Prospective Study to Evaluate the Blood Kinetics of Immune Cells and Immunosuppressive Cytokines After Exposure to an Immunity Checkpoint Inhibitor (ICI): Study of the Impact of Chemotherapy

Overview

Non-small cell lung cancer (NSCLC) is the most common histological form, accounting for 85% of all bronchopulmonary cancers (PBC). The advent of Immunity Checkpoint Inhibitors (ICIs) targeting Programmed cell Death-1 (PD-1) is changing current treatment algorithms. Preliminary results from work carried out in the Medical Oncology Department of the University Hospital of Tours suggest that immunotherapy targeting ICI, when administered beforehand, increases the effect of catch-up chemotherapy. In NSCLC, the progression-free survival (PFS) of 3rd line chemotherapy after anti-PD-1 immunotherapy was better than the PFS of 3rd line chemotherapy performed at the end of conventional chemotherapy. Moreover, the combination of chemotherapy and immunotherapy gives paradoxically better results than immunotherapy alone. Immunotherapy restores the anti-tumor T immunity inhibited by the cancer cell. While the mode of action of ICIs is well known, the mechanisms of resistance to them are poorly understood. Several pathways are evoked, in particular the modulation of cellular interactions within the tumour microenvironment (TME), the molecular expression profile of cancer cells, or the immunological status of the patient. Regulatory T lymphocytes (Treg) participate in the maintenance of immune system homeostasis by ensuring tolerance to self antigens. Within TME, Treg inhibit anti-tumor T cell activity and potentiate tumor proliferation. The latter, by specifically recognizing tumor antigens, block the activity of effector T lymphocytes directed against tumor cells. Thus, an increase in circulating Treg concentrations and in TME is a poor prognostic factor, especially in NSCLC. Gemcitabine chemotherapy is commonly used in the management of NSCLC. Recent data show that gemcitabine decreases Treg activity and regulates levels of anti-inflammatory TME cytokines such as IL10, TGF-β and interferon-Ɣ. The hypothesis of this study is that the decrease in Treg blood concentration by catch-up chemotherapy restores sensitivity to immunotherapy.

Non-small cell lung cancer (NSCLC) is the most common histological form, accounting for 85% of all bronchopulmonary cancers (PBC). The advent of Immunity Checkpoint Inhibitors (ICIs) targeting Programmed cell Death-1 (PD-1) is changing current treatment algorithms. Preliminary results from work carried out in the Medical Oncology Department of the University Hospital of Tours suggest that immunotherapy targeting ICI, when administered beforehand, increases the effect of catch-up chemotherapy. In NSCLC, the the progression-free survival (PFS) of 3rd line chemotherapy after anti-PD-1 immunotherapy was better than the PFS of 3rd line chemotherapy performed at the end of conventional chemotherapy. Moreover, the combination of chemotherapy and immunotherapy gives paradoxically better results than immunotherapy alone. Immunotherapy restores the anti-tumor T immunity inhibited by the cancer cell. While the mode of action of ICIs is well known, the mechanisms of resistance to them are poorly understood. Several pathways are evoked, in particular the modulation of cellular interactions within the tumour microenvironment (TME), the molecular expression profile of cancer cells, or the immunological status of the patient. Regulatory T lymphocytes (Treg) participate in the maintenance of immune system homeostasis by ensuring tolerance to self antigens. Within TME, Treg inhibit anti-tumor T cell activity and potentiate tumor proliferation. The latter, by specifically recognizing tumor antigens, block the activity of effector T lymphocytes directed against tumor cells. Thus, an increase in circulating Treg concentrations and in TME is a poor prognostic factor, especially in NSCLC. Gemcitabine chemotherapy is commonly used in the management of NSCLC. Recent data show that gemcitabine decreases Treg activity and regulates levels of anti-inflammatory TME cytokines such as IL10, TGF-β and interferon-Ɣ. The hypothesis of this study is that the decrease in Treg blood concentration by catch-up chemotherapy restores sensitivity to immunotherapy.