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Biologie
T Cell-Macrophage duo to harness innate immunity in tumors
Several phase III clinical trials involving the monoclonal antibody magrolimab, which targets the CD47 ‘don’t eat me’ signal, have recently been halted due to issues including poor patient responses and infections. This new study introduces a combination treatment strategy that aims to target phagocytosis specifically against tumor cells while sparing T cells, potentially overcoming past setbacks.
Led by Dr Evangelos Stefanidis during his doctoral studies, and directed by Dr Melita Irving from the Department of oncology UNIL-CHUV and members of the Lausanne Branch of the Ludwig Institute, the research*, published in The Journal of Clinical Investigation developed a two-pronged attack against solid tumors to boost the immune system’s ability to target and eliminate cancer cells.
The Irving lab has developed an innovative combination therapy to enhance the treatment of solid tumors by harnessing the power of both T cells and macrophages. They combined anti-PDL1 and anti-EGFR monoclonal antibodies with T cells coengineered to express an affinity-optimized tumor-specific T cell receptor (TCR) and secrete a decoy of the ‘don’t eat me’ signal CD47. This approach aims to harness endogenous macrophages against tumor cells, improving the efficacy of adoptive T-cell therapy (ACT) in cancer treatment.
The study addresses the critical challenge of improving immune responses to ACT by targeting the CD47/SiRP-α axis, a known inhibitor of macrophage-mediated phagocytosis. Due to CD47's ubiquitous expression on healthy cells, traditional antibody blockade poses significant risks, including toxicity and antigen sinks. To overcome these limitations, the researchers gene-modified T cells to secrete high-affinity SiRP-α decoys of CD47 (CV1-Fc or CV1) directly within the tumor microenvironment. These T cells were engineered with an affinity-optimized TCR targeting the HLA-A2 restricted epitope NY-ESO-1157-165. The study found that T cells expressing CV1 fused to an active Fc tail were themselves phagocytosed by macrophages. By removing the Fc tail, the T cells were spared, and when combined with clinical antibodies (anti-PDL1 and anti-EGFR), phagocytosis of tumor cells was specifically augmented.
The research was generously supported by the Ludwig Institute for Cancer Research, the Swiss National Science Foundation and the University of Lausanne (UNIL).
*Combining SiRP-α Decoy Coengineered T Cells and Antibodies Augments Macrophage-Mediated Phagocytosis of Tumor Cells