Clinical trial NCT06061705: Identification of Individual Histological and Blood Markers in Patients With Recurrent or Metastatic Upper Aerodigestive Tract Squamous Cell Carcinoma in Response to Immunotherapies
Official title: Identification of Individual Histological and Blood Markers in Patients With Recurrent or Metastatic Upper Aerodigestive Tract Squamous Cell Carcinoma in Response to Immunotherapies
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Squamous Cell Carcinoma of the Oropharynx
Lead sponsor: Fondation Hôpital Saint-Joseph
Sponsor class: OTHER
First posted: 2023-09-29
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: Epidermoid Carcinoma of the Upper Aerodigestive Tract (CEVADS) is the 6th most common cancer worldwide. Despite current therapies (radiotherapy, surgery and chemotherapy), cancers of the Upper Aerodigestive Tract (UAT) have a poor prognosis, with a 10-year survival rate of no more than 20%.

For recurrent or metastatic CEVADS, the therapeutic arsenal, based for many years on chemotherapy and anti-EGFR (Epidermal Growth Factor Receptor) agents, has been enriched by a new therapeutic class: PD-1 inhibitors. For CEVADS, PD-1 inhibitors have been approved for second-line treatment of nivolumab for over a year, and are now used in first-line treatment of pembrolizumab.

The results of this therapeutic class in CEVADS are not as spectacular as for melanoma or bronchial cancer. Indeed, only 20% of patients have a favorable response, compared with half who experience disease progression. This low proportion of responders can be explained by tumor heterogeneity within CEVADS and poor patient selection.

The only marker used to select patients is PD-L1 expression detected by ImmunoHistochemistry (IHC). However, it seems that this marker, described as imperfect, is still little explored in ENT. It needs to be compared with the expression of other cell lines in the tumor microenvironment, which could play an important role in resistance to PD-1 inhibitors.

IHC identifies all macrophages using the CD68 marker, while the CD163 marker is specific to M2 macrophages.

Other targets in the microenvironment are also being investigated, with the discovery of a Tertiary Lymphocyte Structure (TLS) in melanoma treated with immunotherapy.

It therefore seems necessary to gain a better understanding of the mechanisms of tumor progression under immunotherapy in order to develop strategies to optimize response to treatment. This would enable better selection of patients likely to benefit from immunotherapy, and open up prospects for therapeutic combinations.

The hypothesis is that macrophages, but also other cells and factors in the CEVADS microenvironment, play a decisive role in resistance to PD-1 inhibitors. The aim is therefore to continue these macrophage analyses, extend them to other cells in the microenvironment and link them to other prognostic factors under investigation.

A prospective study will analyze tumor tissue during treatment with PD-1 inhibitors, in order to correlate all the factors studied with response or resistance to immunotherapies.

In addition, the oral microbiota, in the lineage of the intestinal microbiota, has been shown to be highly stable over time and to play a role in the oncogenesis of certain cancers, notably CEVADS. Like the intestinal microbiota, it could also represent a prognostic factor in the response to immunotherapies.

Of all the bacteria in this oral microbiota, one has been shown to play a major role: Fusobacterium nucleatum (F. nucleatum). However, little is known about the mechanism of action of intratumoral F. nucleatum on the development of CEVADS. In particular, it is thought to play a role in local cancer immunity, via macrophages, regulatory T cells (Tregs) and TLRs. Finally, it appears that specific antimicrobial T-cell responses may cross-react with tumor antigens, hence the importance of also analyzing the metabolome of commensal bacteria.The aim of this study was to evaluate the evolution of the presence of this bacterium in saliva, as well as the specific immune response to F. nucleatum in patients with CEVADS during immunotherapy treatment.


Eligibility criteria: Inclusion Criteria:

* Patients aged ≥ 18 years
* Patients with histologically confirmed CEVADS involving the oral cavity, oropharynx, hypopharynx or larynx
* Pre-treated patients with a first recurrence (locoregional or metastatic) who are candidates for immunotherapy
* Patient affiliated to a health insurance plan
* French-speaking patient
* Patient with free, informed and written consent

Exclusion Criteria:

* Patients with a contraindication to immunotherapy (transplant patients)
* Pregnant or breast-feeding patients
* Patient under guardianship or curatorship
* Patient under court protection
* Patient deprived of liberty

Primary outcomes:
measure: Histological markers linked to the clinical benefit of immunotherapies
timeFrame: Month 6
Secondary outcomes:
measure: Histological markers linked to survival
timeFrame: Month 6
measure: Expression of histological markers with PD-L1 expression
timeFrame: Month 6
measure: Presence of Fusobacterium nucleatum in the oral microbiota
timeFrame: Month 6
measure: Presence of an IgG or IgA anti-Fusobacterium nucleatum humoral response
timeFrame: Month 6
Other outcomes:
Locations:
city: Paris
country: France
facility: Hôpital Saint-Joseph
city: Paris
country: France
facility: Hôpital Bichat
city: Paris
country: France
facility: Hôpital Saint-Louis
Study officials:
affiliation: Hôpital Paris Saint-Joseph
name: Eric Raymond, MD, PhD
role: STUDY_DIRECTOR
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