journal of Clinical Investigation a two-pronged strategy to drive a simultaneous T cell and macrophage attack on tumors. Their approach modifies T cells equipped with affinity optimized cancer antigen-targeting receptors to additionally secrete CV1—a high-affinity version of SiRPα, which effectively silences a “don’t eat me” signal cancer cells transmit to avoid being gobbled up by macrophages. SiRPα normally interacts with CD47 on the cell surface to issue that signal. Irving’s team had previously engineered therapeutic T cells to produce a CV1-Fc decoy to engage a combined macrophage and T cell attack on tumors. But the first run at that strategy failed because the antibody tail fragment (Fc) they’d appended to the CV1 decoy provoked a macrophage attack on the T cells, which were coated with the construct. Expressing CV1 in T cells without the Fc tail, however, circumvented attack by human macrophages. Moreover, combining the T cell therapy with anti-PD-L1 and anti-EGFR antibodies—both used for cancer therapy—further enhanced the dual attack in preclinical studies by giving the macrophages new antibody tails to target. Aside from presenting a new therapeutic strategy, the study suggests efforts to target the SiRPα-CD47 axis have been clinically unsuccessful in part because they stimulate the clearance of tumor-targeting T cells by macrophages.
Combining SiRPα-decoy coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells
The Journal of Clinical Investigation, 2024 June 3