Chang et al. showed that an IL-10hiCSF-1Rlo profile was associated with an immunostimulatory fingerprint and a favorable outcome in HNSCC. In vitro and in mouse models, a fusion protein comprising IL-10 and a CSF-1R-blocking murine IgG2a was shown to be bifunctional, inhibit growth of several macrophage-enriched tumor types – especially head and neck cancer – reduce suppressive TAMs and Tregs in the TME, and induce CD8+ T cell cytotoxicity, clonal diversification, and favorable metabolic alterations of intratumoral T cells. The fusion protein outperformed subcomponent controls, did not cause systemic toxicity, and boosted anti-PD-1 efficacy.
Contributed by Paula Hochman
ABSTRACT: Strategies to increase intratumoral concentrations of an anticancer agent are desirable to optimize its therapeutic potential when said agent is efficacious primarily within a tumor but also have significant systemic side effects. Here, we generate a bifunctional protein by fusing interleukin-10 (IL-10) to a colony-stimulating factor-1 receptor (CSF-1R)-blocking antibody. The fusion protein demonstrates significant antitumor activity in multiple cancer models, especially head and neck cancer. Moreover, this bifunctional protein not only leads to the anticipated reduction in tumor-associated macrophages but also triggers proliferation, activation, and metabolic reprogramming of CD8(+) T cells. Furthermore, it extends the clonotype diversity of tumor-infiltrated T cells and shifts the tumor microenvironment (TME) to an immune-active state. This study suggests an efficient strategy for designing immunotherapeutic agents by fusing a potent immunostimulatory molecule to an antibody targeting TME-enriched factors.
Author Info: (1) Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. (2) Elixiron Immunotherapeutics (Hong Kong) Ltd., Hong Kong. (3) Cancer a
Author Info: (1) Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. (2) Elixiron Immunotherapeutics (Hong Kong) Ltd., Hong Kong. (3) Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. (4) Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11221, Taiwan. (5) Graduate Institute of Life Sciences, National Defense Medical Center, Taipei 11221, Taiwan. (6) Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. (7) Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. (8) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research at University of Lausanne, Lausanne, Switzerland. (9) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research at University of Lausanne, Lausanne, Switzerland. (10) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research at University of Lausanne, Lausanne, Switzerland. (11) Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. (12) Elixiron Immunotherapeutics (Hong Kong) Ltd., Hong Kong. (13) Department of Oncology, University of Lausanne, Lausanne, Switzerland; Ludwig Institute for Cancer Research at University of Lausanne, Lausanne, Switzerland. (14) Elixiron Immunotherapeutics (Hong Kong) Ltd., Hong Kong. Electronic address: hkchen@elixiron.com. (15) Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Institute of Clinical Medicine, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Department of Oncology, Taipei Veterans General Hospital, Taipei 11217, Taiwan; Department of Teaching and Research, Taipei City Hospital, Taipei, Taiwan. Electronic address: mhyang2@nycu.edu.tw.
