NANTES, France—OSE Immunotherapeutics recently presented new preclinical data identifying CLEC-1 as a novel myeloid immune checkpoint target for cancer immunotherapy at the American Association of Cancer Research (AACR) Virtual Annual Meeting II, held June 22-24.
According to Nicolas Poirier, chief scientific officer of OSE Immunotherapeutics, “These data indicate that the myeloid checkpoint CLEC-1 is a new therapeutic target in immuno-oncology and that antagonists of the CLEC-1 pathway constitute an innovative cancer immunotherapy approach synergistic with chemotherapy or tumor-targeting antibodies. The identification of CLEC-1 and its antagonists continues to reinforce our presence in the highly attractive field of myeloid cells and macrophages, identified as poor prognostic factors in oncology and in immune escape mechanisms of cancer immunotherapies.”
These findings come from a research program conducted by OSE’s R&D team, in collaboration with Dr. Elise Chiffoleau of the Center for Research in Transplantation and Immunology UMR 1064, INSERM.
“Immunotherapies targeting at T-cell immune checkpoint have recently revolutionized the treatment of cancers,” Poirier explains. “However, the majority of patients still [do] not respond. Inhibitors of T-cell immune checkpoint are beneficial on the long-term for a limited number of patients, and several types of tumors are not responding at all.”
“Medical needs are still very high, but this first wave of immunotherapies paves the way for a novel generation of immunotherapies—not only targeting an accelerator or break of T lymphocytes, but also targeting innate immune cells, in particular myeloid cells, which orchestrate the immune response, including those of T cells. For example, chemotherapy [combined] with anti-PD1 inhibitors demonstrated great results in lung cancers,” he adds.
The research program focuses on developing a cancer immunotherapy targeting CLEC-1, a newly identified C-type lectin receptor, to block suppressive functions of myeloid cells and restore antitumor response to T lymphocytes. Suppressive myeloid cells have the ability to accumulate in the tumor microenvironment and deregulate the immune activation of T lymphocytes.
“Our collaborative academic partner Dr. Elise Chiffoleau previously identified that the orphan C-type lectin-like receptor CLEC-1 is overexpressed in different situation of heart or kidney allograft immune tolerance, and that CLEC1 genetic deletion increases T cell responses (Thebault et al. Journal of Immunology 2009; Lopez Robles et al. Blood Advances 2017). We thus initiated a collaboration to study whether inhibition of CLEC-1 might increase anti-tumor immune responses in our well characterized models,” Poirier remarks.
“We quickly identified that indeed, tumors were more quickly rejected when CLEC1 was absent, and that immune responses of both T cells and myeloid cells were consequently increased. Our partner identified that CLEC1 inhibits dendritic cell functions such as T-cell responses,” he states. “On our side, by generating anti-CLEC1 antagonist monoclonal antibodies we discovered … that blocking CLEC1 interaction with CLEC1-L (expressed by stressed and dying tumor cells) dramatically increases phagocytosis (destruction of foreign/cancer cells by engulfing and digesting or 'eating' the cells) by both macrophages and dendritic cells.”
Among the findings presented at AACR:
- CLEC-1 is a novel “Don’t eat me” signal
- CLEC-1 acts as a “sensor of death” by recognizing stress conditions and cell necrosis of tumor cells
- CLEC-1 antagonist antibodies developed by OSE Immunotherapeutics restore the phagocytosis function of macrophages and dendritic cells in synergy with tumor-targeting antibodies
- CLEC-1 genetically deficient mice more efficiently eradicate tumor cells, in particular when combined with cytotoxic and immunogenic chemotherapy that induces cell stress conditions
- CLEC-1 is expressed by specific subtypes of dendritic cells specialized in antigen presentation in the tumor; in vivo the receptor inhibits T lymphocytes cross-priming and dampens adaptive memory immune response
- The absence of CLEC-1 favors the generation of adaptive memory immune responses.
“Our teams identified that CLEC1-Ligand (CLEC1-L) is not constitutively expressed by human cells, but starts being expressed by dying and stressed cells,” says Poirier. “Hence, when tumor cells are dying or after exposure to UV or X-rays, for example, or when cultured with chemotherapy, tumor cells will expressed CLEC1-L before completely dying. When myeloid cells will encounter these dying or dead tumor cells to 'eat' them (the process of phagocytosis), CLEC-1 will interact with CLEC1L, expressed by this dying/stressed cells but not healthy cells, and this interaction will deliver an inhibitory ‘Don’t Eat Me’ signal, meaning it prevents macrophage phagocytosis function and antigen capture by dendritic cells.”
“We already identified that genetic deletion of CLEC-1 promotes anti-tumor responses in in-vivo mouse models and that anti-CLEC1 antagonist antibodies restored phagocytosis and antigen capture responses of human myeloid cells cultured in vitro with stressed tumor cells,” notes Poirier. “The next step will be to evaluate and confirm the preclinical efficacy of anti-CLEC-1 antagonist antibody in in-vivo humanized mouse tumor models, and then to prepare a drug-candidate to enter under manufacturing and clinical trials developments.”
“We discovered that CLEC-1 indirectly controls T cell responses via inhibiting antigen presentation and T cell cross-priming by dendritic cells. In parallel, we discovered that CLEC1-L is induced by chemotherapy and that inhibition of CLEC1 synergizes in vivo with chemotherapy. These types of results clearly open the door for a rationally designed combination of therapies by looking for complementarity and synergy between drugs acting at different steps of the cancer immunity cycle,” he concludes.