| Autor: |
Dowling JP; Research & Development, Immunome Inc, Exton, PA, USA., Nikitin PA; Research & Development, Immunome Inc, Exton, PA, USA., Shen F; Research & Development, Immunome Inc, Exton, PA, USA., Shukla H; Research & Development, Immunome Inc, Exton, PA, USA., Finn JP; Research & Development, Immunome Inc, Exton, PA, USA., Patel N; Research & Development, Immunome Inc, Exton, PA, USA., Swider C; Research & Development, Immunome Inc, Exton, PA, USA., Bingaman-Steele JL; Research & Development, Immunome Inc, Exton, PA, USA., Nicolescu C; Research & Development, Immunome Inc, Exton, PA, USA., Sikorski EL; Research & Development, Immunome Inc, Exton, PA, USA., Greenawalt EJ; Research & Development, Immunome Inc, Exton, PA, USA., Morin MJ; Research & Development, Immunome Inc, Exton, PA, USA., Robinson MK; Research & Development, Immunome Inc, Exton, PA, USA., Lundgren K; Research & Development, Immunome Inc, Exton, PA, USA., Harman BC; Research & Development, Immunome Inc, Exton, PA, USA. |
| Abstrakt: |
Immune checkpoint inhibitors that overcome T cell suppressive mechanisms in tumors have revolutionized the treatment of cancer but are only efficacious in a small subset of patients. Targeting suppressive mechanisms acting on innate immune cells could significantly improve the incidence of clinical response by facilitating a multi-lineage response against the tumor involving both adaptive and innate immune systems. Here, we show that intra-tumoral interleukin (IL)-38 expression is a feature of a large frequency of head and neck, lung and cervical squamous cancers and correlates with reduced immune cell numbers. We generated IMM20324, an antibody that binds human and mouse IL-38 proteins and inhibits the binding of IL-38 to its putative receptors, interleukin 1 receptor accessory protein-like 1 (IL1RAPL) and IL-36R. In vivo , IMM20324 demonstrated a good safety profile, delayed tumor growth in a subset of mice in an EMT6 syngeneic model of breast cancer, and significantly inhibited tumor expansion in a B16.F10 melanoma model. Notably, IMM20324 treatment resulted in the prevention of tumor growth following re-implantation of tumor cells, indicating the induction of immunological memory. Furthermore, exposure of IMM20324 correlated with decreased tumor volume and increased levels of intra-tumoral chemokines. Together, our data suggest that IL-38 is expressed in a high frequency of cancer patients and allows tumor cells to suppress anti-tumor immunity. Blockade of IL-38 activity using IMM20324 can re-activate immunostimulatory mechanisms in the tumor microenvironment leading to immune infiltration, the generation of tumor-specific memory and abrogation of tumor growth. |
