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 (CINECI)

Étude Prospective d'évaluation de la cinétique Sanguine de Cellules Immunitaires et de Cytokines Immunosuppressives après Exposition à un Inhibiteur Des Checkpoints de l'immunité (ICI) : étude de l'Impact de la chimiothérapie

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.

Study Overview

• Status: Completed
• Conditions: Non Small Cell Lung Cancer; Bladder Cancer; ENT Cancer
• Intervention / Treatment: Other: Blood samples

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 31

Contacts and Locations

• Study Contact: Name: Romain LEVARD; Phone Number: +33 02 47 47 99 19; Email: rlevard@gmail.com
• Study Contact Backup: Name: Claude LINASSIER, MD-PhD; Phone Number: +33 02 47 47 99 19; Email: claude.linassier@univ-tours.fr

Study Locations

• France
  • Tours, France, 37044
    • Medical oncology department, University Hospital, Tours
  • Tours, France, 37044
    • Pneumology department, University Hospital, Tours

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The study population is patients receiving chemotherapy alone after immunotherapy for NSCLC or bladder cancer or ENT cancer.

Description

Inclusion Criteria:

• Age ≥ 18 years old
• Patients treated with immune checkpoint inhibitor alone or in combination with chemotherapy in 1st or 2nd line
• Patient with locally advanced or metastatic Non-Small-Cell Lung Cancer, or bladder cancer or Ear Nose Throat cancer
• Maximum delay of 2 months between ICI and chemotherapy

Exclusion Criteria:

• Symptomatic brain metastases
• Corticotherapy > 10 mg/day
• Active auto-immune disease
• Oncogenic addiction
• Data processing objection

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cancer; Patients receiving chemotherapy alone after immunotherapy for NSCLC or bladder cancer or ENT cancer	Other: Blood samples; Blood samples

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline blood concentration of regulatory T-lymphocytes (Treg) at 6 months	Blood concentrations will be measured at specific times	Baseline, 3 months and 6 months
Change from baseline blood concentration of lymphocyte populations T, B, NK, CD4+ and CD8+ (effector T-lymphocytes (Teff) included) at 6 months	Blood concentrations will be measured at specific times	Baseline, 3 months and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline blood concentration of anti-inflammatory cytokines at 6 months	Blood concentrations will be measured at specific times	Baseline, 3 months and 6 months
Assess correlation between blood concentration of Treg, blood concentration of Teff and blood concentration of anti-inflammatory cytokines		Baseline, 3 months and 6 months
Determination of PDL1 status		Baseline

Collaborators and Investigators

• Sponsor: University Hospital, Tours

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2021
• Primary Completion (Actual): September 29, 2022
• Study Completion (Actual): September 29, 2022

Study Registration Dates

• First Submitted: July 16, 2020
• First Submitted That Met QC Criteria: July 22, 2020
• First Posted (Actual): July 27, 2020

Study Record Updates

• Last Update Posted (Actual): April 6, 2023
• Last Update Submitted That Met QC Criteria: April 5, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: Non Small Cell Lung Cancer; Bladder Cancer; Immunity checkpoint inhibitor; Rescue chemotherapy
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Urologic Diseases; Urinary Bladder Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Urinary Bladder Neoplasms
• Other Study ID Numbers: RIPH3-RNI20 / CINECI; 2020-A01478-31 (Other Identifier: IdRCB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No