Clinical trial NCT06131775: Characterisation of TLR4+ Blood Cells in Patients With Solid Cancer
Official title: Characterisation of TLR4+ Blood Cells in Patients With Solid Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: All Types of Solid Cancer
Keywords: Immunotherapy
Innate immune system systemic activation
TLR4 positive immune cells
Lipopolysaccharides
Immunostimulant
Lead sponsor: Hospices Civils de Lyon
Sponsor class: OTHER
First posted: 2023-11-14
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: Cohort
Primary purpose: SCREENING

Brief summary: The potential of immunotherapy in the treatment of cancer is now well documented. While excessive activation of the immune system may be associated with severe reactions and/or auto-immune syndromes, it is now clearly established that controlled activation of the adaptive immune system constitutes a major contribution to the treatment of cancer. Antigen-independent activation of the adaptative immune system with " immune checkpoint inhibitors " (ICI) has allowed prolonged survival in a minority of patients with previously intractable disease. However, a variety of tumor indications are still presently inaccessible to immunotherapeutic approaches or poorly responsive to these therapies.

The immune system is a highly reactive complex comprising antigen-specific cells (adaptive immune system) and antigen-agnostic cells (innate immune system) which interact closely in a complex network. The adaptive immune response is mediated by B and T cells upon antigen-specific recognition. The innate response is mediated by macrophages, dendritic cells, Natural Killer cells and assume the immediate defense of the organism against infectious agents. The innate immune system plays a key role in antigen processing and presentation, production of key cytokines and as anti-tumor effector cells. The role of the innate immune system in the control of cancer progression and in cancer therapy is well documented. Natural Killer cells, involved in antibody-dependent cellular cytotoxicity, and cells performing phagocytosis such as macrophages and neutrophils, participate in tumor destruction after intervention of adaptive immune cells and in combination with certain tumor-targeting therapies, such as antibodies recognizing tumor-specific antigens.

The Odyssey project aims to harness the next generation paradigm of cancer immunotherapy : systemic stimulation of the innate immune system.

To achieve this endeavour the investigator will exploit a well-known yet poorly documented phenomenon, i.e. the rare occurrence of cure in cancer patients who have presented a simultaneous severe septic episode at the time of diagnosis.

Several clinical studies have been realized in order to demonstrate the effect of the innate immune response activation by the bacterial LPS (lipopolysaccharides) in cancer therapy. However, severe toxicities have been described even at very low dose of LPS. The LPS-activated immune response is mediated by TLR4 (Toll Like Receptor 4), a transmembrane receptor expressed by several cell types including monocytes and macrophages. The interaction of TLR4 with LPS mainly induces the release of proinflammatory cytokines (so called " canonical pathway "). TLR4-signalling cascade can also induce the release of type I interferon (so called " alternative pathway "), a class of cytokines known to promote antitumoral activity. LPS tolerance is presumed to be rather associated with the activation of the alternative pathway. Therefore, managing this LPS tolerance is a key mechanism that could limit the systemic toxicity of LPS while stimulating the innate immune system.

Héphaïstos-Pharma biotech and the CRCL Onco-Pharmacology lab (Centre de Recherche en Cancérologie de Lyon) have set up a modified formulation of the LPS that improves its pharmacokinetic properties, reduces its toxicity, and preferentially activates TLR4-alternative signalling pathway. Before investigating the effect of this new immunostimulant in a future phase I/II clinical trial, a translational study is required to further characterize the TLR4 positive cells population as well as the innate immune system in patients with solid cancer.


Eligibility criteria: Inclusion Criteria:

* Patient older than 18 years
* Patient who gave its written informed consent to participate to the study
* Patient with histologically confirmed diagnosis of any type of malignancy (solid tumors)
* Patient with a minimum of 6 months life expectation at inclusion
* Patient covered by a medical insurance

Inclusion criteria specific to cohort 1:

- Patient with metastatic disease or unresectable locally advanced malignancy (solid tumors) who is naive of immune checkpoint inhibitors (ICI)-based immunotherapy and is due to initiate an ICI immunotherapy alone or in combination with any other systemic anticancer treatment.

Inclusion criteria specific to cohort 2:

- Patient with a diagnosed malignancy amenable to surgery with curative intent who is naive of any anticancer treatment

Exclusion Criteria:

* Patient with secondary malignancy unless this malignancy is cured with no evidence of recurrence for at least 5 years.
* Pregnant or breastfeeding woman or expecting to conceive
* Patient who is deprived of liberty due to judicial or administrative decision
* Patient with known psychiatric disorders that would interfere with cooperation with the requirements of the trial
* Patient admitted in a social or sanitary institution for an objective other than the one of this trial
* Adult patient under legal protection

Primary outcomes:
measure: Cohort 1 : 24 months-progression free survival (24M PFS)
timeFrame: 24 months
measure: Cohort 2 : describe the evolution of the percentage of TLR4+ cells in peripheral blood after curative ablation of a cancerous tumour.
timeFrame: Before surgery, after 3 months and after 6 months.
Secondary outcomes:
measure: Overall Survival (OS) Cohorts 1 and 2
timeFrame: Baseline,date of death, last recorded date or 24 months
measure: Concentration of innate and adaptive immune cell population Cohorts 1 and 2
timeFrame: Baseline
measure: LPS-mediated activation of TLR4 positive cells Cohorts 1 and 2
timeFrame: baseline
measure: Number of high grade (≥3) immune-related adverse events (irAE) Cohort 1
timeFrame: Baseline ans 6 month
measure: 24 months-relapse free survival (24M RFS) Cohort 2
timeFrame: Before surgery, after 3 months, after 6 months and after 24 month
Other outcomes:
Locations:
city: Bron
country: France
facility: Pneumology Unit
city: Pierre Benite
country: France
facility: Oncology Unit, Hospices Civils de Lyon Sud
city: Pierre-Bénite
country: France
facility: Dermatology Unit
city: Pierre-Bénite
country: France
facility: Oncological and Gynecological Surgery Unit,
Study officials:
References: